StemCell Therapy

Scientists at Sanford Burnham Prebys Medical Discovery Institute and Radboud University Medical Center in the Netherlands have identified mutations in a gene called CNOT1 that affect brain development and impair memory and learning. The study is the first to link neurodevelopmental delays with CNOT1, suggesting that drugs that help restore the genes function may have therapeutic benefit. The research, published in The American Journal of Human Genetics, also revealed that CNOT1 interacts with several known autism spectrum disorder (ASD) genes, opening new research avenues for the condition.Prior to this work, the CNOT1 gene was not on the radar of autism researchers, says Rolf Bodmer, Ph.D., director and professor in the Development, Aging and Regeneration Program at Sanford Burnham Prebys and the studys co-corresponding and co-senior author. This discovery could help us better understand the genetic mechanisms underlying ASD. Our work is also a first step toward exploring drugs that could augment the function of CNOT1 and might be able to help children with neurodevelopmental delays who have these specific mutations.

The cause of developmental disabilities, including ASD, is poorly understood. Research indicates that there may be a genetic component to these conditions, but the precise impact of the genetic variations that have been uncovered to date is unclear. Identifying the underlying cause of developmental disabilities would allow scientists to create diagnostic tests that would provide early diagnoses and potential treatments.

To answer this question, the researchers at Radboud University turned to Bodmer, a world-renowned genetics expert who studies how genes contribute to disease using a fruit fly model. Sreehari Kalvakuri, Ph.D., a postdoctoral researcher in the Bodmer lab, created fruit flies that contained the same CNOT1 variations seen in the patients, including DNA sequences that were misspelled (missense), cut short (truncated) or otherwise altered.

This work identified nine CNOT1 variants that impaired learning and memory, which was measured by several independent approaches including a courtship assay that tested the ability of male fruit flies to remember if their female partners had paired with other males. All of these variants appeared spontaneously (de novo) in the patients, meaning they were not inherited. The scientists also discovered that these CNOT1 mutations interact with known ASD genes revealing a genetic link to ASD that can be further explored.

Fruit flies are a great biological model because we can complete genetic studies very quickly. This work only took a few months instead of the potential decade using a mouse model, says Kalvakuri, the studys co-first author. Additionally, the CNOT1 gene is highly conserved between fruit flies and humans, meaning it does not change much, so we are optimistic these findings can be extrapolated to people.

Next, the scientists plan to identify which molecular components interact with CNOT1, which functions as a scaffold that builds up a larger protein complex. This work might uncover additional potential drug targets for intellectual, learning or memory disorders, including ASD.

The first step toward helping children with neurodevelopmental delays is to determine the cause of the condition, says Bodmer. Our ultimate hope is to find a treatment that could be given as early as possible to help these children stay on track developmentally.

Surprisingly, the findings also have implications for heart disease, the primary focus of Bodmers lab.

A significant fraction of these patients also have cardiac defects, says Bodmer. Conversely, children who are born with heart defects are at a higher risk of developing ASD, too. This study on CNOT1 also provides a previously unknown genetic link between heart function and ASD.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

Excerpt from:
New Genetic Mutations Linked to ASD - Technology Networks

To some, the idea of taking a summer vacation amid the COVID-19 pandemic is out of the question. With COVID-19 cases reported in all 50 states, the Centers for Disease Control and Prevention recommends people stay home to protect themselves and others from getting sick.

"COVID-19 remains an ongoing pandemic with sustained community transition even if you are traveling to a place with fewer cases," said Dr. Benjamin Singer, assistant professor of medicine (pulmonary and critical care) and biochemistry and molecular genetics at the Northwestern University Feinberg School of Medicine.

To others, a carefully distanced excursion to the woods or a secluded beach is in the works after months of staying close to home.

"There will be lots of people who take trips, come home and everything is fine. But there are going to be other people who take trips and end up sick who wouldnt have otherwise gotten sick if theyd stayed home," said Dr. Emily Landon, associate professor of medicine, infectious diseases expert and epidemiologist at University of Chicago Medicine. "Its really up to you, about what you want to spend your personal risk on."

For those planning a trip away from home this summer, the Tribune asked medical experts what precautions and items to take on every step of a journey by airplane, car or train. What follows are their answers, along with guidance from the CDC, Transportation Security Administration, and other state and federal agencies.

Whatever your plans, dont lose sight of this opportunity to enjoy quality time with those youve been hunkering down with since March. "2020 may not be the summer we thought we would have, but find time to read, explore and find the joy around you and savor what you can," said Dr. Amy Bohnert, associate professor of clinical and developmental psychology at Loyola University Chicago, "That is a gift we can give our kids that will last a lifetime."

BEFORE YOU GO

Q: First off, is travel safe?

CDC: Travel increases your chances of getting and spreading COVID-19. We dont know if one type of travel is safer than others; however, airports, bus stations, train stations and rest stops are all places travelers can be exposed to the virus in the air and on surfaces.

Q: What factors should go into picking a destination?

CDC: The following should be considered when thinking about planning a trip away from home:

Is COVID-19 spreading in your community? Even if you dont have symptoms, you can spread COVID-19 to others while traveling.

Is COVID-19 spreading at your destination? You can get infected while traveling. You can also spread the coronavirus without symptoms to loved ones when you return.

Would you have to quarantine for 14 days after arriving at your destination? Check the state and local requirements.

Q: Are there any groups of people for whom you would not recommend travel for this summer due to the coronavirus pandemic?

Singer: "Higher-risk groups, including older adults and people with chronic health conditions."

Q: Is one form of travel safer or limits exposure to COVID-19 better than others?

Singer: "Staying at home is the safest option, but travel options that allow you to stay socially distant would be considered the safest."

Dr. Erica Hartmann, assistant professor of environmental engineering at Northwestern University: "I personally would opt for modes of transportation that are less densely crowded and allow for lots of ventilation."

TAKING A ROAD TRIP

Q: What is the general guidance?

CDC: Making stops along the way for gas, food or bathroom breaks can put you and your traveling companions in close contact with other people and surfaces. You may have to stop less often, but RV travel typically means staying at RV parks overnight and getting gas and supplies at other public places. These stops may put you and those with you in the RV in close contact with others. One approach for eating is to pick up food at drive-thrus or curbside restaurant service.

Q: Its inevitable Ill need to stop and use the restroom during my trip. Is there any way to prevent germs from following me back to my car?

Hartmann: "Wash your hands. Which really, you should be doing regardless of COVID-19.

"Perhaps not directly related to your question, but remember to practice social distancing in the restroom if there are multiple people in the restroom. And maybe you shouldnt talk while youre in there."

GOING BY AIR?

Q: What is the general guidance?

CDC: Air travel requires spending time in security lines and airport terminals, which can bring you in close contact with other people and frequently touched surfaces. Most viruses and other germs do not spread easily on flights because of how air circulates and is filtered on airplanes. Social distancing, however, is difficult on crowded flights, and you may have to sit near others (within 6 feet), sometimes for hours. This may increase your risk for exposure to the virus that causes COVID-19. Wear a nonmedical, fabric face covering during the flight.

AT THE AIRPORT

Q: A trip to the airport is in my future and Im worried about potential COVID-19 exposure. How can I protect myself in the terminal?

Landon: "My moms 75 years old. Shes been stuck in Florida much longer than usual because of the pandemic, but its time to come home. Shes traveling in a week and a half. Weve had a lot of discussions about what to do. Heres what I would do if I was going to fly right now, and this is what I advised my mom to do, as well.

"When you get in the security line, then try to keep distance from the people around you. Make sure you are wearing your mask, if you can, then manipulate the situation so youre in line with other people wearing their masks. If the person in line in front of you doesnt have a mask on, then let other people go ahead. Security will touch your stuff. Dont freak out about it. Hopefully, they will be wearing masks, too, because thats required and recommended. When you get your stuff back from security what you should do every single time is wash your hands. If you dont have time to stop and wash your hands in the bathroom, then use your hand sanitizer.

"After security, get some space and keep some space between yourself and other people before you have to board your flight. You dont want to be stuck sitting close to other people. Maybe that means finding an empty gate or one that doesnt have a flight going out right now where you can sit at instead. Theres no rule that says you have to sit at your crowded gate before your flight. When its time to line up to board the flight, try to keep some space. Just remember the CDC doesnt count an exposure unless youre within 6 feet of someone for 15 minutes or more. Just wait to get up and only get in line when its your turn. The person standing behind you is going to do what they want to do, and theres not much you can do about it."

ON THE PLANE

Q: I know I will need a face covering. What type would you suggest for the flight?

Landon: "Youll want to bring a really high-quality fabric mask or a medical mask for traveling. You need to make sure your mask is super protective not just preventive. Fabric masks are great for holding in your own respiratory droplets. But if other people arent wearing their masks, then they are not holding in their respiratory droplets. If everyone wears a preventive mask, then, together, everything is safer all around. But if you cant count on other people to do that, then you need to have a really good fabric mask like the World Health Organization recommends. Probably two or three layers with a high thread-count cotton and/or silk inside of it or a filter pocket inside of it. One that fits you well. Thats what I would wear. I find fabric masks to be a lot more comfortable than medical masks.

"I would try not to take off my mask during the flight you may need to in order to have a drink of water on a 4-hour flight. But on a short flight, you could probably get away with drinking before you board and then drinking again when you get off the plane."

Q: What should I do when I arrive at my seat?

Landon: "I would wipe down the armrest and the tray table. If Im in the window seat, then I would wipe that down, too, because thats what people often lean against and put their hands on. Then I would sit in my seat, wash my hands again with hand sanitizer and sit tight. Leave your mask on for the flight.

"Youre really only at risk from the people within a couple of seats of you in any direction. So, two seats behind you, two seats diagonally, two seats in front of you. Thats what youre really worried about.

"If someone is coughing in the back of the plane, then dont freak out. People passing you in the aisle, dont freak out. Theoretically, the window seat is the safest."

Q: I see people sitting near me who have taken off their mask during the flight. What should I do?

Landon: "When we think about how to protect people out in the world from COVID-19, I like to describe it as a layered or stacked approach. We stack up interventions. None is meant to be perfect on its own. You can rely on cleaning your hands, wiping down your seat, keeping your distance from other people these are all ways to reduce your risk when traveling. But some of them arent as easy to do when traveling, like protecting your eyes. So, if other people are coughing or sneezing or have respiratory droplets that are contagious, then that can get in through your eyes. A mask doesnt protect them. And your regular glasses arent great protection either.

If you find yourself stuck on an airplane with someone two rows behind you or one seat behind you coughing or, say, the guy next to you doesnt look all that well you want to be able to add an extra layer of protection.

Dr. Emily Landon, University of Chicago Medicine:

"I strongly recommend bringing one of these plastic face shields that covers your mask. It will help protect your face, your eyes and mask from becoming contaminated. They are really comfortable. The first time you put one on, youre like, This is ridiculous, but you can see your whole face through it. You can wear your mask underneath it. In fact, were recommending them for little kids at school, when schools go back, that they might be a better form of protection than trying to get them to keep their masks on. They are available on Amazon. You could even make one yourself. I would bring one with me. I wouldnt, necessarily, wear it the whole time. I would definitely have it with me so I could add a layer of safety. If I feel like I cant keep my distance from people and other people arent wearing masks, then that would be the time I would want to put on a face shield. The real time to need them is when youre around people who arent wearing masks. I think you need to have something that will help you add a layer of protection if someone else isnt doing their part. That, for me, would be a face shield."

WHAT ABOUT STAYING AT A HOTEL?

Q: What is the general guidance?

CDC: If staying at a hotel, then check the hotels COVID-19 prevention practices before you go. When you are there, limit close contact with others in the lobby or other common areas, take the stairs instead of the elevator and choose contactless options for check-in when possible.

Q: Ive arrived at my destination. Are there any inside surfaces at my lodging I should wipe down as a precaution?

Hartmann: "If youre really set on taking matters into your own hands, focus on high-touch surfaces (keys, doorknobs, light switches, maybe remote controls)."

Q: What should I look for when booking a hotel?

Landon: "The most important thing is to look on the hotels website ahead of time and make sure the hotel has a good written policy about COVID-19. You want to see that they require masks to be worn by staff and guests in the inside common areas all the time. You want to see that they say something about their disinfection plan in rooms. Not just cleaning them in between guests, but they are disinfecting them using an EPA-registered disinfectant and theyve trained their staff in how to do so. You want to see that they have a social distancing plan in place and they have policies for use of their common-use areas like gyms or pools. That means the hotel is taking steps to protect its workers and guests. If the hotel is taking a lot of steps to protect their workers and guests, then its less likely there will be sick people wandering around your hotel, which makes it safer.

"Its important that the hotel has a clear policy, but you want to go a step further. You want to find information on travel websites or talk to someone whos been there recently. I would want to know what is really happening on the ground.

A lot of places have policies. If you call the front desk ahead of time and they have no idea what the hotels policies are, then thats a bad sign.

Q: Is it safe to use a hotels pool?

Landon: "Pools are not inherently bad. Chlorine in pools should kill COVID-19. Thats not a problem, but people dont wear masks when they are in pools. In general, the recommendation in Illinois is that pools are not open for recreation right now, but could be opened for exercise.

"Look for sun loungers to be spaced apart, signs saying the pool is not allowed to be used for recreation, only for exercise, and a limited number of swimmers can be inside at one time. If you scope it out and it appears you can safely do that, then, sure, go ahead and swim some laps."

Q: What about camping?

CDC: Going camping at a time when much of the United States is experiencing community spread of COVID-19 can pose a risk to you if you come in close contact with others or share public facilities (like restrooms or picnic areas) at campsites or along the trails.

Q: What if Im staying with family?

Landon: "Take care of yourself. Be pretty socially distant from people in the week leading up to your trip. If your family is really, really anxious about your visit, then plan to leave a few days early and take a break in a hotel for five days before you stay with family. And get tested, maybe, if everyone is really concerned."

PACKING

Q: What are some precautions to take for any type of travel?

CDC: Consider the following when leaving your home:

- If taking prescription medicine, then bring enough to last you for the entire trip.

- Pack hand sanitizer with at least 60% alcohol.

- Bring a cloth face covering to wear in public places.

- Prepare food and water for your trip. Pack nonperishable food in case restaurants and stores are closed.

- Follow state and local travel restrictions. Check state and local health department information at home, along your route and at your destination.

RETURNING HOME

Q: OK, Ive made it back home after my trip. How can I prevent the entire trips germs from ending up inside my living space?

Hartmann: "Again, wash your hands when you return. Consider disinfecting high-touch objects that you may have had with you or objects that other people outside your trusted circle may have handled, if you intend on using them again very soon."

Landon: "If you come home from a trip, then assume youve been exposed (to the new coronavirus). Get tested five to seven days after your last exposure, stay home for a little extra time. If I was going to travel like that this summer, then I would book another week off afterward so that I wasnt spreading anything that I might have picked up."

OK, THIS IS HARD

Q: My partner wants to travel this summer, but Im unsure about it. Can you suggest some ways we can have a conversation and try to understand each other?

Bohnert: "Partners should strive to appreciate what their partners would and would not feel comfortable doing. It is also important to understand where those concerns come from. Does a partner have a health condition that makes them more vulnerable? Is a partner worried about losing time away from work and reductions in salary if they are exposed? Is your partner worried about the potential of encountering racism? Are they concerned about whether there would be adequate medical care in the place where they are visiting? If one partner is particularly uneasy with one locale, perhaps another that is more familiar, closer to home or involves less time away could provide a more comfortable escape. The more you can understand what specific things make your partner uneasy about traveling, the easier it will be to come up with some options that may be more palatable if one of the partners feels strongly about the need to get away."

Q: After months of sheltering at home, Im now afraid to head out into public and be around other people. What can I do to make a trip away from home seem less stressful?

Bohnert: "To start, I would encourage people to normalize these stressful feelings. After all, we have been told to avoid people and shelter at home to prevent getting sick. So heading out in public runs counter to the advice we have been heeding over the past three months how could we not feel nervous about it?

It would be hard not to feel unsettled by the prospect of being in public after all the precautions we have been asked to take. So dont judge yourself for feeling uncertain.

Dr. Amy Bohnert, Loyola University Chicago:

"Next, try and pinpoint exactly what makes you feel uncomfortable. Is it being in closer contact with others? Fears of dining out? If you can figure out what makes you feel uneasy, you may be able to control some aspects of that situation that will make it feel more manageable. As with most things, when we feel anxious or concerned about a situation, we may seek to avoid it so we dont have to feel anxious. This, of course, reinforces that the situation is something to be feared because when we avoid it, we dont feel worried. So figuring out what you can control wearing a mask (properly), washing/sanitizing your hands and finding less crowded outdoor places where you can better manage how close you have to get to others may make the decision to get out more palatable. All these behaviors will decrease (but not eliminate) the likelihood you get infected if you encounter someone who is contagious."

Q: How can we have a fun, productive summer as a family if we decide to not take a vacation and choose, instead, to stay home?

Bohnert: "For many people, traveling introduces a lovely element of novelty to our lives. We get to see different scenery, eat different foods and have new experiences. With all the novelty we are currently facing and the uncertainty that lies ahead, the risk incurred by traveling may be more than families are ready for during challenging time. But finding little ways to enjoy the spaces and people around you, even while distancing, is important.

"There are many lovely places to explore in the Chicago area during the summertime that provide a nice respite from our homes. Some are closed but may be reopening in the coming weeks. The botanic gardens and forest preserves are lovely, nature-filled spaces. Some of our renowned Chicago university campuses also have splendid grounds in which to stroll. Springfield is a bit farther away but a great place to explore for history buffs, as is Cantigny in the western suburbs."

Consider setting some up some new family rituals bike rides, walks to look for birds, berry picking and picnics can all be nice ways to escape.

Continue reading here:
Should you travel this summer? Heres a guide to vacation amid the coronavirus pandemic. - Peoria Journal Star

In these fractious times, when we are confronting the reality of systemic racism, how can we have an informed discussion about genetics and race?

One way is to calmly state the increasing evidence of meaningful genetic differences between human populations and then engage in honest and robust debate about the social and political implications, if any, of such inter-group divergence.

Back in the real world, meanwhile where open discussion of race and biology is largely taboo (a state of affairs recently exacerbated by DNA pioneer James Watson) a better idea might be to quickly change the subject. So what about the weather, eh?

But battening down the hatches and sitting out the storm isnt really an option. For a start, it would mean blithely ignoring the deluge of data from the recent revolution in molecular biology about our species evolution and of the genetic divergence of separate human populations over time. More importantly, it would also miss the opportunity to genuinely level the playing field for those very peoples most marginalised by an undeniable history of prejudice and neglect.

Note, though, the numerous alternatives for race already employed above: populations, groups, peoples (to which ancestry, descent and the like could also be added). Far from simply being politically correct euphemisms for a tainted term, it is important to distinguish between the word race as it is socially used say, the Black/African American, Native American, White, etc. racial categories used in the US census from the biological sense, used to describe distinct populations within a species.

Because of the historical misuse of the term race, this is an important distinction to make. In 19th century Britain, for example, two groups who would now be simply lumped together as White were regarded as separate biological races namely, and complete with the picturesque descriptors of the time, the careless, squalid, unaspiring Irish and the frugal, foreseeing, self-respecting Scots. (Full disclosure: my own genetic ancestry is of the careless, squalid and uninspiring variety.) A more modern perspective, however, does not deny the existence of genetically distinct indigenous British populations such groupings do indeed exist rather, it avoids describing them in meaningless racial terms. Similarly, the idea of an overarching Black race utterly fails to capture the genetic diversity of African (or African-descended) peoples, irrespective of how we are now able to distinguish genetically related groups within the wider human population of Africa.

Nor is this simply overly-sensitive quibbling over the meaning of a word. Historically, race was often used synonymously with varieties, breeds or sub-species (in the Descent of Man, for instance, Darwin considers at great length what was then still an open question: Arguments in favour of, and opposed to, ranking the so-called races of man as distinct species). But whether we like it or not, words have power, and once-acceptable descriptors of human inter-group variation now carry obvious egregious connotations (such as the slur half-breed).

Indeed, the limitations of language have long been a bane of everyday discussion of human evolution, with phrases and concepts survival of the fittest, say, or struggle for existence inevitably being interpreted in terms of intrinsic worth. Descriptions of sub-species of flora and fauna, for instance, would ruffle few feathers; similar talk of sub-populations of human beings, however, inevitably evokes hierarchical notions of superiority and inferiority. (As a light-heartened analogy, think of the hierarchical distinction between language and dialect then tell the Germans that their language is a dialect of Dutch.)

In sum, then, anyone discussing genetics and race must be conscious of the connotations and impact of words. And this is especially true when engaging in dialogue with those with a standard social science conception of race, one in which human evolved biology is seen as irrelevant to social issues a paradigm, moreover, in which the very idea of human biological difference is treated with the utmost suspicion. Given this latter mindset and the human tendency towards righteous indignation it is hardly surprising that many liberal-minded people react badly when confronted with arguments about human difference that they perceive (rightly or wrongly) as morally offensive. If worthwhile or meaningful discussion of genetics and race is to proceed, therefore, it is beholden on geneticists and their ilk to take this into account not through political timidity but through simple courtesy and common-sense.

Of course, as pointed out above, such is the toxic nature of this topic that open discussion is often avoided, especially by those cowed by the likely reaction of their peers. In this respect, political scientist James Flynn discoverer of the eponymous Flynn effect of rising IQ over time points to the counterproductive nature of intellectual censorship: [T]hose who boycott debate forfeit a chance to persuade. They have put their money on indoctrination and intimidation. A good bet in the short run but over the long course that horse never wins.

The sort of censorious indignation highlighted by Flynn also has another detrimental effect: it opens a space for nationalistic populists and race supremacists to claim they are simply telling it as it is or bravely saying what others are too scared to admit. The losers here, of course, are the very people that the taboos were designed to protect those marginalized minorities likely to face greater prejudice from emboldened bigots.

Moreover, Flynns own work provides a further explicit example of how such taboos can have counterproductive consequences; if Flynn had been unable to research the causes of reported racial differences in IQ he would never have discovered the Flynn effect, the best evidence we have of environmental influences on intelligence (and of how improvements in impoverished environments can lead to dramatic changes in IQ scores over time).

This points not only to the benefits of openly addressing sensitive subjects, but also to a possible way to assuage some of the suspicion that surrounds genetic research into inter-group difference that even if such differences are shown to exist, this does not dictate any particular social or political response. Facts do not determine values.

At the same time, however, facts can certainly inform social policy. Take, for example, the overwhelming evidence of strong genetic influences on academic achievement. Contrary to what many might pessimistically assume, this genetic evidence does not mean that nothing can be done for those currently failing in the education system. As the Flynn effect shows, environmental change does make a difference, despite the high heritability of IQ.

Indeed, the strong genetic determinants of educational attainment are much less straightforward than they appear. For example, some studies that indicate a causal link between genes and learning hinge on the observation that older mothers have offspring who are more likely to succeed in school. As older mothers also have fewer children (with whom they can devote more time and resources), the relevant genetic influence here pertains to fertility rather than academic smarts. Given this, and given a political desire to raise academic attainment amongst specific groups, ameliorative social policy could focus on womens reproductive health and opportunities in marginalised communities.

Be this as it may. The point is that genetic facts including evidence of genetic differences between racial populations carry no necessarily social or political implications. Nevertheless, these same genetic facts may help highlight obstacles to achieving desired social outcomes, and could provide information that assists in overcoming them. In this respect, just as greater awareness of social and environmental barriers can assist in designing policies to reduce inequalities, so too could greater recognition of possible genetic hurdles to improved life outcomes.

In the past in the era of Social Darwinism and eugenics hereditarian political beliefs equated biology with destiny. Unfortunately, much of the present-day antipathy to human genetic research appears premised on a similar erroneous belief: that if human behavior is under the influence of biology/genes then certain social outcomes, such as disparities in wealth or status, are inevitable. Hence the desire to denigrate genetic research that touches on the raw nerve of race for, as many well-intentioned egalitarians may mistakenly believe, if meaningful differences between different peoples really do exist, then the goal of greater equality could prove unattainable.

The biological study of human behavior is notoriously fraught hardly surprising, given that fallible humans are both the subject and the object of scrutiny. Furthermore, given the egregious history of political ideas based on supposed facts of human biology, the results of human behavioral research are often held to a higher standard of proof and most especially with research relating to politically sensitive topics, such as race, gender or sexuality.

Whether always warranted or not, such critical inspection comes with the territory; indeed, one higher standard that human geneticists can impose upon themselves is to understand the motivation of the opposition, however wrong-headed this might appear. Such awareness would not mean avoiding discussion of troublesome topics but it might avoid discussing them in ways more likely to inflame than inform.

A version of this article was originally published by the Genetic Literacy Project on Feb 13, 2019.

Patrick Whittle has a PhD in philosophy and is a freelance writer with a particular interest in the social and political implications of modern biological science. Follow him on his website patrickmichaelwhittle.com or on Twitter @WhittlePM

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Genetics and race: An awkward conversation during volatile times - Genetic Literacy Project

While its undeniable that logging miles has major health benefits, scientists dont exactly understand how it affects your body at the molecular levelbut researchers are attempting to figure that out.

A Stanford University study published in Cell set out to determine what happens in the body just after exercise, and try to get one step closer to explaining exactly what makes exercise so good for your health.

In the study, 36 people aged 40 to 75 completed a peak VO2 testwhich measures maximum oxygen consumption during intense exercise as a marker of aerobic fitnesson a treadmill. Before running, researchers sampled their blood. Then, after about 9 to 10 minutes of running, the participants blood was sampled multiple times: immediately after exercise, and then 15, 30, and 60 minutes after they reached their peaks.

Researchers then completed multi-omic profiling, where they looked at the participants blood to see how exercise affected molecular changes in the cellsincluding how exercise affects immune cells and plasma. Over 17,000 molecules were measured, and 9,815 moleculesmore than halfshowed significant change, Michael Snyder, Ph.D., professor and chair of genetics at the Stanford University School of Medicine, in Stanford, California, told Runners World.

Exercise has a lot of health benefits, but nobody knows how exercise really works, Snyder said. Im not saying our study figured it out, but it gives us a window into whats going on in the body.

Researchers were able to see changes in oxidative stress, which is a harmful chemical process when theres too much of it. They also saw immune system markers and molecular markers of healing and inflammation go up right away as the body began to recover.

These results give a window into different systemic events, such as the potential to look into how oxidative stress affects aging, how exercise affects your immune system, how your body reacts to metabolic stresswhich occurs in exercise as energy depletes, leading to accumulation of lactic acid in musclesand how muscles are engaged during exercise as researchers work to further study the effects exercise has on the body.

I do view it as just trying to work out the choreography of whats going on, Snyder said. Its like a symphony, maybe the violins start off first, then the next instrument and the next come in.

[Smash your goals with a Runners World Training Plan, designed for any speed and any distance.]

This kind of testing can give researchers the ability to see whats happening in peoples bodies, such as seeing how muscle markers and markers for cardiovascular disease are all stimulated and engaged.

While we know that exercise is important for heart health, its not exactly known how it benefits your ticker. This is something researchers hope to use these findings to study more in the future, Snyder said. And, while this test was only done using a treadmill stress test, researchers will look at how molecules in the body are affected by other types of exercise.

Results showed that peoples fitness and health levels were consistent with how much exercise affected the molecules in their bodies. For example, people that were healthy had similar molecular changes before and after exercise; those who were insulin resistant (prediabetic and diabetic) didnt have as large of an immune response, which may be able to show how exercise affects this condition or helps predict the onset of diabetes.

And, through these blood samples, the molecular patterns found anemia that other testing hadnt picked up in one healthy individual, Snyder said.

So what can this tell you about your health? Right now, researchers are still figuring that out. But as the molecules change, they are able to see things like how different systems in your body engage during exercise, how your cardiovascular pathways are affected, and when different types of fat burning may occur. All of these elements give researchers a better look at how exercise engages the entire body.

Were looking at the details of how the symphony is able to play, Snyder said.

In the future, the researchers hope that a version of molecular profiling can be used as a way to measure aerobic fitness and along with typical treadmill testing.

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One Run Can Alter 9,815 Molecules in Your BodyHeres Why Thats Important - runnersworld.com

Genetics is that the study of genes, their functions and their effects. Among the varied sorts of biology like genetic science, developmental genetic science, population genetics and quantitative genetic science, human genetics is that the study that deals with the inheritance happens in folks. It encompasses a range of overlapping fields like classical biology, genetics, genetic science, genetics and plenty of additional.

The Human Genetics Market is expected to exceed at a CAGR of 9.5% in the given forecast period.

Browse Full Report: https://www.marketresearchengine.com/human-genetics-market

The Human Genetics Market is segmented on the lines of its methods, product, applications, end-users and regional. Based on methods segmentation it covers cytogenetic, molecular, presymptomatic and prenatal. Based on product it covers Consumables, devices and accessories. Based on end-user analysis it covers hospitals, clinics, research centers and forensic departments. Based on application it covers research, diagnostic and forensic science and others. Based on Others it covers Hysteroscopy Instruments Market on geographic segmentation covers various regions such as North America, Europe, Asia Pacific, Latin America, Middle East and Africa. Each geographic market is further segmented to provide market revenue for select countries such as the U.S., Canada, U.K. Germany, China, Japan, India, Brazil, and GCC countries.

This report provides:

1) An overview of the global market for Human Genetics Market and related technologies.2) Analyses of global market trends, with data from 2015, estimates for 2016 and 2017, and projections of compound annual growth rates (CAGRs) through 2024.3) Identifications of new market opportunities and targeted promotional plans for Human Genetics Market.4) Discussion of research and development, and the demand for new products and new applications.5) Comprehensive company profiles of major players in the industry.

Report Scope:

The scope of the report includes a detailed study of Human Genetics Market with the reasons given for variations in the growth of the industry in certain regions.

The report covers detailed competitive outlook including the market share and company profiles of the key participants operating in the global market. Key players profiled in the report include Agilent Technologies, Bode Technology, GE Healthcare, Illumina, LGC Forensics, Orchid Cell mark, Inc., Promega Corporation, QIAGEN N.V., Thermo Fisher Scientific, Inc. Company profile includes assign such as company summary, financial summary, business strategy and planning, SWOT analysis and current developments.

The Human Genetics Market has been segmented as below:

The Human Genetics Market is Segmented on the lines of Application Type, Methods, Product Type, End-user and Regional Analysis. By Application Type this market is segmented on the basis of Research, Diagnostic, Forensic science and Others. By Methods this market is segmented on the basis of Cytogenetic, Molecular, Presymptomatic and Prenatal.

By Product Type this market is segmented on the basis of Consumables, Devices and Accessories. By End-user this market is segmented on the basis of Hospitals sector, Clinics sector, Research centers sector and Forensic departments sector. By Regional Analysis this market is segmented on the basis of North America, Europe, Asia-Pacific and Rest of the World.

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Human Genetics Market 2020: Challenges, Growth, Types, Applications, Revenue, Insights, Growth Analysis, Competitive Landscape, Forecast- 2025 - Cole...

While the risks for young healthy people are comparatively low, other experts warn about reading too much into the data recorded during lockdown.

Dr Peter Ellis, a lecturer in molecular genetics and reproduction at the School of Biosciences at the University of Kent, notes that Sir Davids data represent only the residual risk not the natural one.

The reason relatively few people have died of Covid is because only a small percentage of the population have had the disease, he says

A more appropriate conclusion in my view would be to rejoice that the lockdown has done its job and thus kept the overall risk of death low.

Also, the fact that younger demographics are comparatively protected does not mean it is necessarily safe for younger people to mix more freely.

This may be true, but it does rely on our ability as a society to cocoon and protect more vulnerable demographics: a feat not achieved by any country so far, warns Dr Ellis.

In any calculation of mortality risks, it can be also misleading to compare infectious and non-infectious causes of death. Car accidents and bombing raids have very different characteristics to viruses and bacteria.

Infectious disease risk is socialised rather than individual, says Dr Ellis. My actions affect others' chances of death as well as my own.

Protect yourself and your family by learning more aboutGlobal Health Security

Read more:
Crunching the numbers: what are the real risks of dying from Covid-19? - Telegraph.co.uk

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Nadia had a cough and it wouldnt go away. She didnt feel like eating. X-rays and ultrasounds, blood work, all turned up nothing. So a decision was made to test Nadia a four-year-old Malayan tiger at the Bronx Zoo in New York for the latest bug going around, the one that had already put much of the world, including her zoo, into lockdown: COVID-19.

On the other side of the globe, a 42-year-old woman in Melbourne had come down with similar symptoms to Nadia the same dry cough, the fatigue. And, when the tests came back from the labs, the sample of the virus found in both human and tiger was near identical too. Within days, another swab with that tell-tale genetic signature would be extracted from a 21-year-old in Taiwan.

How does the same strand of virus end up in a woman in Melbourne, someone in Taiwan, and a tiger in the Bronx?

Unlike historic plagues, COVID-19 is not spreading in a straight line, from house to house or country to country. Instead, versions of the virus each with their own tiny genetic tweaks are jumping from continent to continent via plane (and cruise ship), and crossing back on each other. The story scientists who specialise in reading COVIDs genes see is that of the worlds first truly globalised pandemic.

Since researchers in Wuhan, China, where the outbreak began, first published the genetic code of the virus, hundreds of labs around the world have followed suit. Their efforts to join the dots among patients, under the microscope as well as on the ground, mean this pandemic is being tracked like never before in real time. Already the family tree of COVID-19 is helping us understand where the outbreak came from, how it took hold in different continents and where its going next.

DNA detectives have tracked one distinct strand of coronavirus from Wuhan through Europe, Australia and Taiwan all the way to Nadia the tiger, pictured, at the Bronx Zoo in New York.Credit:Stephen Kiprillis, Kirsten Burghard

There are more viruses in the world than stars in the sky. They are found in almost every corner of the Earth, they fill its oceans. If lined up, side by side, scientists say they would fill our galaxy too. Most of them cant infect us and the few that can we catch mostly from animals in that knife-edge moment of chance when a pathogen long circulating in one species leaps to another.

Ten thousand times smaller than a grain of sand, viruses can drive forward evolution and unleash hell think of them as zombie shells of protein waiting to spring into action.

Theyre half living, half dead, says Professor Seshadri Vasan, from behind several Get Smart-style levels of security at the CSIROs dangerous pathogens lab.

Unlike bacteria, which can thrive wherever it's warm and wet, viruses need a host to survive. They are the pirates of the microscopic world, commandeering the cellular machinery of other organisms to make copies of themselves and spread.

All they need is a way in.

Thats why its Mission Impossible here at the lab, Vasan says.

Some time in late 2019, a coronavirus now known as SARS-CoV-2 found a door into the human genome this tiny ball of protein evolved a spike able to unlock our cells by binding to ACE2 receptors, a type of enzyme found throughout our bodies. In the bustling city of Wuhan, the virus jumped from an animal into a person, most likely through the handling and slaughter of wildlife for the meat, fur and traditional medicine trade. From there, the germ spread like wildfire between humans infecting more than six million people and killing 400,000 within its first six months.

"Trouble wrapped in protein": Inside its spiky outer shell the coronavirus contains a folded-up strand of RNA.Credit:Kirsten Burghard

Beneath the coronaviruss signature spikes, youre looking at an envelope of fat encasing a long strand of RNA. Like our own double-stranded DNA, this holds the viruss instruction manual for making more copies of itself.

Its like a manuscript written in a language made up of only four letters: A, C, G and U, which is more commonly called T, Vasan says. How they are arranged on the page can change how the virus behaves.

SARS-COV-2s manual is long made up of 30,000 letters or nucleotides. By contrast, the influenza strain that caused the worlds last pandemic in 2009, swine flu, was just 13,500 letters long, Vasan says. This is more than twice the size, its a very big virus.

It is also more deadly.

Once a virus is inside a cell, it sets up shop, replicating at speed. Imagine photocopying this viral manuscript, Vasan says but each copy is then used to make the next. Before too long, mistakes smudges or missing letters will start to creep in. These typos are known as mutations. Some of them slow the virus and are dropped from the text over time. Most are silent they dont affect the viruss structure or function and so you can still understand the sentences. But then there are the rarer mistakes, the ones that improve the virus.

Perhaps it's a really bad manuscript, laughs Professor Francois Balloux, who heads up the genetics institute at University College London.

Before it emerged in humans, scientists say two key mutations had already primed SARS-CoV-2 to jump species lines and spread further than the other two dangerous coronaviruses to come before it, SARS-CoV-1 and MERS-CoV. One change allowing the virus to fuse cells together and tunnel its way through the body faster came down to just three letter changes in its RNA code, says Dr Denis Bauer at the CSIRO.

But now that it is circulating in humans, scientists say the coronavirus is mutating at a fairly stable rate about 20 mutations a year, Balloux calculates. Thats a little faster than he expected, although not as fast as less predictable viruses such as influenza, which requires an updated vaccine every season to keep up with all its mutant stains.

Runaway COVID-19 outbreaks in parts of Europe and the Americas have fuelled speculation that more deadly or infectious strains of the virus may be circulating already some early studies have suggested as many as 30 kinds of SARS-CoV-2. But most scientists stress the mutations so far havent changed how the virus behaves.

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Nadias particular virus, for example, when examined under the microscope by Dr Leyi Wang at the University of Illinois, had racked up just six recurrent mutations or protein changes since it travelled out of Wuhan to her zoo in New York.

Critically, Vasan notes, mutations in the RNA code or even observed in how the virus behaves in the petri dish must be matched against clinical outcomes in patients to truly warrant the distinction. Otherwise they might look like theyre having an effect when theyre not, he says. Im not seeing anything sinister in the mutations so far.

At the Bedford lab, which pulls together global genomic data on COVID-19 through the platform Nextstrain, Dr James Hadfield agrees. Most of the time when a virus starts to behave differently its down to its environment not its biology as it encounters different healthcare systems, population vulnerabilities and public health interventions.

Nadia's virus was traced back through Europe to the original outbreak in China.Credit:Stephen Kiprillis, Kirsten Burghard

But mutations do come in handy for tracking the virus. Over time, differences between samples (good, bad and not worth mentioning) build up, leaving tiny molecular clues for scientists to follow each genome is timestamped to when (and where) it was collected.

The small team behind Nexstrain works around the clock to crunch this data when Hadfield signs off in New Zealand, Dr Emma Hodcroft and her colleagues in Switzerland are ready to take over, followed by Dr Trevor Bedfords team in Seattle.

Hodcroft says the very first genomes out of China were just one mutation apart. Six months on, the branches of the tree still arent very long samples of the virus vary by only about 10 recurrent mutations on average and their roots all go back to a common relative: that first genome sequenced in Wuhan. Thats how scientists know the spillover from animals into humans happened recently in China, likely in November 2019.

Now weve moved from the sparks being thrown off by the Chinese epidemic, to individual epidemics starting in certain countries, Hodcroft says.

Local mutations may develop as the virus spreads in a specific community, particularly with much of global travel grounded, but no country has a distinct national strain yet. There is no US strain or Australian strain, Balloux says.

On April 1, a woman was swabbed in Melbourne. Within days, virtually the same genetic signature would be extracted from Nadia in New York.Credit:Stephen Kiprillis, Kirsten Burghard

In Australia, COVID-19 cases are comparatively few but our virus is among the most sequenced in the world. More than 60 per cent of all confirmed Victorian cases have now had their sample sequenced, Dr Sebastian Duchene of the Peter Doherty institute for Infection and Immunity says. And in NSW, genomic detectives have tracked early cases in Australia back to Iran as well as China, based on distinct mutations.

When you compare Australias viral tree with somewhere like the US, you see more genetic diversity, Hadfield says most cases tend to be imported from overseas, giving us not just one initial case or patient zero but hundreds. But where clusters emerge without a clear source, genomic data can help contact tracers crack the case.

Sequencing or tracking the viruss genetic passport has now revolutionised how health authorities fight pandemics, says Professor Benjamin Howden at the Doherty Institute, and will become critically important as countries ease restrictions. In some cases in Victoria, he says, clusters in which people had no known links to each other were uncovered after the lab team traced a connection in the viruss genes.

Usually, when you do contact tracing, everyone in a cluster has the same virus, Duchene says.

This observation is what makes Nadia and her Melbourne strain so strange, on the face of things.

Every dot below is a Victorian case, and every line is a link between that patient and another made by contact tracers. Dots of the same colour share the same genetic virus signature as others. Some clusters, such as the large 75-person outbreak that erupted in March (shown in red down the bottom) were also linked genetically to other clusters although no connections were found on the ground.

Victorian clusters between January 25 and April 29 were linked by genetics as well as contact tracing. Credit:Source: The Doherty Institute

Still, the worlds genomic dataset on COVID-19 is both museum and live recording its not over yet.

Scientists stress they have only part of the picture most virus lineages infecting people will not be sequenced. Even that first sample published in Wuhan did not come from a definitive patient zero but one of the earliest known cases: a 41-year-old worker in the wet market where the virus is suspected to have first broken out or circulated.

We might not ever find the very first because so many people get no symptoms or mild symptoms, Balloux says.

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Vasan warns theres a danger in any outbreak: in the race to find a cure, scientists could pick up the first sample that comes their way and run with it - in the wrong direction. When the Doherty Institute became the first lab outside China to sequence and grow the virus, it was passed like a baton in a relay, straight to Vasan at the CSIRO for mass production as his team test some of the worlds top vaccine candidates.

But in the back of my mind, I wanted to be sure what we were working with was a typical strain, Vasan says.

So, he called in experts in artificial intelligence, including Bauer, to help screen samples for unusual mutations, particularly in areas where changes could cause a real difference to how the virus behaves, such as in its unstable and much-discussed spike. The results were reassuring they found that the first Wuhan strain, now used all around the world as a reference, was a good sample, as were the baseline strains used in Washington, Sydney, Melbourne and elsewhere. Even labs in the UK use our first Victorian strain now, Vasan says.

But they did find some outliers, including a NSW sample which contained a curious deletion. Another, collected in Italy, had mutations in common with both a Sydney virus cluster and one on the other side of the world in Chongqing, China.

Were not sure why, Bauer says. It could have been a recombination, where someone is infected with two lineages of virus at the same time that gave rise to this particular version.

The probability of two different viral lineages evolving the exact same mutations on their own is very low, Bauer says, though Vasan notes not impossible.

Influenza, meanwhile, spits out hybrid strains all the time on a much bigger scale known as reassortment. While coronaviruses can also recombine, they are less likely to produce anything too radically new in one go, Balloux says, because these spiky pathogens come with their own in-built proofreader a kind of molecular quality control.

Bauer likens it to the difference between using a cookie cutter to make Christmas biscuits and letting your toddler loose kneading the dough into the right star shape. Thats probably what allowed it to become larger and more sophisticated than other RNA viruses, she says.

Nadias nasal swabs were tested in two different labs, the University of Illinois and Cornell University, then driven through the night to a government lab for further checks all came back positive.Credit:Stephen Kiprillis, Kirsten Burghard

In Nadia the tiger, one strand of COVID-19 that had stretched all around the world reached the end of the line the big cat is thought to have caught it from a zookeeper without symptoms in March but did not pass it back to another human.

But she was part of a big cat cluster inside the Bronx Zoo. Nadia was tested first in early April because she seemed the sickest but five tigers and three lions would test positive in total. All are now recovering well, says Professor Karen Terio who helped co-ordinate the tests at her zoological pathology lab at the University of Illinois.

Nadia was coughing, which is an odd clinical sign for a tiger, so we had a suspicion, Terio says.

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The labs virologist, Leyi Wang, who had to devise a whole lab test for the felines, admits Nadias positive still came as a shock. The zoo had already been shut for weeks when the tiger got sick [at the end] of March Now were looking at the other cats. The tigers strain was very similar to the human New York virus but the lion samples look a bit different to the tigers. Its not clear yet how they were all infected.

Balloux notes that the fact the virus can infect other species makes it possible two different lineages human and animal could recombine into a hybrid strain down the line. Some think thats how we got COVID-19 to begin with. An old bat coronavirus might have mixed with one in a pangolin [a mammal trafficked in China] or maybe it just jumped to the pangolin or [another mammal] that has ACE2 [receptors] like humans and evolved there.

But he is not worried.

Next to the millions of human COVID-19 cases already confirmed, only a tiny handful of animals, including cats, dogs and ferrets, have tested positive and then only in mild or asymptomatic cases (or at high deliberate doses in the lab). Aside from a cluster of mink in cramped fur farms in the Netherlands, there has been no sign animals can pass the virus back to people. Experts say this suggests transmission between species (notably humans and their pets) is very weak and no cause for alarm.

So how did eight big cats fall sick all at once?

The Bronx Zoo did not answer questions on the circumstances or whether staff members had also tested positive, and Terio says that contact tracing work is ongoing and has not been disclosed to her for privacy reasons. While the cluster does offer new clues about what species are particularly susceptible to SARS-CoV-2, she thinks its probably too much of a leap to say it narrows down the search into the viruss origins.

Evolutionary biologist Professor Edward Holmes points to another cluster, this time of mink falling severely ill in Dutch farms, as the best place to start looking - mink are also widely farmed in China for their fur. Another lead could lie with the highly endangered and heavily trafficked pangolin which has been found via genomics to carry a similar (though not identical) virus. Holmes says the wildlife trade, including fur farming, remains the most likely origin of the pandemic, as happened with SARS and many other outbreaks.

CSIRO scientists are growing both the coronavirus and vaccine candidates in their lab in Geelong, Victoria as part of a global race for a cure.Credit:Stephen Kiprillis, Kirsten Burghard

Fortunately, most scientists say it is unlikely the virus will mutate into something nastier by its very nature a germ wants to spread, not kill.

Over time Vasan expects it will become milder the way past pandemic flu strains have as they adapted to their new host. But, also like pandemic flu, COVID could linger on as a seasonal problem that flares up in the cold winter months at least until it is properly stamped out by vaccination programs.

Back at the CSIROs sprawling lab in Geelong, vast stores of the coronavirus enough for at least two years of vaccine and treatment experimentation sit in high-security freezers at minus 80 degrees. A virus that mutates slowly is unlikely to lose its bite any time soon. But it's also less likely to change to evade a vaccine.

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Im not worried its going to get worse or mutate out of control of a vaccine, Balloux says. Its already [spreading] out of control now. It's already bad."

Finding an effective vaccine or treatment is critical to getting the world back to some degree of normality while so many of us are still susceptible, Vasan says. Scientists developing vaccines arent closing their eyes to the virus genome much of the work is focused on areas of its molecular structure less likely to mutate.

Its like a child in a playground, were keeping an eye on it, Vasan says. That doesnt mean were worried but well keep looking back while [we work], so we know the child is still there.

Of course, for all the attention on COVID-19s genome, he stresses there is still crucial data missing matching, de-identified clinical records that could show the severity, outcome and personal risk factors of each case.

Mother Nature is running a giant experiment all around the world right now. Thats where we need to look to see what the mutations mean.

The problem, Vasan says, is that even very basic patient metadata is maddeningly inconsistent across jurisdictions, both interstate and international and no one is showing much enthusiasm for cleaning it up. Mild and moderate mean different things everywhere.

Of the many thousands of virus samples sequenced and shared worldwide, the CSIRO team managed to find just 300 with meaningful, matching patient information.

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Their resulting analysis was underpowered, Bauer says, but they could already make a preliminary link between changes in clinical outcomes and mutations in the viruss spike protein. Imagine what we could do if we had more.

Only the World Health Organisation could co-ordinate an international approach to streamlining such data into uniform categories, Vasan says, but Australia could still lead the charge with some show and tell.

If we can pull this data together [nationally], we can show the world what it can teach us, he says. What we find out could change the game.

Read more here:
Coronavirus: How COVID-19 is mutating across the world - Sydney Morning Herald

By Hemant Khanna, The Conversation

In recent months, even as our attention has been focused on the coronavirus outbreak, there have been a slew of scientific breakthroughs in treating diseases that cause blindness.

Researchers at U.S.-based Editas Medicine and Ireland-based Allergan have administered CRISPR for the first time to a person with a genetic disease. This landmark treatment uses the CRISPR approach to a specific mutation in a gene linked to childhood blindness. The mutation affects the functioning of the light-sensing compartment of the eye, called the retina, and leads to loss of the light-sensing cells.

According to the World Health Organization, at least 2.2 billion people in the world have some form of visual impairment. In the United States, approximately 200,000 people suffer from inherited forms of retinal disease for which there is no cure. But things have started to change for good. We can now see light at the end of the tunnel.

I am an ophthalmology and visual sciences researcher, and am particularly interested in these advances because my laboratory is focusing on designing new and improved gene therapy approaches to treat inherited forms of blindness.

Gene therapy involves inserting the correct copy of a gene into cells that have a mistake in the genetic sequence of that gene, recovering the normal function of the protein in the cell. The eye is an ideal organ for testing new therapeutic approaches, including CRISPR. That is because the eye is the most exposed part of our brain and thus is easily accessible.

The second reason is that retinal tissue in the eye is shielded from the bodys defense mechanism, which would otherwise consider the injected material used in gene therapy as foreign and mount a defensive attack response. Such a response would destroy the benefits associated with the treatment.

In recent years, breakthrough gene therapy studies paved the way to the first ever Food and Drug Administration-approved gene therapy drug, Luxturna TM, for a devastating childhood blindness disease, Leber congenital amaurosis Type 2.

This form of Leber congenital amaurosis is caused by mutations in a gene that codes for a protein called RPE65. The protein participates in chemical reactions that are needed to detect light. The mutations lessen or eliminate the function of RPE65, which leads to our inability to detect lightblindness.

The treatment method developed simultaneously by groups at University of Pennsylvania and at University College London and Moorefields Eye Hospital involved inserting a healthy copy of the mutated gene directly into the space between the retina and the retinal pigmented epithelium, the tissue located behind the retina where the chemical reactions takes place. This gene helped the retinal pigmented epithelium cell produce the missing protein that is dysfunctional in patients.

Although the treated eyes showed vision improvement, as measured by the patients ability to navigate an obstacle course at differing light levels, it is not a permanent fix. This is due to the lack of technologies that can fix the mutated genetic code in the DNA of the cells of the patient.

Lately, scientists have been developing a powerful new tool that is shifting biology and genetic engineering into the next phase. This breakthrough gene editing technology, which is called CRISPR, enables researchers to directly edit the genetic code of cells in the eye and correct the mutation causing the disease.

Children suffering from the disease Leber congenital amaurosis Type 10 endure progressive vision loss beginning as early as one year old. This specific form of Leber congenital amaurosis is caused by a change to the DNA that affects the ability of the genecalled CEP290to make the complete protein. The loss of the CEP290 protein affects the survival and function of our light-sensing cells, called photoreceptors.

One treatment strategy is to deliver the full form of the CEP290 gene using a virus as the delivery vehicle. But the CEP290 gene is too big to be cargo for viruses. So another approach was needed. One strategy was to fix the mutation by using CRISPR.

The scientists at Editas Medicine first showed safety and proof of the concept of the CRISPR strategy in cells extracted from patient skin biopsy and in nonhuman primate animals.

These studies led to the formulation of the first ever in human CRISPR gene therapeutic clinical trial. This Phase 1 and Phase 2 trial will eventually assess the safety and efficacy of the CRISPR therapy in 18 Leber congenital amaurosis Type 10 patients. The patients receive a dose of the therapy while under anesthesia when the retina surgeon uses a scope, needle and syringe to inject the CRISPR enzyme and nucleic acids into the back of the eye near the photoreceptors.

To make sure that the experiment is working and safe for the patients, the clinical trial has recruited people with late-stage disease and no hope of recovering their vision. The doctors are also injecting the CRISPR editing tools into only one eye.

An ongoing project in my laboratory focuses on designing a gene therapy approach for the same gene CEP290. Contrary to the CRISPR approach, which can target only a specific mutation at one time, my team is developing an approach that would work for all CEP290 mutations in Leber congenital amaurosis Type 10.

This approach involves using shorter yet functional forms of the CEP290 protein that can be delivered to the photoreceptors using the viruses approved for clinical use.

Gene therapy that involves CRISPR promises a permanent fix and a significantly reduced recovery period. A downside of the CRISPR approach is the possibility of an off-target effect in which another region of the cells DNA is edited, which could cause undesirable side effects, such as cancer. However, new and improved strategies have made such likelihood very low.

Although the CRISPR study is for a specific mutation in CEP290, I believe the use of CRISPR technology in the body to be exciting and a giant leap. I know this treatment is in an early phase, but it shows clear promise. In my mind, as well as the minds of many other scientists, CRISPR-mediated therapeutic innovation absolutely holds immense promise.

In another study just reported in the journal Science, German and Swiss scientists have developed a revolutionary technology, which enables mice and human retinas to detect infrared radiation. This ability could be useful for patients suffering from loss of photoreceptors and sight.

The researchers demonstrated this approach, inspired by the ability of snakes and bats to see heat, by endowing mice and postmortem human retinas with a protein that becomes active in response to heat. Infrared light is light emitted by warm objects that is beyond the visible spectrum.

The heat warms a specially engineered gold particle that the researchers introduced into the retina. This particle binds to the protein and helps it convert the heat signal into electrical signals that are then sent to the brain.

In the future, more research is needed to tweak the ability of the infrared sensitive proteins to different wave lengths of light that will also enhance the remaining vision.

This approach is still being tested in animals and in retinal tissue in the lab. But all approaches suggest that it might be possible to either restore, enhance or provide patients with forms of vision used by other species.

Hemant Khanna is an associate professor of ophthalmology at the University of Massachusetts Medical School

Read more:
The Incredible Gene-Therapy Breakthroughs to Cure Blindness - Daily Beast

XconomyNational

A new playbook is needed to ensure consistent chemistry, manufacturing, and controls (CMC) reviews for gene therapy products, the lack of which is hindering the development of these products, asserted a top official at the US Food and Drug Administration .

Now is the time to get things right asserted Peter Marks, director of the FDAs Center for Biologics Evaluation and Research, who spoke at a 15 June virtual Drug Information Association annual meeting session on how innovation can help overcome hurdles for these products.

The sessions moderator, Nancy Myers, president of Catalyst Healthcare Consultants, asked the panelists to describe some of their main CMC constriction points in developing gene therapy products, and to identify potential solutions. The other panelists were Karen Walker, the senior advisor for cell and gene therapy at Genentech, who formerly was at Novartis (NYSE: NVS) and worked on the development of Kymriah, and Michael Paglia, director of CMC for ElevateBio.

Myers said that there are two common types of roadblocks to getting gene therapy products through the development pipeline, and these are logistical and technical challenges. The logistical challenges are having a well-trained workforce, managing global distribution networks and ensuring products are transported in cold temperatures, while the technical challenges are ensuring the quality of the starting materials and scaling up production from the research site to commercial manufacturing.

Another roadblock is the lack of standards and lack of a regulatory framework for these products. Myers said that this is a new and growing field and companies are trying to lay the track as they are trying to drive the train down the track at the same time.

CONSISTENT CMC PLAYBOOK NEEDED

Myers first asked the panelists to discuss what they see as constriction points in manufacturing gene therapy products. In response, Marks said that a lack of consistent reviews is hindering their development.

It has become apparent over the last couple of months that, while we have excellent reviewers, it does happen that people can have differences of opinion. I think we will have to come around and have a clear playbook so that everyone gets the same advice especially as we have grown. I know that someone out there will say, we had two different CMC reviewers and two differences pieces of advice. I am not going to argue with that. That is an issue here. As we come to the post-COVID period we should to try to have more unity in what comes from our CMC reviews. I cannot say the problem is solved but the problem has been identified and is amenable to solutions.

He further noted that the lack of clear regulatory pathway for these products is a major roadblock in accelerating their development. We do not have the preclinical pathways set up and the clinical set up and the regulatory paradigm is yet to be fleshed out. Now is the ripe time to get things right.

Marks also noted some of the manufacturing challenges in the cell and gene therapy space: We are in a place where our current vectors are limiting what we can address in terms of our ability to product them on a very large scale, and what will probably take some years to get there. On the other hand, the piece that really interests me is how do we deal with hundreds and thousands of rare diseases that we cant address right now through the production of gene therapy products where we simply do not have the manufacturing capacity to be able to produce these products in a rapid manner because we just dont have the systems.

MORE ON WHY DEVICE-LIKE REVIEW COULD HELP

Marks expanded on an idea he had suggested in February, that reviews for gene therapies should be more aligned with the device model. (Also see Individualized Gene Therapy: US FDA Considering Device-Like Manufacturing Approval Process Pink Sheet, 28 Feb, 2020.)

It is becoming increasingly clear that for cell and gene therapies, the manufacturing is more like a device paradigm with continued innovations, he said. With a traditional drug you come up with a chemical process to make a small molecule and you are probably using the process similarly across the lifecycle, but you are not constantly finding ways to do things that fundamentally change the yield or quality of a product. Here we have issues that manufacturing changes can potentially change the product for the better.

He added that we have to find some balance here between the traditional drug manufacturing model of once and done to something that is asking you go through multiple cycles of a device every two to three years where you are changing the technology. With device cycles, you may have multiple generations of the device over years. With a device you can measure things nicely, with biologicals you cannot measure easily.

Walker concurred that these are not well-characterized products and so we need to invest heavily in analytics so that we can gain product and process understanding so that we can facilitate rapid changes that we know will not negatively impact the health of the patients.

KYMRIAH TECHNOLOGY ALREADY OUTDATED

Walker said a constriction point for her is not keeping up to date with current technologies. She said that a technology platform developed today may be outdated tomorrow. The rate of change of innovation is now every two or three years, she said.

That mirrors the rate of the device cycles that Marks mentioned, lending further credence to the idea that cell and gene therapies should be reviewed similarly.

Walker said that the technology that Kymriah has been based on has been eclipsed. It took three years for start up to approval and now no one is using the same technology as the basis for their platform. The technology and the state of the art is advancing very rapidly. This is a challenge for regulators. They need to understand we can be early adopters of these technologies without changing the product.

Kymriah was the first gene therapy product approved to treat B-cell acute lymphoblastic leukemia (ALL) and diffuse B-cell lymphoma (DLBCL). The product used spherical beads to isolate, activate and expand T-cells. After the cells are modified, they are infused back into the patient. The FDA approved the drug in August 2017 (Also see FDAs NDA And BLA Approvals: Kymriah, Vabomere, Cyltezo Pink Sheet, 1 Sep, 2017.) and the EU approved it in June 2018. (Also see First CAR T-Cell Therapies OKd In EU: Novartiss Kymriah And Kites Yescarta Pink Sheet, 29 Jun, 2018.)

Walker said there also needs to be flexibility from regulators to allow new technologies. The technology is advancing very rapidly, and that is another challenge for regulators. To understand where they can have flexibility.

AVAILABLE TALENT POOL A MAJOR CHALLENGE

Michael Paglia, senior VP of CMC operations for ElevateBio, said that his main constriction point has to do with staff and talent and supply chain and the cost of goods and quality and access to capacity.

To address the capacity challenges, the company came up with a model of funding multiple start-ups and to utilize the same R&D and manufacturing facility, rather than individual companies whose cell and gene therapy R&D is slowed by the need to build their own lab and production spaces. (Also see ElevateBio Brings Centralized Model To Cell And Gene Therapy Scrip, 13 May, 2019.)

We took the approach to build our own and to build an integrated research to support out cell and gene therapies.

The company in July 2019 announced a partnership with Massachusetts General Hospital. Under the agreement, which runs for 10 years, MGH has access to ElevateBios research, process development and manufacturing facility in Waltham, MA, for development and production of cell and gene therapies.

Paglia said that there are now more skilled employees compared to seven or 10 year ago, but that it is still challenging to find talent. We are fortunate to have experienced staff. It is necessary to put procedures in place to have rigorous training. Training is very important, and we are involved with local universities as well to give them an idea of if you come out of this how do you get into cell and gene therapy.

This article was first published in the Pink Sheet on June 18, 2020.

Image: iStock/IvelinRadkov

Joanne Serpick Eglovitch is a senior editor for Pink Sheet where she writes about manufacturing and quality issues.

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FDA Official: New "Playbook" Needed for CMC Reviews of Gene Therapy Products - Xconomy

The Gene Therapy Market Research Report 2020 published by Prophecy Market Insights is an all-inclusive business research study on the current state of the industry which analyzes innovative strategies for business growth and describes significant factors such as top developers/manufacturers, production value, key regions, and growth rate. Impact of Covid-19 pandemic on the market will be completely analyzed in this report and it will also quantify the impact of this pandemic on the market.

The research study encompasses an evaluation of the market, including growth rate, current scenario, and volume inflation prospects, based on DROT and Porters Five Forces analyses. The market study pitches light on the various factors that are projected to impact the overall market dynamics of the Gene Therapy market over the forecast period (2019-2029).

Regional Overview:

The survey report includes a vast investigation of the geographical scene of the Gene Therapy market, which is manifestly arranged into the localities. The report provides an analysis of regional market players operating in the specific market and outcomes related to the target market for more than 20 countries.

Australia, New Zealand, Rest of Asia-Pacific

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Gene TherapyMarket Key Companies:

GlaxoSmithKline plc, Bluebird Bio, Inc., Adaptimmune Therapeutics plc, Celgene Corporation, Shanghai Sunway Biotech Co. Ltd., Merck KGaA, Transgene SA, and OncoGenex Pharmaceuticals, Inc.

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The report provides an in-depth analysis of the Gene Therapy market segments and highlights the latest trending segment and major innovations in the market. In addition to this, it states the impact of these segments on the growth of the market. Apart from key players analysis provoking business-related decisions that are usually backed by prevalent market conditions, we also do substantial analysis of market based on COVID-19 impact, detailed analysis on economic, health and financial structure.

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Gene Therapy Market: Predictable To Witness Sustainable Evolution over 2020-2030 - 3rd Watch News

A Boston biotech trying to develop the first gene therapy to treat hearing loss raised $213 million Friday as it made its stock market debut, 70 percent more than the firm had projected four days ago.

Akouos sold 12.5 million shares at $17, above the original range of $14 to $16, and in line with the upsized share offering and price it filed Thursday morning. On Monday, the company said in a filing with the Securities and Exchange Commission that it hoped to raise $125 million in the initial public offering.

Shares in the company, which is listed on the Nasdaq under the symbol AKUS, closed Friday at $22, up more than 29 percent.

Akouos is the latest biotech to see higher than expected demand in the public markets despite the pandemic-related recession: the 2020 biotech IPO class is averaging a return of 80 percent, according to Renaissance Capital, a pre-IPO research provider for institutional investors.

Some analysts say COVID-19 has underscored the promise of biotechnology to address deadly health threats, generating investor enthusiasm. Among the biotechs whose market values have soared during the epidemic is Moderna, a Cambridge drug company that was the first to get an experimental coronavirus vaccine into human trials. Moderna, which went public in 2018, has a market value of more than $22 billion, though it has no approved products.

Akouos, founded in 2016, is trying to develop the first gene therapy to treat hearing loss in particular, a form of deafness caused by mutations in a single gene. Gene-based hearing loss afflicts 300,000 people in the United States each year, including more than 4,000 newborns.

Its lead candidate is a treatment for a type of genetic hearing loss that afflicts about 7,000 people. The company hopes to use a small virus called adeno-associated virus, or AAV, as a vector to deliver DNA that encodes a functioning gene in target cells. These viruses dont typically cause disease and can be customized to treat different inherited conditions.

Akouos has partnerships with Massachusetts Eye and Ear and Lonza, a Swiss multinational manufacturer that has contracts with drugmakers.

Jonathan Saltzman can be reached at jonathan.saltzman@globe.com

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Akouos raises $213m in its IPO, gains nearly 30 percent on first day of trading - BetaBoston

Base editing, a new player in the gene editing arena, could have an important role in the development of immune-based cell therapies to treat solid tumors. Using cell therapies, such as CAR-T cells, in solid tumors remains challenging: the current word on the street is that such chimeric antigen receptors (CARs) will need multiple gene modifications to make them efficient and it is in this space that base editing could have a substantial advantage.Immune-cell-based therapy is an exciting cell therapy approach to treat cancer where the natural defenses of a patients immune system are used to target and kill cancer cells. Hopes were high following the initial FDA approvals of the first autologous CAR-T therapies for Novartis KYMRIAH (Aug 2017) and Gilead/Kite Pharmas YESCARTA (Oct 2017), both for blood-based cancers, but translating these successes into solid tumors remains a challenge. This is a consequence of the complexity and heterogeneity of solid tumors together with the immune inhibitory nature of the tumor microenvironment.For T cell-based therapies to work, the patient is treated with modified T cells that are rendered capable of identifying and killing tumor cells and, through this, generating a wider immune response against the tumor. Two key approaches used to modify T cells are through expressing a T cell receptor (TCR) known to target the tumor cell or a CAR. Other approaches include using and/or modifying natural killer cells, gamma delta cells or tumor infiltrating lymphocytes. It is not clear which approach will provide the most effective treatment option and in fact it might be that each tumor type responds better to one approach or to a combination of approaches. Irrespective of the approach, it is clear that the current therapies all face similar challenges; the risk of graft vs host disease (GvHD), a lack of durable remissions, on-target or off-target toxicity and cytokine release syndrome.Another layer of complexity for T cell-based therapies lies with the source of T cellsusing the patients own (autologous T cells), or a donor or iPSC-derived T cells (allogeneic). Each approach has advantages and challenges. Briefly, autologous treatments are attractive because they mitigate the risk of immune rejection and GvHD when infused back into the patient. However, they require a complex manufacturing process that necessitates specialist equipment local to the patient to enable the isolation of their T cells followed by rapid manufacture to transform them into engineered T cells ready to infuse back into the patient. At all points during this manufacturing pipeline, the product must be kept sterile and tracible to ensure the correct cells are transfused back into the correct patient. The allogeneic T cells approach is appealing because of the possibility that these could be engineered to be universal donor cells (suitable for all or most patients). Such cells can be manufactured in bulk and administered to multiple patients all over the world. This bulk manufacturing would attract cost-savings once a critical mass of therapy is reached. It could also allow for engineered T cells to be available on-tap to any patient, a game-changer for particular patients whose own T cell count is either too low for engineering, or that transduce poorly with the engineered construct during manufacture. The challenge for allogeneic T cell therapies is the ability to generate cloaked T cells that do not provoke an immune-response in the patient, as this could kill the engineered T cells after transplantation such that they have no efficacy or potentially lead to the death of the patient as a result of a disseminated cytokine storm. Despite these challenges, in April 2019 the US Food and Drug Administration (FDA) approved the first allogeneic CAR-T for investigational use in patients with multiple myeloma and more are expected to follow.To try and achieve a stealth allogeneic T cell that flies under the radar of the patients immune system, genetic engineering is key. Although T cells can be engineered to express a specific TCR or CAR, additional genetic changes are required to provide a cloak of invisibility, prolong the survival of the cells in the patient and enable them to function in an immune suppressive tumor microenvironment. From a simplistic point of view, one could view the modified CAR or TCR as a sat nav, with the T cell being the engine. You need both to get to your destination and, if youre able to improve your engine, its possible the outcome could be achieved faster and in a more reliable fashion. There are several gene knockouts or gene knockdowns that are seen as a natural first step to improving the properties of engineered allogeneic T cells and these are summarized in the table below:As there are multiple gene knockout options, a gene engineering technology capable of making multiple gene edits with as few off-target effects as possible is needed. Indeed, it is conceivable that an effective allogeneic T cell-based therapy might require ten or more gene edits.This prompts the question What is the best gene editing platform or technology to support multiple gene edits? On the surface of it, and owing to its phenomenal adoption in research labs worldwide over the past decade, most currently use the gene editing approach provided by CRISPR-Cas9. CRISPR was first commercialized in 2012 and quite staggeringly made its debut in a clinical trial for cell therapy in June 2016. Although CRISPR is an efficient gene editing tool, its mode of action of generating double-strand breaks in the DNA could be a source of concern. DNA double-strand breaks, which tend to be repaired by the cells repair machinery in an error prone fashion, can cause unintended changes in the genome of engineered cells. Although there are methods for minimizing these off-target effects when single genes are targeted, targeting multiple genes in one cell all at the same time could lead to genome-altering insertions, deletions and/or chromosomal translocations. The impact of this on a patient could be that the cell therapy is effective but the off-target genetic changes lead to deleterious side-effects, impacting patient recovery and potentially survival. Well-known alternatives to CRISPR include transcription activator-like effector nucleases (TALENS) and zinc finger nucleases (ZFN). These approaches have slightly different safety profiles to CRISPR and while optimized for single gene edits or knockouts, multiple gene knockouts still present a challenge for these technologies. Freedom to operate using these technologies in the therapeutics space can also be challenging, particularly for start-up and biotech companies.The potential deleterious impact of off-target effects, particularly for multiple gene edits has opened the door to a newcomer on the gene engineering scene: base editing. This technology first gained prominence from peer-reviewed papers published by researchers from Harvard University.1 Others, such as Rutgers University, have also developed base editing platforms.2 In brief, base editing uses a deaminase enzyme to make a specific base pair change in the DNA. The base pair alteration can either be an A to G or a C to T depending on which deaminase is used. Importantly, the CRISPR-Cas system is used to guide the deaminase to the base pair that is going to be altered, but in this version of CRISPR-Cas, a DNA double-strand break is not made, meaning that the off-target effects with base editing in terms of insertions, deletions or translocations should be substantially reduced.On the surface, this crucial characteristic makes base editing an excellent choice of gene editor for cell therapyit can be used to specifically knock-out multiple genes through the introduction of stop codons or splice site disruptions with limited capacity to introduce substantial, large-scale chromosomal abnormalities. However, as base editing was first published in May 2016,1 substantial research is required to understand fully the utility of base editing in the therapeutic space and to appreciate its advantages and challenges compared with standard gene editing approaches, such as CRISPR-Cas, TALENs and ZFNs.As is somewhat expected of a fashionable area for scientific research, the gene editing space does not stand-still for very long: Prime editing has followed hot on the heels of base editing. Unlike base editing, which makes changes to specific base pairs in the DNA, prime editing allows changes to be made to a run of base pairs by forcing the cell to use a DNA copying system that exists naturally in cells as part of the DNA repair mechanism. Initial data suggest3 that prime editing has higher off-target effects compared with base editing, in terms of introducing insertions and deletions, and more work is needed to understand the comparison and utility of base editing vs. prime editing. It will be interesting to see how prime editing evolves over the months and years within the cell and gene therapy space.Although cell therapy has demonstrated its potential for driving complete remissions in some patients with hematological cancers, the next big step is to translate these early successes into patients with solid tumors. However, due to the complexity of solid tumors, this is not a simple or straight-forward process and multiple factors need to be considered. While the sat nav in the form of an engineered TCR or CAR is crucial, the T cell engine could be the natural starting point for improving efficacy in patients with solid tumors, as could the use of allogeneic rather than autologous approaches. The multiple edits that will be needed to deliver a stealth, engineered, allogeneic off-the-shelf T cell are only now being investigated in earnest and it could be that the new kid on the block, base editing, provides a compelling route forward.References1. Komor, A.C., Kim, Y.B., Packer, M.S., Zuris, J.A. and Liu, D.R. (2016). Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature, 533(7603), 420424. Doi:10.1038/nature179462. Horizon Discovery to provide access to novel base editing technology, January 2020;https://horizondiscovery.com/en/news/2020/Horizon-Discovery-to-provide-access-to-novel-base-editing-technology (accessed May 2020)3. Anzalone, A.V., Randolph, P.B., Davis, J.R., et al. (2019). Search-and-replace genome editing without double-strand breaks or donor DNA. Nature, 576(7785), 149157. doi:10.1038/s41586-019-1711-4Dr. Jonathan Frampton is a business development professional who has been working for Horizon Discovery for the past 9 years and currently as their Corporate Development Partner. He is always scouting for exciting novel technology that could complement Horizons already extensive gene engineering toolkit. In addition to this he works closely with Horizons partners to manage out-licensing opportunities.

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Cell Therapy For Solid Tumors - Contract Pharma

On the heels of research deals with two small biotechs, shares of Sarepta Therapeutics Inc. (NASDAQ:SRPT) hit their all-time high of more than $172 on June 23.

The share price of the Cambridge, Massachusetts-based biopharmaceutical company has doubled since mid-March. It has a market cap of more than $13 billion.

Sarepta has made a host of deals in the past several years that have made gene therapy a key part of its business, which had been dominated by drugs for muscular dystrophy. One of those pacts, with Roche (RHHBY), could be worth more than $3 billion.

Sarepta currently has a half dozen gene therapies in clinical trials, with another six waiting in the wings, according to BioPharma Dive. One of the companys compounds has shown promise in treating a type of muscular dystrophy, a genetic disease that causes weakness and wasting of the muscles in the arms and legs.

A major challenge of gene therapy is immune system reactions. Sarepta, like other developers, uses a type of virus in its therapy that, while effective, may not be able to given more than once because patients can create antibodies to it.

Thats a problem Sarepta is trying to address in its latest deals with privately held Codiak Biosciences and Selecta Biosciences Inc. (NASDAQ:SELB). In both cases, Sarepta has an option to license the biotechs' technology to develop and commercialize its therapies.

The Selecta deal focuses on gene therapies for Duchene muscular dystrophy and certain limb-girdle muscular dystrophies.

A Zion Market Research report said the global demand for the Duchenne muscular mystrophy therapeutics market was valued at approximately $2.4 billion in 2018 and is expected to grow to more than $20 billion by the end of 2025, a compound annual growth rate of more than 36% between 2019 and 2025.

Given the size of the opportunity, its no surprise Sarepta has plenty of competitors vying for a share of the business, including Pfizer Inc. (NYSE:PFE), PTC Therapeutics (NASDAQ:PTCT), FirbroGen Inc. (NASDAQ:FGEN), Roche and Bristol-Myers Squibb Co. (NYSE:BMY).

The two-year deal with Codiak gives Sarepta the right to license its technology for up to five neuromuscular diseases. If Sarepta exercises an option, Codiak will then handle research until right before the candidate goes into human testing. Sarepta will then be responsible for clinical development and commercializing the drug.

In April, the company announced it has resurrected its antiviral program in response to Covid-19. It has a therapy that is meant to block the coronavirus ability to replicate. The treatment will be tested at the U.S. Army Medical Research Institute of Infectious Diseases.

If it works, it will reduce the ability of the virus to replicate and its ability to infect other cells, Sarepta CEO Doug Ingram told Forbes. He cautioned that the drug is at an early stage.

According to CNN Money, the 21 analysts offering 12-month price forecasts for Sarepta have a median target of $192, with a high estimate of $260 and a low $152. The stock is rated a buy.

Disclosure: The author hold positions in Pfizer and Bristol-Myers Squibb.

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Sarepta Addressing Gene Therapy Issue With Two Acquisitions - GuruFocus.com

Tom Farrell didnt have much to do after Bellicum announced in January 2017 that they were bringing in a new CEO. He had led the CAR-T company for over a decade, since before Carl Junes New England Journal of Medicinepaper had made cell therapy the hottest thing in cancer research. Now he was facing an 18-month non-compete.

So he worked quickly when, not long after that clock expired in 2018, a banker who helped take Bellicum public told him about a South Korean company called Green Cross LabCell that had built a natural killer cell factory and was looking to develop therapies off it. Farrell hopped a plane to Seoul.

It was hugely impressive, Farrell told Endpoints News.There was nothing [else] I came across that was truly disruptive from a business model perspective.

A year and a half later, Farrell has his new company. Called Artiva, it launches with $78 million in Series A funding and an exclusive deal with Green Cross to push some of their natural killer cell technology into the clinic. Theyll start with a therapy that combines NKs with an approved antibody therapy like rituximab to improve the antibodys effectiveness. Behind that, theyre working on CAR-NK therapy and, longer term, gene-edited CAR-NK cells. RA Capital Management, venBio and 5AM Ventures led the round.

Artiva joins what, after many years, has recently become a booming field. In February, MD Anderson showed that a Takeda-licensed CAR-NK therapy cleared tumors completely in 7 of 11 non-Hodgkins lymphoma patients. Two months later, J&J gave Fate Therapeutics, one of the earliest biotechs in the field, an up-to $3.1 billion deal for their CAR-NK and CAR-T therapies. The Big Pharmas are joined by a slate of recent upstarts, including Celularity, Nkarta, NantKwest, and Cytovia.

Unlike the other newcomers, Artiva makes virtually no claim on having original science. In fact, Farrell said, biotechs emphasis on novel technologies is part of why cell therapy has advanced only incrementally since the approval of the first two CAR-T therapies. Industry hasnt focused enough on addressing the manufacturing issues that have made therapies so costly and difficult to scale, he said.

Lewis Lanier, an immunologist at the University of California, San Francisco and an early pioneer in NK cell research, said Artiva would still face the same questions other drug developers face will some patient reject the cells? Will the natural killer cells actually last a significant amount of time after infusion? but the collaboration could give them an edge.

The Korean Green Cross manufacturing facility is really first rate, thats where the advantage is, Lanier, who is not involved in Artiva, told Endpoints. The science is really routine, theyre not doing anything particularly innovative.

For years, NK cells have been viewed as one of the key potential ways of making off-the-shelf cell therapy. Part of the innate immune system, implanting these cells from donors doesnt lead to the same resistance that donor T cells can. One of the problems, though, is that NKs are finicky, as Lanier puts it, vastly more difficult to grow and manipulate in a lab. Only recently have a couple companies figured out ways to do it consistently. Fate, for instance, uses master lines of iPSC stem cells.

At the Green Cross facility Farrell toured two Novembers ago, the South Korean company had refined a process to derive NK cells from donated umbilical cord blood and cryo-preserve it. A week after his tour, Farrell flew to San Diego for the ASH conference, where he ran into Pete Flynn, another longtime biotech executive out of a job. Flynn had run early development for Fate in its early years before leaving to run R&D for the anti-obesity company Orexigen, which had just gone bankrupt.

Farrell explained what he saw in Seoul and the two debated different approaches to off-the-shelf therapy. They figured the manufacturing base could be a launching pad.

Even though were a Series A company, were looking to become the go-to NK cell, Flynn, now COO, told Endpoints. Basically all the pieces are in place already, whereas for some of those other companies, there might still be some work to do.

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Out of jobs, a pair of early cell therapy executives went to Seoul, came back with a new company, $70M and a plan to leapfrog natural killer...

Global Hemophilia Gene Therapy market report from Fact.MRs viewpoint

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Hemophilia Gene Therapy Market Overview on Demanding Applications 2028 - The Cloud Tribune

PARIS--(BUSINESS WIRE)--Regulatory News:

Lysogene (FR0013233475-LYS) (Paris:LYS) held its ordinary annual and extraordinary general meeting of shareholders on June 26, 2020, in closed session, which was chaired by Karen Aiach, Chairman of the Board of directors and chief executive officer, without the physical presence of the shareholders.

With a quorum of 53.64%, the shareholders have adopted all the resolutions recommended by the Board of Directors, including the financial statements for the 2019 financial year, the compensation policy applicable to the Chairman and Chief Executive Officer and the directors, as well as delegations granted to the Board of Directors related to financial transactions.

Shareholders also approved the renewal of Karen Aiach, Philippe Goupit, Peter Lichtlen, David Schilansky, Mathieu Simon and Carole Deffez as Board members.

Details on the vote results will be available on the companys website.

About LysogeneLysogene is a gene therapy company focused on the treatment of orphan diseases of the central nervous system (CNS). The company has built a unique capability to enable a safe and effective delivery of gene therapies to the CNS to treat lysosomal diseases and other genetic disorders of the CNS. A phase 2/3 clinical trial in MPS IIIA in partnership with Sarepta Therapeutics, Inc. is ongoing and a phase 1/3 clinical trial in GM1 gangliosidosis is in preparation. In accordance with the agreements signed between Lysogene and Sarepta Therapeutics, Inc., Sarepta Therapeutics, Inc. will hold exclusive commercial rights to LYS-SAF302 in the United States and markets outside Europe; and Lysogene will maintain commercial exclusivity of LYS-SAF302 in Europe. Lysogene is also collaborating with an academic partner to define the strategy of development for the treatment of Fragile X syndrome, a genetic disease related to autism. http://www.lysogene.com.

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LYSOGENE Releases the Results From June 26, 2020 Ordinary Annual and Extraordinary General Meeting - Business Wire

Axsome Therapeutics surprise win in a late-stage Alzheimers study, unveiled just two months ago, has registered with regulators. The New York-based biotech has notched a breakthrough therapy designation for AXS-05 for the indication, its second after major depressive disorder.

So whats the big deal here? The drug is an oral agent with multimodal activity consisting of two components: dextromethorphan, an NMDA receptor antagonist, and bupropion whose main purpose is to slow down the metabolism of the former.

In the pivotal Phase II/III ADVANCE-1 study, patients treated with AXS-05 saw their Cohen-Mansfield Agitation Inventory (CMAI) total score decrease in 5 weeks from baseline by 15.4 points on average, compared to 11.5 points for placebo (p=0.010). It was also superior to bupropion alone (p<0.001), proving the necessity of a combo.

The CMAI score measures some of the most visible behaviors as reported by caregivers of Alzheimers patients, including episodes of screaming or hitting.

This FDA Breakthrough Therapy designation is an important milestone in the development of AXS-05 for Alzheimers disease agitation, a serious, prevalent, and debilitating condition for which there is currently no approved therapy, CEO Herriot Tabuteau said in a statement.

Analysts tracking Axsome hadnt been paying much attention to Alzheimers agitation, focusing instead on MDD, where the company is lining up a near-term application with the FDA after reporting upbeat data in one of the toughest fields in R&D.

But after consulting with physicians, Cowen analyst Joseph Thome recently noted that the disease has historically been difficult to treat, and that the results were impressive especially given the placebo group actually performed better than expected.

We expect that AXS-05 will be successfully developed for the indication following another Ph. III study and model $750MM in peak U.S. sales, he wrote, adding to the $2 billion opportunity with MDD.

The fact that no other drug has ever been approved for the specific use, though, can be a double-edged sword. Otsukas Avanir has previously scored a Phase III win for AVP-786 deudextromethorphan hydrobromide [d6-DM]/quinidine sulfate) only to be disappointed in the second.

Axsome seems to have the FDA on its side for now. And that has investors stoked, sending shares up 11.33% to $85.29.

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Presented with upbeat Alzheimer's agitation data, FDA sees another 'breakthrough' in Axsome's AXS-05 - Endpoints News

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, announced today that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA, Mercks anti-PD-1 therapy, as monotherapy for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation. This approval is based on data from the Phase 2 KEYNOTE-629 trial, in which KEYTRUDA demonstrated meaningful efficacy and durability of response, with an objective response rate (ORR) of 34% (95% CI, 25-44), including a complete response rate of 4% and a partial response rate of 31%. Among responding patients, 69% had ongoing responses of six months or longer. After a median follow-up time of 9.5 months, the median duration of response (DOR) had not been reached (range, 2.7 to 13.1+ months).

Cutaneous squamous cell carcinoma is the second most common form of skin cancer, said Dr. Jonathan Cheng, vice president, clinical research, Merck Research Laboratories. In KEYNOTE-629, treatment with KEYTRUDA resulted in clinically meaningful and durable responses. Todays approval is great news for patients with cSCC and further demonstrates our commitment to bringing new treatment options to patients with advanced, difficult-to-treat cancers.

Immune-mediated adverse reactions, which may be severe or fatal, can occur with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation (HSCT). Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more information, see Selected Important Safety Information below.

Data Supporting Approval

The efficacy of KEYTRUDA was investigated in patients with recurrent or metastatic cSCC enrolled in KEYNOTE-629 (NCT03284424), a multi-center, multi-cohort, non-randomized, open-label trial. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. The major efficacy outcome measures were ORR and DOR as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ.

Among the 105 patients treated, 87% received one or more prior lines of therapy and 74% received prior radiation therapy. Forty-five percent of patients had locally recurrent only cSCC, 24% had metastatic only cSCC and 31% had both locally recurrent and metastatic cSCC. The study population characteristics were: median age of 72 years (range, 29 to 95); 71% age 65 or older; 76% male; 71% White; 25% race unknown; 34% Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 and 66% ECOG PS of 1.

KEYTRUDA demonstrated an ORR of 34% (95% CI, 25-44) with a complete response rate of 4% and a partial response rate of 31%. Among the 36 responding patients, 69% had ongoing responses of six months or longer. After a median follow-up time of 9.5 months, the median DOR had not been reached (range, 2.7 to 13.1+ months).

Patients received KEYTRUDA 200 mg intravenously every three weeks until documented disease progression, unacceptable toxicity or a maximum of 24 months. Patients with initial radiographic disease progression could receive additional doses of KEYTRUDA during confirmation of progression unless disease progression was symptomatic, rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Assessment of tumor status was performed every six weeks during the first year and every nine weeks during the second year.

Among the 105 patients with cSCC enrolled in KEYNOTE-629, the median duration of exposure to KEYTRUDA was 5.8 months (range, 1 day to 16.1 months). Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. Adverse reactions occurring in patients with cSCC were similar to those occurring in 2,799 patients with melanoma or non-small cell lung cancer (NSCLC) treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included lymphopenia (11%).

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,200 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [combined positive score (CPS) 10], as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3-5 in 1.5% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hepatotoxicity in Combination With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%). Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of adrenal insufficiency, hypophysitis (including hypopituitarism), thyroid function (prior to and periodically during treatment), and hyperglycemia. For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 adrenal insufficiency or hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barr syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptorblocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-002, KEYTRUDA was permanently discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). The most common adverse reactions were fatigue (43%), pruritus (28%), rash (24%), constipation (22%), nausea (22%), diarrhea (20%), and decreased appetite (20%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

Adverse reactions occurring in patients with SCLC were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (20%) were fatigue (33%), constipation (20%), and rash (20%).

In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those 1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

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FDA Approves Merck's KEYTRUDA (pembrolizumab) for the Treatment of Patients with Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma (cSCC) that...

NEW HAVEN, Conn.--(BUSINESS WIRE)--Simcha Therapeutics, a biotechnology company developing first-in-class biologic drugs that modulate powerful cytokine pathways, launched today with $25 million in Series A financing and a mission to harness the precision and power of the immune system through the use of directed evolution.

Simchas lead program involves a customized variant of interleukin-18 (IL-18), a cytokine with potent antitumor effects, developed in the lab of Scientific Founder Aaron Ring, M.D., Ph.D., Assistant Professor of Immunobiology at the Yale School of Medicine. The biology and preclinical profile of this molecule, which Simcha expects to advance to the clinic in the first half of 2021, is described in detail in a scientific paper published today in the journal Nature.

Cytokine therapies heralded the immuno-oncology revolution more than 30 years ago with the discovery that interleukin-2 (IL-2) could promote rare, but dramatic, responses in melanoma and kidney cancer patients. However, they have not lived up to their promise as a class due to substantial toxicities and limited efficacy. Simcha was founded to overcome those obstacles by using directed evolution to engineer a new generation of cytokines with improved properties relative to those of their native variants. Simchas molecules are purpose-built to control immune cell activation, differentiation and proliferation and to reverse the immunosuppressive tumor microenvironment that is a barrier to effective eradication of the cancer.

Cytokines represent a compelling therapeutic class because they tap into pathways that are hard-wired into immune cells. The challenge is that nature didnt design them to be anti-cancer therapies; theyre signaling molecules, so their activity can be hard to specifically direct, Dr. Ring said. At Simcha, we set out to improve on natures design by engineering custom-built proteins that can precisely activate and expand populations of crucial immune responders, such as natural killer (NK) cells and T cells. Too many cancer patients do not respond to the immunotherapies available today. Were hopeful that our approach will provide new options and potential benefits to these patients.

Evading a Decoy Receptor

Simchas lead asset, ST-067, activates the IL-18 receptor, triggering potent inflammatory signaling in antitumor immune cells of both the adaptive and innate branches of the immune system.

Early efforts by leading pharmaceutical companies to develop IL-18 into a drug failed. Dr. Rings lab broke new ground by identifying the reason for that failure: The tumor microenvironment is teeming with a decoy called IL-18BP, which binds IL-18 and blocks it from activating its receptor. When infused as a drug, IL-18 is drawn to the decoy and fails to reach its true target. As described in the Nature paper, the decoy receptor is a major barrier to IL-18 immunotherapy.

To overcome that barrier, Dr. Rings lab used directed evolution to create a version of the cytokine that would evade the decoy and bind only to the true IL-18 receptor. This was a difficult task, since IL-18 normally binds its decoy 10,000 times tighter than it does to the IL-18 receptor. The designer version of IL-18 made in Rings lab has dramatic alterations in its receptor binding properties, biasing binding towards the IL-18 receptor and away from the decoy by more than one million-fold. This decoy-resistant property enables the custom-built cytokine to work effectively in the immunosuppressive tumor microenvironment.

Potent Single-agent Antitumor Effects

When Rings lab tested the decoy-resistant IL-18 and compared it to natural IL-18 in mice, they found that just as in human patients natural IL-18 had little to no antitumor activity. By contrast, the decoy-resistant IL-18 had potent single-agent activity that inhibited tumor growth and even produced complete tumor regression in many animals, including in tumor types that are refractory to checkpoint inhibitors.

Rings lab also examined the effect of decoy-resistant IL-18 on the tumor microenvironment. A key finding: The engineered IL-18 acted on a crucial population of stem-like T cells within tumors, increasing their numbers over tenfold and skewing their development toward a highly active effector phenotype, as opposed to an exhausted or dysfunctional state. In checkpoint-resistant tumors, the engineered IL-18 also acted on innate NK cells, increasing their numbers and maturation to promote antitumor activity.

The mechanism of action of decoy-resistant IL-18 is unique and distinct from immunotherapeutic agents that are being developed for other pathways. For this reason, we are hopeful it could be effective in tumors that have not otherwise responded to immune-based treatments, as well as enhance the activity of standard cancer immunotherapies, said Dr. Ring.

Founders Strong Record in IO Drug Discovery

Dr. Ring has a strong track record in immuno-oncology drug discovery. He co-invented the first described CD122-biased IL-2 variant, originally detailed in Nature in 2012, which is now advancing through preclinical studies at Medicenna Therapeutics. He also developed a high-affinity SIRP antagonist, featured in Science in 2013, that is now in clinical development at ALX Oncology as ALX-148. For these and other discoveries, Ring was named to Forbes 30 under 30 list of rising stars in health care in 2016 and has been honored with an NIH Directors Early Independence Award and recognition as a Pew-Stewart Scholar in Cancer Research.

Simcha plans to build out a full executive team as the company prepares to move ST-067 into the clinic next year.

The companys investors include WuXi AppTecs Corporate Venture Fund, Sequoia Capital China and Connecticut Innovations.

About Simcha Therapeutics

Simcha Therapeutics uses directed evolution to engineer novel cytokines designed to unlock the precision and power of the immune system. Simchas lead program, ST-067, is a designer IL-18 cytokine that has shown potent antitumor effects in animal models, both as a monotherapy and when combined with anti-PD-1 checkpoint inhibitors, as described in Nature in June 2020. A Phase 1 trial is expected to be launched in the first half of 2021. Simcha was founded by Aaron Ring, M.D., Ph.D., Assistant Professor of Immunobiology at the Yale School of Medicine. The company has received $25 million in funding to date and is based in New Haven, Conn.

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Simcha Therapeutics Launches to Engineer Therapeutic Cytokines to Unlock the Full Potential of the Immune System - Business Wire

Staff and congregants should stay home and not attend service if they have any symptoms like fever, cough or shortness of breath. If you have been diagnosed with COVID-19 infection, you should not leave your home until approved by your medical provider or the health department. If you are on home quarantine for 14 days because you have been in contact with someone with COVID-19 infection, you should not attend in-person worship services.

Screening individuals before they enter place of worship will ensure that individuals who are attending worship service are currently healthy and not experiencing any COVID-19 related symptoms. Asking a few simple questions and taking the temperature of individuals entering is a great step in preventing the spread of COVID-19. Below is what should be asked prior to entering the worship facility:

Have you had close contact (within 6 feet for at least 10 minutes) in the last 14 days with someone diagnosed with COVID-19, or has any health department or health care provider been in contact with you and advised you to quarantine?

Have you experienced any of the following symptoms in the last 72 hours Fever Chills Shortness of breath or difficulty breathing New cough New loss of taste of smell

Have you been diagnosed with COVID-19?

If anyone responds yes to any of the above questions, has symptoms, or has been exposed to COVID-19 they should go home, stay away from other people, and call their doctor.

If you are a senior citizen or have an underlying health condition, you are at high risk for severe disease. Consider asking your pastor to video the service for you. This allows you to view the service from the safety of your home.

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Health department urges COVID-19 preventative measures upon returning to places of worship - Statesville Record & Landmark