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The genome-wide association study was the "largest ever study" looking into genes that could be associated with anxiety, according to Daniel Levey, a postdoctorate associate at the Yale School of Medicine and one of the authors of the study.

Levey's research group focused on 199,611 veterans in the data that had a continuous trait for anxiety based on a diagnostic scale for Generalized Anxiety Disorder.

Although anxiety is common across the human condition, Levey said "some people experience it in a way that becomes pathological."

Generalized Anxiety Disorder can manifest often in those who've experienced trauma while waging war far from home and looking at the genetic traits of veterans it affects can help the population as a whole.

They cast a wide net and came up with a few gems

Levey said having a "very large cohort is very effective" and the Veterans Affairs program is "one of the richest resources in the world" for data linking anxiety and genetics.

He noted that the veteran's data bank is valuable because of its racial diversity. Similar large-scale studies like this have been hamstrung by too many participants coming from a similar background, oftentimes only those with European ancestry.

In this most recent study, the researchers found that veterans of European descent had five genes that could be associated with anxiety.

One of the most useful findings was an association between anxiety and a gene named MAD1L1. In previous genome-wide association studies, MAD1L1 had shown indicated vulnerability to several other psychiatric conditions, including bipolar disorder and schizophrenia.

"It keeps coming up over and over again," Levey said.

They also identified a gene connected to estrogen. Levey said that potential estrogen link was important because this veteran cohort was 90% male, and that particular hormone is often associated with women.

For African Americans, the researchers identified a gene associated with intestinal functions that was potentially linked to anxiety.

"That gene variant doesn't exist outside African populations," Levey said.

The goal is to pinpoint more targeted treatments

Results like these could lead to more specific studies on each of the genes identified to determine how exactly they might be linked to anxiety and other psychological disorders. If further scrutiny of the genes reinforces the study's conclusions, that could lead to pharmaceutical research targeting how these genes operate.

Levey said he hoped that the study could lead to even more proactive outcomes, including early genetic testing to determine someone's susceptibility to anxiety. Individuals could then receive therapy to learn positive coping and stress management techniques even before symptoms began to surface, he said.

"We're making a lot of progress in genetics into what causes these conditions and how we might approach treatment," he said.

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A genetic study of 200,000 veterans with anxiety points toward potential new avenues for treatment - CNN

The fruit fly is a valuable animal model to unravel the genetic causes of both rare and more common human diseases. This Image of the Month presents work from Dr. Hugo Bellens lab showing in the fruit fly embryo the location of the protein schizo, which is involved in neural development.

In his laboratory at Baylor College of Medicine, Dr. Hugo Bellen and his colleagues investigate the mechanisms involved in neural development and function in the fruit fly, Drosophila melanogaster. In many instances, their approach includes developing new technologies to manipulate genes and creating the reagents to implement these techniques for most fruit fly genes.

As the Drosophila Core of the Model Organisms Screening Center of the Undiagnosed Diseases Network, the Bellen lab participates in the discovery of unknown human neurological diseases. They also study mechanisms of neurodegeneration associated with more common neurodegenerative conditions, such as Alzheimers disease, Parkinsons disease, Amyotrophic Lateral Sclerosis and Friedreich Ataxia.

Dr. Hugo Bellenis a professor at Baylor College of Medicine, an investigator at theHoward Hughes Medical Instituteand a member of theJan and Dan Duncan Neurological Research InstituteatTexas Childrens Hospital.

By Ana Mara Rodrguez, Ph.D.

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Image of the Month: Nervous tissue of the fruit fly embryo - Baylor College of Medicine News

Jesse Bloom, left, and Lea Starita are genetic scientists pursuing advances with the technique known as Deep Mutational Scanning, which will be the subject of a symposium and workshop at the University of Washington in Seattle on Jan. 13 and 14. (GeekWire Photo / Todd Bishop)

It has been nearly two decades since scientists accomplished the first complete sequencing of the human genome. This historic moment gave us an unprecedented view of human DNA, the genetic code that determines everything from our eye color to our chance of disease, unlocking some of the biggest mysteries of human life.

Twenty years later, despite the prevalence of genetic sequencing, considerable work remains to fulfill the promise of these advances to alleviate and cure human illness and disease.

Scientists and researchers are actually extremely good at reading genomes, but were very, very bad at understanding what were reading, said Lea Starita, co-director of Brotman Baty Institute for Precision Medicines Advanced Technology Lab, and research assistant professor in the Department of Genome Sciences at the University of Washington.

But that is changing thanks to new tools and approaches, including one called Deep Mutational Scanning. This powerful technique for determining genetic variants is generating widespread interest in the field of genetics and personalized medicine, and its the subject of a symposium and workshop on Jan. 13 and 14 at the University of Washington.

I think approaches like Deep Mutational Scanning will eventually allow us to make better countermeasures, both vaccines and drugs that will help us combat even these viruses that are changing very rapidly said Jesse Bloom, an evolutionary and computational biologist at the Fred Hutchinson Cancer Research Center, the Howard Hughes Medical Institute and the University of Washington Department of Genome Sciences.

Bloom, who researches the evolution of viruses, will deliver the keynote at the symposium, held by the Brotman Baty Institute and the Center for the Multiplex Assessment of Phenotype.

On this episode of the GeekWire Health Tech Podcast, we get a preview and a deeper understanding of Deep Mutational Scanning from Bloom and Starita.

Listen to the episode above, or subscribe in your favorite podcast app, and continue reading for an edited transcript.

Todd Bishop: Lets start with the landscape for precision medicine and personalized medicine. Can you give us a laypersons understanding of how personalized medicine differs from the medicine that most of us have encountered in our lives?

Lea Starita: One of the goals of precision medicine is to use the genomic sequence, the DNA sequence of the human in front of the doctor, to inform the best course of action that would be tailored to that person given their set of genes and the mutations within them.

TB: Some people in general might respond to certain treatments in certain ways and others might not. Today we dont know necessarily why thats the case, but personalized medicine is a quest to tailor the treatment or

Starita: To the individual. Exactly. Thats kind of personalized medicine, but you could also extend that to infectious disease to make sure that youre actually treating the pathogen that the person has, not the general pathogen, if you would. How would you say that, Jesse?

Jesse Bloom: I would elaborate on what Lea said when it comes to infectious diseases and other diseases. Not everybody gets equally sick when they are afflicted with the same underlying thing, and people tend to respond very differently to treatments. That obviously goes for genetic diseases caused by changes in our own genes like cancer, and it also happens with infectious diseases. For instance, the flu virus. Different people will get flu in the same year and some of them will get sicker than others, and thats personalized variation. Obviously wed like to be able to understand what the basis of that variation is and why some people get more sick in some years than others.

TB: Where are we today as a society, as a world, in the evolution of personalized medicine?

Starita: Pretty close to the starting line still. Theres been revolutions in DNA sequencing, for example. Weve got a thousand dollar genome, right? So were actually extremely good at reading genomes, but were very, very bad at understanding what were reading. So you could imagine youve got a human genome, its three billion base pairs times two, because youve got two copies of your genome, one from your mother, one from your father, and within that theres going to be millions of changes, little spelling mistakes all over the genome. We are right now very, very, very I cant even use enough verys bad at predicting which ones of those spelling mistakes are going to either be associated with disease or predictive of disease, even for genes where we know a lot about it. Even if that spelling mistake is in a spot in the genome we know a lot about, say breast cancer genes or something like that, we are still extraordinarily bad at understanding or predicting what effects those changes might have on health.

Bloom: In our research, were obviously also interested in how the genetics of a person influences how sick they get with an infectious disease, but we especially focus on the fact that the viruses themselves are changing a lot, as well. So theres changes in the virus as well as the fact that were all genetically different and those will interact with each other. In both cases, it really comes back to what Lea is saying is that I think weve reached the point in a lot of these fields where we can now determine the sequences of a humans genome or we can determine the sequence of a virus genome relatively easily. But its still very hard to understand what those changes mean. And so, thats really the goal of what were trying to do.

TB: What is deep mutational scanning in this context?

Lea Starita: A mutation is a change in the DNA sequence. DNA is just As, Cs, Ts and Gs. Some mutations which are called variants are harmless. You can think of a spelling mistake or a difference in spelling that wouldnt change the word, right? So the American gray, which is G-R-A-Y versus the British grey, G-R-E-Y. If you saw that in a sentence, its gray. Its the color.

But then it could be a spelling mistake that completely blows up the function of a protein, and then in that case, somebody could have a terrible genetic disease or could have an extremely high risk of cancer, or a flu virus could now be resistant to a drug or something like that, or resistant to your immune response. Or, mutations could also be beneficial, right? This is what allows evolution. This is how flu viruses of all the bacteria evolve to become drug resistant or gain some new enzymatic function that it needs to survive.

Bloom: For instance, in the case of mutations in the human genome, we know that everybody has mutations relative to the average human. Some of those mutations will have really major effects, some of them wont. The very traditional way or the way that people have first tried to understand what those mutations do is to sequence the genomes of a group of people and then compare them. Maybe here are people who got cancer and here are people who didnt get cancer and now you look to see which mutations are in the group that got cancer versus the group that didnt, and youll try to hypothesize that the mutations that are enriched in the group that did get cancer are associated with causing cancer.

This is a really powerful approach, but it comes with a shortcoming which is that theres a lot of mutations, and it gets very expensive to look across very, very large groups of people. And so the idea of a technique like deep mutational scanning is that we could simply do an experiment where we test all of the mutations on their own and we wouldnt have to do these sort of complicated population level comparisons to get at the answer. Because when youre comparing two people in the population, they tend to be different in a lot of ways, and its not a very well-controlled comparison. Whereas you can set up something in the lab where you have a gene that does have this mutation and does not have this mutation, and you can really directly see what the effect of that mutation is. Really, people have been doing that sort of experiment for many decades now. Whats new about deep mutational scanning is the idea that you can do that experiment on a lot of mutations all at once.

Starita: And its called deep because we try to make every possible spelling mistake. So every possible change in the amino acid sequence or the nucleotide sequence, which is the A, C, Ts and Gs, across the entire gene or the sequence were looking at.

Bloom: Lets say we were to compare me and Lea to figure out why one of us had some disease and other ones didnt. We could compare our genomes and theres going to be a lot of differences between them, and were not really going to know what difference is responsible. We dont even really know if it would be a change in their genomes thats responsible. It could be a change in something about our environment. So the idea behind deep mutational scanning is we would just take one gene. So in the case of Lea, she studies a particular gene thats related to breast cancer, and we would just make all of the individual changes in that gene and test what they do one by one. And then subsequently if we were to see that a mutation has some effect, if we were to then observe that mutation when we sequenced someones genome, we would have some idea of what it does.

Starita: The deep mutational scanning, the deep part is making all possible changes. We have all of that information at hand in an Excel file somewhere in the lab that says that this mutation is likely to cause damage to the function of the protein or the activity of the protein that it encodes. Making all of the possible mutations. Thats where the deep comes from.

TB: How exactly are you doing this? Is it because of advances in computer processing or is it because of a change in approach that has enabled this increase in volume of the different mutations you can look at?

Bloom: I would say that theres a number of technologies that have improved, but the really key one is the idea that the whole experiment can be done all at once. The traditional, if you were to go back a few decades way of doing an experiment like this, would be take one tube and put, lets say the normal or un-mutated gene variant in that, and then have another tube which has the mutant that you care about, and have somehow do an experiment on each of those two tubes and that works well.

But you can imagine if you had 10,000 tubes, it might start to become a little bit more difficult. And so the idea is that really the same way that people have gotten very good at sequencing all of these genomes, you can also use to make all of these measurements at once. The idea is you would now put all of different mutants together in the same tube and you would somehow set up the experiment, and this is really the crucial part of the whole thing, set up the experiment such that the cell or the virus or whatever youre looking at, how well it can grow in that tube depends on the effect of that mutation. And then you can just use the sequencing to read out how the frequencies of all of these mutations have changed. You would see that a good mutation that lets say helped the cell grow better would be more representative in the tube at the end, and a bad mutation would be less representative in the tube. And by doing this you could in principle group together tens of thousands or even hundreds of thousands or millions of mutations all at once and read it all out in one experiment.

Starita: This has been enabled by that same revolution that has given us the thousand dollar genome. These DNA sequencers that were now using, not really to sequence human genomes, but were using them as very expensive counting machines. So, were identifying the mutation and were counting it. Thats basically what were using the sequencers for. Instead of sequencing human genomes, were using them as a tool to count all of these different pieces of DNA that are in these cells.

TB: At what stage of development is deep mutational scanning?

Starita: It started about 10 years ago. The first couple of papers came out in 2009 and 2010 actually from the Genome Sciences department at University of Washington. Those started with short sequences and very simplified experiments, and we have been working over the years to build mutational scanning into better and more accurate model systems, but that are increasing the complexity of these experiments. And so weve gone from almost, Hey, thats a cute experiment you guys did, to doing impactful work that people are using in clinical genetics and things like that.

TB: When youre at a holiday party and somebody asks you what you do and then they get really into it and they ask you, Wait, what are the implications of not only personalized medicine but this deep mutational scanning? Whats this going to mean for my life?

Starita: Right now it hasnt been systematically used in the clinic, but well get phone calls from UW pathology that says, Hey, I have a patient that has this variant. We found the sequence variant and this patient has this phenotype. What does this mutation look like in your assay? And were like, Well, it looks like its damaging. And then they put all of that information together and they can actually go back to that patient and say, You are at high risk of cancer. Were going to take medical action. That has happened multiple times. Were working right now to try to figure out how to use the information that we are creating. So these maps of the effect of mutations on these very important proteins and how to systematically use them as evidence for or against their pathogenicity. Right now for a decent percentage of these people who are telling them, Well, youve got changes but we dont know what they do. We want those tests to be more informative. So you go, you get the test, they say, That is a bad one. That ones fine. That mutation is good. That ones OK. That one, though. That ones going to cause you problems. We want more people to have more informative genetic testing because right now in a decent proportion of tests come back with an I have no idea, answer.

Bloom: You can also think about mutations that affect resistance to some sort of drug. For many, many types of drugs, these include drugs against viruses, drugs against cancers and so on, the viruses and the cancers can become resistant by giving mutations that allow them to escape from that drug. In many cases there are even multiple drugs out there and you might have options of which drug to administer, but you might not really know which one. Clinicians have sort of built up lore that this drug tends to work more often or you try this one and then you try this other one, but because how well the drug works is probably in general determined by either the genetic mutations in lets say the cancer or the person or the genetic mutations in the virus or pathogen, if you knew what the effects of those mutations were ahead of time, you could make much more intelligent decisions about which drugs to administer. And there really shouldnt be a drug that works only 50 percent of the time; youre probably just not giving it in the right condition 50 perfect of the time. Wed like to be able to pick the right drug for the right condition all the time.

TB: And thats what precision medicine is about.

Starita: Yes.

TB: Deep mutational scanning as a tool.

Starita: To inform precision medicine.

Bloom: These deep mutational scanning techniques were really developed by people like Jay Shendure and Stan Fields, and Lea and Doug Fowler to look at these questions of precision medicine from the perspective of changes in our human genomes affecting our susceptibility to diseases. I actually work on mutations in a different context, which has mutations in the viruses that infect us and make us sick. These viruses evolve quite rapidly. In the case of flu virus, youre supposed to get the flu vaccine every year. The reason why you have to get it every year is the virus is always changing and we have to make the vaccine keep up with the virus. The same thing is true with drugs against viruses like flu or HIV. Sometimes the viruses will be resistant, sometimes the drugs will work. These again have to do with the very rapid genetic changes that are happening in the virus. So, were trying to use deep mutational scanning to understand how these mutations to these viruses will affect their ability to, lets say, escape someones immunity or escape a drug that might be used to treat that person.

TB: How far along are you on that path?

Bloom: Were making progress. One of the key things weve found is that the same mutation of the virus might have a different impact for different people. So we found using these approaches that the ways that you mutate a virus will allow the virus sometimes to escape from one persons immunity much better than from another persons immunity. And so were really right now trying to map out the heterogeneity across different people. And hopefully that could be used to understand what makes some people susceptible to a very specific viral strain versus other people.

TB: And so then would your research extend into the mutations in human genes in addition to the changes in the virus?

Bloom: You could imagine eventually wanting to look at all of those combinations together, and we are very interested in this, but the immediate research were focusing on right now actually probably is not so much driven by the genetics of the humans. In the case of influenza virus, like I was saying, we found that if theres a virus that has some particular mutation, it might, lets say, allow it to escape from your immunity but not allow it to escape from the immunity of me or Lea. That doesnt seem to be driven as much we think by our genetics, but rather our exposure histories. So in the case of influenza, were not born with any immunity to influenza virus. We build up that immunity over the course of our lifetime because we either get infected with flu or we get vaccinated with flu and then our body makes an immune response, which includes antibodies which block the virus. Each of us have our own personal history, not genetic history, but life history of which vaccinations and which infections weve gotten. And so, that will shape how our immune response sees the virus. As a result, we think that that doesnt really have so much of a genetic component as a historical component.

TB: Just going with the flu example, could this result in a future big picture where I go in to get my flu vaccine and its different than the one the next person might go in to get?

Bloom: What we would most like to do is use this knowledge to just design a vaccine that works for everybody. So that would just be the same vaccine that everyone could get. But its a very interesting I think at this point I would say its almost in the thought experiment stage to think about this. When you think of something like cancer, like Lea was saying, you can use these tools to understand when people have mutations that might make them at risk for a cancer, but thats actually often a very hard thing to intervene for, right? Its not so easy to prevent someone from getting cancer even if you know theyre at risk. But obviously if people are able to do that, theyre interested in spending a lot of money to do it, because cancer is a very severe thing and you often have a very long window to treat it.

Something like a flu virus is very much at the other end. If I had the omniscient capability to tell you that three days from now youre going to get infected with flu and youre going to get really sick, we could prevent that. We have the technology basically right now to prevent that, if its nothing else than just telling you to put on a bunch of Purell and dont leave your bedroom. But theres also actually some pretty good interventions including prophylactics to flu that work quite well. But the key thing is, right now we think of everyone in the world as being at risk all the time and you cant be treating everybody in the world all the time against flu. Theres just too many people and the risk that any person

Starita: Not that much Tamiflu on the market.

Bloom: Not that much, and the risk of it So I think to the extent that we could really identify whos at the most risk in any given year, that might allow us to use these interventions in a more targeted way. Thats the idea.

TB: And how does deep mutational scanning lead to that potentially?

Bloom: Yeah. So the idea, and at this point, this is really in the research phase, but the idea is if we could identify that say certain people or certain segments of the population, that because of the way their immunity, lets say, is working makes them very susceptible to the viral mutant that happens to have arisen in this particular year, we could then somehow either suggest that theyre more at risk or, as you suggested, design a vaccine thats specifically tailored to work for them. So thats the idea. I should make clear that that is not anywhere close to anybody even thinking of putting it into economic practice at this point because even the concepts behind it are really quite new. But I do think that theres a lot of potential if we think of these infectious diseases not so much as an act of God, where you just happened to someone sneezed on you as youre walking down the street, but actually a complex interaction between the mutations in the virus and your own either genetics or immune system, we can start to identify who might be more at risk for certain things in certain years, and that would at least open the door to using a lot of interventions we already have.

Starita: The first year was three years ago, and some very enthusiastic graduate students started it. Basically, it was almost like a giant lab meeting where everybody who is interested in this field came. Somebody tweeted it out and then all of a sudden people from UCSF were there and were like, What the heck? It was great and we all talked about the technology and how we were using it. The next year, the Brotman Baty Institute came in and were like, OK, well, maybe if we use some of this gift to support this, we can have a bigger meeting. And then it was 200 people in a big auditorium and that was great. And now this year, its a two-day symposium and workshop, and its also co-sponsored by a grant from the National Human Genome Research Institute. But now weve got hundreds of people, so about 200 people again, but now flying in from all over the world. Weve got invited speakers, and the workshop, which is Tuesday, is a more practical, If youre interested in this, how do you actually do these experiments?

TB: Whats driving the interest in deep mutational scanning?

Bloom: We are starting to have so much genetic information about really everything. It used to be, going back a couple of decades, a big deal to determine even the sequence of a single flu virus. It was totally unthinkable to determine the sequence of a human genome, right? If you dont know what mutations are there, you dont really care that much what they do. Now we can determine the sequence of tens of thousands of flu viruses. I mean, this is happening all the time, and we can determine the sequence of thousands, even tens of thousands of human genomes. So now it becomes, as Lea said, really important to go from just getting these sequences to understanding what the mutations that you observe in these sequences actually will mean for human health.

See this site for more on the Brotman Baty Institute for Precision Medicine and the Deep Mutational Scanning Symposium and Workshop, Jan. 13 and 14 in Seattle. The symposium is free to attend if youre in the Seattle area, and it will also be livestreamed, with archived video available afterward.

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Scientists pursue new genetic insights for health: Inside the world of deep mutational scanning - GeekWire

Doctors say digital technology and data are driving change that will create a different world of medicine in the next couple of decades, a new report from Stanford Medicine finds.

In a survey, physicians, residents and medical students say they expect almost a third of their current duties could be automated in 20 years. And doctors are preparing for that very different healthcare future now, according to the report (PDF).

Nearly half of physicians (73%) and most medical students (73%) are seeking additional training in areas such as advanced statistics, genetic counseling, population health and coding. One-third are studying artificial intelligence, according to the national survey of more than 700 physicians, residents and medical students commissioned by Stanford Medicine to understand how changing trends will reach the doctors office and shape patient care.

"We found that current and future physicians are not only open to new technologies but are actively seeking training in subjects such as data science to enhance care for their patients," saidLloyd Minor, M.D., dean of theStanford UniversitySchool of Medicine, in a statement.

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"We are encouraged by these findings and the opportunity they present to improve patient outcomes. At the same time, we must be clear-eyed about the challenges that may stymie progress, he said.

Key trends that are reshaping healthcare include a maturing digital health market, new health laws opening patient access to data and AI gaining regulatory traction for medical use.

And the jurys still out when it comes to whether the private industrys foray into healthcarein the form of companies such as Amazon, Google and Apple will solve problems.

Physicians, residents and students had mixed views about the impact these companies will have on healthcare, with 30% of students and residents and 21% of physicians still undecided. While patient outcomes are likely to improve, respondents are divided on whether physician effectiveness will improve and say physician job satisfaction will likely decrease, while healthcare costs likely increase.

Other findings include:

The value of data. The survey also showed that providers are heavy digital users and they believe patient data from wearables can be clinically valuable. Nearly half the survey respondents wear a health monitoring device, and most of them use the data to inform their personal healthcare decisions (71% of physicians, 60% of students and residents). A majority of students and residents (78%) and physicians (80%) say self-reported data from a patients health app would be clinically valuable in supporting their care. They also see value in data from consumer genetic testing reports.

Doctors arent prepared to implement innovations. However, most providers dont believe the current generation of practitioners is ready for the data-driven future, even current medical students and residents. When asked to rate the effectiveness of their education to prepare them for these developments, only 18% of current medical students and residents surveyed said that their education was very helpful. And 44% of physicians surveyed said their education was either not very helpful or not helpful at all.

The report pointed to the need to modernize curriculum and training programs so current and future physicians can make the most of new technologies.

The ongoing struggle with medical practice burdens. And, no surprise, physicians and residents say they are struggling under medical practice burdens. Nearly 1 in 5 would change their career path if given the opportunity, citing poor work-life balance and administrative burdens as the top reasons to reconsider their decision.

Originally posted here:
Physicians expect almost one-third of their jobs to be automated by 2040, Stanford Medicine report finds - FierceHealthcare

The NHS states that it will be the world-leading healthcare system in its use of cutting-edge genomic technologies to predict and diagnose inherited and acquired disease, and to personalise treatments and interventions. As all diseases are either inherited or acquired, this is no modest claim.

This approach to medical care is known as precision medicine, and given the hype that surrounds the model, you might be forgiven for thinking that the usual practice of imprecise medicine is greatly inferior. And yet it has been the routine and, in many respects, indiscriminate use of effective treatments for a range of common diseases that has improved the health of large numbers of patients over the past few decades.

Precision medicine assumes that genes play a big role in causing diseases and that new treatments targeting genes and their processes can have significant benefits. The government is so enthusiastic about this new approach that in 2019 it offered gene sequencing to the entire UK population, albeit for a fee. In announcing this initiative, Health Secretary Matt Hancock said there are huge benefits to sequencing as many genomes as we can every genome sequenced moves us a step closer to unlocking life-saving treatments.

But just how big are the benefits likely to be? How relevant is precision medicine to preventing and treating the diseases responsible for most premature deaths and hospital admissions in the UK, such as heart disease, stroke, hip fracture and dementia diseases where genetic links are not clear.

In a study of half a million participants in the UK Biobank project, 1.7 million separate gene variants were shown to be associated with heart disease. Yet in combination, these variants accounted for less than 3% of heart disease after considering known causes such as smoking and high cholesterol.

Precision medicine seems likely to offer most promise for preventing and treating less common diseases, as they are more likely to have a major genetic cause. The poster child for precision medicine is the drug trastuzumab (also known as Herceptin), which was developed following the discovery of HER2, a genetic factor implicated in about 20% of breast cancer cases.

Trastuzumab targets a specific biological mechanism that is involved in HER2 positive cancer, and treatment with this drug improves survival and reduces cancer recurrence. But the effects are not quite as remarkable as has been sometimes suggested. A meta-analysis of clinical trials reported that after ten years, 74% of patients treated with trastuzumab remained alive and recurrence-free compared with 62% of those who did not receive trastuzumab. A worthwhile effect for sure, but only for about 10-15% of patients.

Comparing these important but small gains with the impact of an imprecise approach taken to other diseases offers a stark contrast. For example, HIV used to be a death sentence. Today, 94% of people with the disease are still alive after 30 years, thanks to antiretroviral drugs. Similarly, deaths in the five-year period following a heart attack declined by 70% between 1979 and 2013, largely due to the routine use of drugs such as aspirin, ACE inhibitors and statins.

Interestingly, for both heart attacks and HIV, when efforts have been made to personalise treatment, it has generally led to worse outcomes; in large part as a consequence of doctors withholding treatments they believe may not be beneficial or could be dangerous for a particular person. Unfortunately, such clinical insights are more often wrong than right.

Its hard not to conclude that the nations health would be better served by the NHS if it aspired to be a global leader in the standardisation of care for common serious diseases. Lets not let the current enthusiasm for precision medicine blind us to the benefits of the imprecise medicine we know saves millions of lives every year.

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In defence of imprecise medicine: the benefits of routine treatments for common diseases - The Conversation UK

SOUTH SAN FRANCISCO, Calif., Jan. 10, 2020 /PRNewswire/ -- IDEAYA Biosciences, Inc. (NASDAQ:IDYA), an oncology-focused precision medicine company committed to the discovery and development of targeted therapeutics, announced that the company has entered into a Sponsored Research Agreement with Boston Children's Hospital for preclinical evaluation of the role of protein kinase C (PKC) in Sturge Weber syndrome (SWS), a rare neurocutaneous disorder characterized by capillary malformations and associated with mutations in GNAQ.

Under the agreement, IDEAYA will collaborate with and support research at Boston Children's Hospital in the laboratory of Dr. Joyce Bischoff, Ph.D., Research Associate, Department of Surgery and Professor, Harvard Medical School, who is Principal Investigator of the research studies. The preclinical research will evaluate IDE196, a potent, selective PKC inhibitor, in vitro to assess whether pharmacological inhibition of PKC in endothelial cells having GNAQ mutations will restore normal cell function, as well as in vivo to assess whether pharmacological inhibition of PKC can regulate blood vessel size in murine models that recapitulate enlarged vessels seen in SWS capillary malformations.

SWS is a rare disease characterized by a facial birthmark, neurological abnormalities (e.g. seizures) and glaucoma, which occurs in 1 to 20,000 to 50,000 live births. The disease is believed to be mediated by a somatic GNAQ mutation in skin or brain tissue which enhances signaling in the PKC pathway in a reported 88% (n=26) of SWS patients. (NEJM Shirley et al., May 2019). "SWS is a rare disease that can present debilitating symptoms for patients, such as choroidal hemangiomas which may lead to glaucoma. There are no current FDA approved treatments specifically developed for SWS highlighting the high unmet medical need for these patients," noted Dr. Bischoff, Ph.D.

IDE196 is a potent, selective, small molecule inhibitor of protein kinase C (PKC), which IDEAYA is evaluating in a Phase 1/2 basket trial in patients with Metastatic Uveal Melanoma or other solid tumors, such as cutaneous melanoma, having GNAQ or GNA11 hotspot mutations which enhance signaling in the PKC pathway. "We are excited to work with Boston Children's Hospital to evaluate IDE196 activity in preclinical models relevant to Sturge Weber, a rare disease believed to be driven by genetic mutation of GNAQ. This important work is part of our broader strategy to deliver precision medicine therapies for patients with GNAQ or GNA11 mutations, by targeting the underlying biology of the disease," said Yujiro S. Hata,Chief Executive Officer and President at IDEAYA Biosciences.

About IDEAYA Biosciences

IDEAYA is an oncology-focused precision medicine company committed to the discovery and development of targeted therapeutics for patient populations selected using molecular diagnostics. IDEAYA's approach integrates capabilities in identifying and validating translational biomarkers with small molecule drug discovery to select patient populations most likely to benefit from the targeted therapies IDEAYA is developing. IDEAYA is applying these capabilities across multiple classes of precision medicine, including direct targeting of oncogenic pathways and synthetic lethality which represents an emerging class of precision medicine targets.

Forward-Looking Statements

This press release contains forward-looking statements, including, but not limited to, statements related to IDE196 activity in preclinical models relevant to Sturge Weberand IDEAYA's ability to deliver precision medicine therapies. Such forward-looking statements involve substantial risks and uncertainties that could cause IDEAYA's preclinical and clinical development programs, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainties inherent in the drug development process, including IDEAYA's programs' early stage of development, the process of designing and conducting preclinical and clinical trials, the regulatory approval processes, the timing of regulatory filings, the challenges associated with manufacturing drug products, IDEAYA's ability to successfully establish, protect and defend its intellectual property and other matters that could affect the sufficiency of existing cash to fund operations. IDEAYA undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the business of IDEAYA in general, see IDEAYA's recent Quarterly Report on Form 10-Q filed on November 13, 2019 and any current and periodic reports filed with the U.S. Securities and Exchange Commission.

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IDEAYA Biosciences and Boston Children's Hospital Collaborate on Preclinical Evaluation of IDE196 for Sturge Weber Syndrome - a Rare Disease...

Biofidelity assay has potential to make high precision, cost-effective and non-invasive diagnosis more widely available, improving treatment and patient outcomes

Cambridge, UK, 9th January 2020 Biofidelity Ltd, a company developing high performing novel molecular assays for the detection of targeted, low-frequency genetic mutations, today announced the successful completion of a study to detect key lung cancer mutations in collaboration with Agilent Technologies, a global leader in life sciences, diagnostics, and applied chemical markets.

The collaboration, using an assay developed by Biofidelity, demonstrated an improvement in sensitivity of 50 times that achieved with current FDA-approved PCR-based diagnostics, matching that of specialized NGS assays, which require error-correction technology, while providing a dramatic simplification of workflows from more than 100 steps, to just 4 (four). Assays were performed using standard laboratory instrumentation, demonstrating the potential for straightforward adoption of Biofidelitys panels in decentralised testing laboratories around the world.

As well as extremely high sensitivity, 100% specificity was achieved in the detection of multiplexed panels of mutations from both tissue and plasma, with no false positives observed across more than 750 assays. Analysis of results is also dramatically simpler than sequencing-based assays, providing physicians a clear, simple, actionable result, with a turnaround time of less than 3 hours, making the Biofidelity assay suitable for recurrent patient monitoring.

Genetic testing for lung cancer mutations is usually carried out through invasive tissue biopsy, an expensive procedure carrying significant risk for patients with advanced disease. Up to 10% of such tests fail due to the lack of sensitivity of current testing solutions and poor sample quality.

Liquid biopsy, or testing directly from the patients blood, offers a non-invasive alternative with significant potential benefits to patients. However, its use has been limited by the lack of cost-effective, robust and rapid tests which are sufficiently sensitive to enable detection of the very small fractions of tumor DNA present in such samples.

Of the nearly 2 million new cases of non-small-cell lung cancer (NSCLC) diagnosed each year worldwide, fewer than 5% of patients receive high-sensitivity, non-invasive genetic testing. The assay developed by Biofidelity could provide a simple solution, enabling access to high-precision genetic testing for more than 1.7m new NSCLC patients every year with a test that outperforms DNA sequencing in a fraction of the time.

Work was supported by InnovateUK grant number 105202 as part of the Investment Accelerator: Innovation in Precision Medicine program.

Dr Barnaby Balmforth, Chief Executive Officer of Biofidelity, commented: Our goal is to improve patient outcomes in oncology by enabling much greater access to the highest precision diagnostic tests. This collaboration with Agilent in lung cancer has again demonstrated that Biofidelitys molecular assays dramatically increase the effectiveness and speed of diagnosis, supporting early detection of disease, better targeting of therapies and improved patient monitoring. By combining diagnostic outperformance and rapid results in a simple, cost-efficient format using existing instrumentation, we believe we have the potential to bring high precision testing to many more NSCLC patients, substantially reducing the need for invasive biopsies.

Tad Weems, Managing Director, Agilent Early Stage Partnerships, commented: As both a scientific collaborator and an investor in the company, Agilent has been impressed by the data from Biofidelitys assays, which detected a selection of NSCLC DNA mutations at extremely low frequencies in both tissue and plasma samples without the need for DNA sequencing. Biofidelitys assays are specific and sensitive, with the potential to provide improved and rapid routine cancer diagnostics.

Notes To Editors

About Biofidelity

Biofidelity has developed a molecular assay with a simple workflow and fast time-to-result which can transform the detection of genetic abnormalities within a sample by reliably detecting large panels of DNA mutations at extremely low frequencies.

This assay has a simple workflow and is suitable for routine use in diagnostics labs around the world, without the need for investment in new instrumentation or infrastructure.

Biofidelity is developing genetic panels for use in precision medicine and patient monitoring across a range of diseases including NSCLC and colorectal cancer

Located in Cambridge, UK, Biofidelity is a private company founded in 2019.

For more information, visit http://www.biofidelity.com, or follow us on LinkedIn: Biofidelity.

Issued for and on behalf of Biofidelity by Instinctif Partners.For more information please contact:

BiofidelityDr Barnaby Balmforth, CEOT: +44 1223 358652E: info@biofidelity.com

Instinctif PartnersTim Watson / Genevieve WilsonT: +44 20 7457 2020E: Biofidelity@instinctif.com

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Biofidelity and Agilent complete successful molecular assay study for rapid and accurate detection of key lung cancer mutations - BioSpace

The advent of large data sets from many sources (big data), machine learning, and artificial intelligence (AI) are poised to revolutionize asthma care on both the investigative and clinical levels, according to an article published in the Journal of Allergy and Clinical Immunology.

According to the researchers, a patient with asthma endures approximately 2190 hours of experiencing and treating or not treating their asthma symptoms. During 15-minute clinic visits, only a short amount of time is spent understanding and treating what is a complex disease, and only a fraction of the necessary data is captured in the electronic health record.

Our patients and the pace of data growth are compelling us to incorporate insights from Big Data to inform care, the researchers posit. Predictive analytics, using machine learning and artificial intelligence has revolutionized many industries, including the healthcare industry.

When used effectively, big data, in conjunction with electronic health record data, can transform the patients healthcare experience. This is especially important as healthcare continues to embrace both e-health and telehealth practices. The data resulting from these thoughtful digital health innovations can result in personalized asthma management, improve timeliness of care, and capture objective measures of treatment response.

According to the researchers, the use of machine learning algorithms and AI to predict asthma exacerbations and patterns of healthcare utilization are within both technical and clinical reach. The ability to predict who is likely to experience an asthma attack, as well as when that attack may occur, will ultimately optimize healthcare resources and personalize patient management.

The use of longitudinal birth cohort studies and multicenter collaborations like the Severe Asthma Research Program have given clinical investigators a broader understanding of the pathophysiology, natural history, phenotypes, seasonality, genetics, epigenetics, and biomarkers of the disease. Machine learning and data-driven methods have utilized this data, often in the form of large datasets, to cluster patients into genetic, molecular, and immune phenotypes. These clusters have led to work in the genomics and pharmacogenomics fields that should ultimately lead to high-fidelity exacerbation predictions and the advent of true precision medicine.

This work, the researchers noted, if translated into clinical practice can potentially link genetic traits to phenotypes that can for example predict rapid response, or non-response to medications like albuterol and steroids, or identify an individuals risk for cortisol suppression.

As with any innovation, though, challenges abound. One in particular is the siloed nature of the clinical and scientific insights about asthma that have come to light in recent years. Although data are now being generated and interpreted across various domains, researchers must still contend with a lack of data standards and disease definitions, data interoperability and sharing difficulties, and concerns about data quality and fidelity.

Machine learning and AI present their own challenges; namely, those who utilize these technologies must consider the issues of fairness, bias, privacy, and medical bioethics. Legal accountability and medical responsibility issues must also be considered as algorithms are adopted into routine practice.

We must, as clinicians and researchers, constructively transform the concern and lack of understanding many clinicians have about digital health, [machine learning], and [artificial intelligence] into educated and critical engagement, the researchers concluded. Our job is to use [machine learning and artificial intelligence] tools to understand and predict how asthma affects patients and help us make decisions at the patient and population levels to treat it better.

Reference

Messinger AI, Luo G, Deterding RR. The doctor will see you now: How machine learning and artificial intelligence can extend our understanding and treatment of asthma [published online December 25, 2019]. J Allergy Clin Immunol. doi: 10.1016/j.jaci.2019.12.898

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Machine Learning and Artificial Intelligence Are Poised to Revolutionize Asthma Care - Pulmonology Advisor

More than 250,000 participants in Pennsylvania and New Jersey have enrolled in Geisingers groundbreaking precision medicine project, MyCode. With DNA sequence and health data currently available on 145,000 of these participants, MyCode is the largest study of its kind in the world.

The program has the potential to help nearly 1,500 people who are at increased risk for potentially life-threatening conditions. Results will allow patients to work with their care providers to prevent or detect disease in its early stages, leading to better health outcomes.

Geisinger has reached a major milestone in precision health, said David H. Ledbetter, Ph.D., executive vice president and chief scientific officer for Geisinger and one of the principal investigators of the MyCode study. This number of enrolled participants speaks to the trust that our community has in Geisingers expertise and the ability we have through this project to make precision health accessible to all of our patients.

MyCode analyzes DNA samples to look for genes known to increase the risk of developing 35 specific health conditions. These include the BRCA1 and BRCA2 genes known to increase risk for breast and ovarian cancer; as well as genes for familial hypercholesterolemia, which can cause early heart attacks and strokes; Lynch syndrome, which can cause early colon, uterine and other cancers; and several heart conditions, including cardiomyopathy and arrythmia.

The project has also identified several genes that can contribute to the development of cognitive disorders. While not always medically actionable, these results can provide valuable information to patients about probable genetic causes for neuropsychiatric conditions like epilepsy, bipolar disorder and depression, as well as learning disabilities and other similar conditions.

There are a lot of genes that have medical actionability, like finding a change in a gene that causes breast cancer and doing more frequent mammograms as a result, said Christa Martin, Ph.D., associate chief scientific officer and one of the principal investigators of the MyCode study. But there are other ones that might not be medically actionable but could have important implications to patients. So, one of our research projects is exploring reporting information back to individuals who have certain brain conditions.

When given the option to receive test results that included genetic changes that could explain their brain condition, more than 90 percent of patients responded in favor of receiving the results. The majority found the information personally useful to explain medical diagnoses they had been dealing with most of their lives.

Giving these patients a unifying medical explanation for their multiple, apparently unrelated learning, behavioral and psychiatric conditions had a powerful impact on these patients and their family members, Dr. Ledbetter said.

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DNA project will aid in early disease detection - Reading Eagle

The U.S. Food and Drug Administration (FDA) has approved avapritinib (Ayvakit; Blueprint Medicines, previously known as BLU-285) for the treatment adults patients with unresectable or metastatic gastrointestinal stromal tumor (GIST), a type of tumor that occurs in the gastrointestinal tract, most commonly in the stomach or small intestine, harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation.

The approval includes GIST that harbors a PDGFRA D842V mutation, which is the most common exon 18 mutation. Avapritinib is a kinase inhibitor, meaning it blocks a type of enzyme called a kinase and helps keeps the cancer cells from growing.

Each year, approximately 5,000 new cases of GIST are diagnosed in the United States. However, GISTs may be more common because small tumors, without clear signs or symptoms, often remain undiagnosed.

CauseGastrointestinal stromal tumors are caused by genetic changes in one of several genes

About 80% of cases are associated with a mutation in the KIT gene, and about 10 percent of cases are associated with a mutation in the PDGFRA gene. Mutations in the KIT and PDGFRA genes are associated with both familial and sporadic GISTs. A small number of affected individuals have mutations in other genes.

GISTs arise from specialized nerve cells found in the walls of the gastrointestinal tract. One or more mutations in the DNA of one of these cells may lead to the development of GIST. These cells aid in the movement of food through the intestines and control various digestive processes.

More than half of GISTs start in the stomach. Most of the others start in the small intestine, but GISTs can start anywhere along the gastrointestinal tract. The activating mutations in PDGFRA have been linked to the development of GISTs, and up to approximately 10% of GIST cases involve mutations of this gene.

Response to PDGFRAGIST harboring a PDGFRA exon 18 mutation do not respond to standard therapies for GIST. However, todays approval provides patients with the first drug specifically approved for GIST harboring this mutation, noted Richard Pazdur, M.D., director of the FDAs Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDAs Center for Drug Evaluation and Research.

Clinical trials showed a high response rate with almost 85% of patients experiencing tumor shrinkage with this targeted drug, Pazdur added.

ApprovalThe FDA approved avapritinib based on the results of a clinical trial involving 43 patients with GIST harboring a PDGFRA exon 18 mutation, including 38 patients with PDGFRA D842V mutation.

In this trial, patients received avapritinib 300 mg or 400 mg orally once daily until disease progression or they experienced unacceptable toxicity. The recommended dose was determined to be 300 mg once daily.

The trial measured how many patients experienced complete or partial shrinkage of their tumors during treatment, referred to as overall response rate or ORR. For patients harboring a PDGFRA exon 18 mutation, the overall response rate was 84%, with 7% having a complete response (CR) and 77% having a partial response (PR).

For the subgroup of patients with PDGFRA D842V mutations, the overall response rate was 89%, with 8% having a complete response and 82% having a partial response. While the median duration of response was not reached, 61% of the responding patients with exon 18 mutations had a response lasting six months or longer (31% of patients with an ongoing response were followed for less than six months).

The full approval of [avapritinib] is based on robust data from our Phase I NAVIGATOR study. This is an incredibly exciting milestone for our company and, more importantly, for GIST patients with a PDGFRA exon 18 mutation, who have been waiting for a new treatment option, explained Jeff Albers, Chief Executive Officer at Blueprint Medicines.

[Avapritinib] is the first of what we hope will be many approved medicines enabled by our research platform. Now, as we begin to deliver [avapritinib] to patients and their healthcare providers, we aim to fortify our leadership in the field of precision medicine and build a foundation for our broader portfolio by pairing our strong research and development capabilities with an equally talented commercial organization focused on addressing patient needs, accelerating diagnostic testing and enabling access, Albers added.

Adverse eventsCommon side effects for patients taking avapritinib were edema (swelling), nausea, fatigue/asthenia (abnormal physical weakness or lack of energy), cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation (secretion of tears), abdominal pain, constipation, rash and dizziness.

Avapritinib can cause intracranial hemorrhage (bleeding that occurs inside the skull) in which case the dose should be reduced, or the drug should be discontinued. The newly approved agent can also cause central nervous system effects including cognitive impairment, dizziness, sleep disorders, mood disorders, speech disorders and hallucinations.

If this happens, the highlights of prescription information specifies that, depending on the severity, the drug should be withheld and then resumed at the same or reduced dose upon improvement or permanently discontinued.

Breakthrough TherapyThe FDA granted this application Breakthrough Therapy designation, which expedites the development and review of drugs that are intended to treat a serious condition, when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies.

Avapritinib was also granted Fast Track designation, which expedites the review of drugs to treat serious conditions and fill an unmet medical need. Avapritinib received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

New Drug ApplicationAs part of the approval process, the FDA administratively split the proposed indications for avapritinib under the initial New Drug Application (NDA) into two separate NDAs. These NDAs include one for the indication for PDGFRA exon 18 mutant GIST, and one for fourth-line GIST.

The Prescription Drug User Fee Act (PDUFA) action date for the fourth-line GIST indication is currently February 14, 2020. For the NDA for fourth-line GIST an extension of up to three months for the PDUFA action date will likely be required to enable Blueprint Medicines to provide top-line data to the FDA from VOYAGER, a Phase III clinical trial evaluating avapritinib versus regorafenib (Stivarga; Bayer) in third- or fourth-line GIST.

Ongoing studiesIn addition to the approved indication in GIST, Blueprint Medicines is investigating avapritinib in the treatment of acute myeloid leukemia and systemic mastocytosis and systemic mastocytosis with an associated hematologic neoplasm and mast cell leukemia.[1]

These studies are based on the understanding that mutations in two type-3 receptor tyrosine kinases, KIT and FLT3, are common in acute myeloid leukemia and systemic mastocytosis, leading to hyperactivation of key signalling pathways. [1]

Based on the structural similarity between FLT3 and KIT, researchers have found that tyrosine kinase inhibitors targeting either FLT3 or KIT offer significant clinical benefit. [1]

These benefits have been shown in the ongoing PIONEER study, a multicenter, randomized, double-blind, placebo-controlled, phase II study in patients with indolent or smoldering systemic mastocytosis whose symptoms are not adequately controlled by best supportive care. These patients typically have a single driver gain-of-function KIT mutation making them promising candidates for KIT D816V inhibitor therapy, including avapritinib.

Avapritinib is now being studies to help identify the recommended phase II dose (RP2D) in indolent systemic mastocytosis and to investigate efficacy of avapritinib vs. placebo in patients with indolent and smoldering systemic mastocytosis.

Clinical trialsStudy of BLU-285 in Patients With Gastrointestinal Stromal Tumors (GIST) and Other Relapsed and Refractory Solid Tumors (NAVIGATOR) NCT02508532Study of Avapritinib vs Regorafenib in Patients With Locally Advanced Unresectable or Metastatic GIST (VOYAGER) NCT03465722Early Access Program (EAP) for Avapritinib in Patients With Locally Advanced Unresectable or Metastatic GIST NCT03862885Study to Evaluate Efficacy and Safety of Avapritinib (BLU-285), A Selective KIT Mutation-targeted Tyrosine Kinase Inhibitor, in Patients With Advanced Systemic Mastocytosis (PATHFINDER) NCT03580655Study to Evaluate Efficacy and Safety of Avapritinib (BLU-285), A Selective KIT Mutation-targeted Tyrosine Kinase Inhibitor, Versus Placebo in Patients With Indolent and Smoldering Systemic Mastocytosis (PIONEER) NCT03731260

Reference[1] Weisberg E, Meng C, Case AE, et al. Comparison of effects of midostaurin, crenolanib, quizartinib, gilteritinib, sorafenib and BLU-285 on oncogenic mutants of KIT, CBL and FLT3 in haematological malignancies. Br J Haematol. 2019;187(4):488501. doi:10.1111/bjh.16092

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First Targeted Therapy Approved for Rare Mutation of Gastrointestinal Stromal Tumors - OncoZine

As a doctor of Chinese medicine, I'm always looking for ways to get toxins out of my life. Whether it be skin care products, clean eating, or plastics, health is affected by lifestyle behaviors. And, in our current society, we are exposed to an unhealthy amount of chemicals throughout our lifetime, and I believe that they eventually take a toll on our body.

Nutrigenomics is a facet of epigenetics that integrates genomic science with nutrition and other environmental factors such as cigarette smoking, alcohol consumption, and exercise. Each of us carries a blueprint, if you will, within our genetic code, that signals our body to express genetic variations. This means that by studying your individual genetic code, you can help your body minimize unfavorable genetic expressions, like chronic disease.

Even though our genes are fundamental for determining expression and function, what we put in our mouth directly affects the extent to which certain genes are expressed.

This gives an individual a certain power over their genetic expression. But first, you must understand your genes and epigenetics.

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Are You Doing The Wrong Detox For Your Genes? Plus, Foods & Habits To Use - mindbodygreen.com

According to Barringer, rigid hereditary determinism predetermined the absolute limit of African Americans biological and social advancement. He argued that with emancipation came reversion of African Americans to savage status, creating a new, degenerate black generation that could not possibly survive in contact with civilized white society.

Barringer believed that under the conditions of slavery, blacks had advanced beyond their natural selection through selective breeding by slave owners. With emancipation came reversion of African Americans to their original savage nature, which put them on a path toward extinction, accelerated by an irrational procreation which further exacerbated their genetic inferiority and susceptibility to disease and criminality.4

The drastically high incidence of tuberculosis, syphilis and typhoid fever among African Americans (locally and in cities around the country) indicated nothing to Barringer about overcrowded housing or lack of clean water, sanitation or safe meats and pasteurized milk. Instead the high morbidity and mortality rates of African Americans proved the genetic unfitness of a markedly criminal race. Without white intervention, Barringer condemned blacks to a life of barbarism and death. To Barringer, the Negro Problem was more than a political problem; it was a huge public health threat to whites.

Barringers tripartite solution to the Negro Problem was political disfranchisement, transferring responsibility for African American education from black to white teachers, and training blacks to be law-abiding laborers and artisans. As he wrote, Every Negro doctor, lawyer, teacher or other leader in excess of the immediate needs of his own people is an antisocial produce, a social menace.5

Eugenics flourished under the leadership of President Edwin Alderman (1903-27) as he set out to build the research base of the University with recruitment of leading men of eugenic science into schools across Grounds: These included Harvey Jordan, Robert Bean and Lawrence Royster in the medical school; George Ferguson in education; Orlando White as director of UVAs biological station; and Ivey Lewis as chair of biology.

Together these faculty created eugenics research and education programs at UVA and throughout the state, and in doing so, trained UVA students as well as high school and college teachers in eugenic racism. They also collaborated with nationally renowned eugenics investigators, and presented their work at international eugenics meetings. Fully immersed in race science, these men contributed directly and indirectly to ethically contemptuous laws and policies designed to maintain a culture of white supremacy, and exclusionary white privilege.

Jordan, a professor of embryology, genetics and histology, was one of Aldermans early recruits. Joining the faculty in 1907, he served as dean of the medical school from 1939 to 1949. Believing that blacks inherited a susceptibility to contracting diseases such as syphilis and tuberculosis, Jordan called for compulsory registration of all who were ill. He argued that proposed eugenic marriage, segregation and sterilization laws, were public and racial health measures that should form part of the health code, to be administered under the State Police powers.6 The promise of eugenics as a solution to societys ills, and the power of physicians in solving such problems was best summed up when Jordan declared at the 1st International Congress of Eugenics in 1912 that the future physician must also take a more active part in helping to shape legislation in the interest of race welfare.7

Chair of Anatomy Dr. Robert Bean argued that the physical features of African Americans confirmed their inferiority when compared to whites. Furthermore, he advanced human types that represent different degrees of susceptibility of disease may be segregated and given differential treatment.8 Through medical school core courses, Jordan and Bean, combined, taught about 20% of the medical school curriculum.

Along similar lines, George Oscar Ferguson, a professor in the education school, in his use of intelligence testing among blacks, mixed-race and white children concluded, It does not seem possible to raise the scholastic attainment of the Negro to an equality with that of the white. [N]o expenditure of time or money would accomplish this end, since education cannot create mental power, but can only develop that which is innate.9

Eugenics began to shape public policy nationally as early as 1907, when Indiana passed a sterilization law. Two Virginia eugenics laws, both passed in 1924, had a profound impact in the commonwealth and throughout the country. The Virginia Sterilization Act and the Racial Integrity Act not only legalized sterilization of the mentally ill and persons of low literacy, but also cemented discrimination against marginalized and vulnerable populations, including African Americans. These laws codified Jim Crow into every aspect of community life, and in doing so, denied African Americans access to medical care, jobs and fair wages, as well as higher education and professional training. Simply put, eugenic laws created the one drop rule, where one drop of African American blood restricted a person of color to life behind the veil.10

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UVA and the History of Race: Eugenics, the Racial Integrity Act, Health Disparities - UVA Today

(Mainichi)

Some iPS cells for regenerative medicine, distributed by a stock project at Kyoto University's Center for iPS Cell Research and Application (CiRA), showed cancer-related genetic and chromosomal abnormalities when differentiated to the target cells, several sources close to the project revealed.

Some of the iPS cells, even those produced at the same time, showed various abnormalities while others did not, depending on the research institution they were distributed to, prompting experts to voice concerns over their safety. The CiRA has acknowledged the facts, and the cells that developed abnormalities were not used in patients.

The project stockpiles iPS cells provided by the same suppliers at the same time in a cell line. In clinical research and a trial, iPS cells and differentiated cells go through genome analysis, and are transplanted into mice to check whether they turn cancerous. It is then decided which cell line should be distributed to implementing agencies.

Of the 27 cell lines distributed since August 2015, test results were revealed for four. Of these, abnormalities were found in two cell lines. The two cell lines were distributed in several containers to two research institutions, respectively, and were differentiated to the same target cells at each institution.

For one of the cell lines, one institution found a genetic abnormality in relation to cancer, while the other found a numerical disorder in the chromosome. For the other cell line, one institution found a different genetic abnormality, while the other institution did not find any irregularities. Furthermore, the institution that found the abnormality did not find any problems in the cells kept in a different container.s

Genetic abnormalities included a high-risk abnormality, similar to those found in humans with cancer. When implanted in mice, abnormal tissue growth that cannot be seen with normal cells was confirmed.

"No matter what kind of cell, an error could occur during the process of cultivation and differentiation," said specially appointed professor and manufacturing supervisor Masayoshi Tsukahara of the iPS cell stock project. He explained, "There's no other choice but to conduct careful tests before putting them to use."

Several experts in Japan, however, expressed concerns that safety cannot be ensured if test results vary depending on containers.

Michael Snyder, professor at Stanford University's School of Medicine and the director of the Center for Genomics and Personalized Medicine, pointed to the need to evaluate the matter in an open discussion.

(Japanese original by Momoko Suda, Science & Environment News Department)

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Kyoto Univ.-distributed iPS cells found with abnormalities after differentiation - The Mainichi

Puzzling injury: Some children who carry variants in a gene called ZNF292 have injured blood vessels in their brains.

Mutations in a gene called ZNF292 lead to a variety of developmental conditions, including autism and intellectual disability, according to a new study1.

ZNF292 encodes a protein that influences the expression of other genes. It is highly expressed in the developing human brain, particularly in the cerebellum, an area that controls voluntary movement and contributes to cognition. However, its function in neurodevelopment is unknown.

Scientists first linked ZNF292 to intellectual disability in a 2012 study. A 2018 analysis of five ZNF292 variants tied the gene to autism, but the work was preliminary2.

In the new study, researchers identified 28 people who have mutations in ZNF292. The participants come from six countries and are between 10 months and 24 years old. The group carries a total of 24 mutations in the gene, 23 of which are spontaneous meaning that they were not inherited from a parent.

The sheer number of families and children that have been identified so far has been quite high, says Ghayda Mirzaa, lead investigator and assistant professor of genetic medicine at Seattle Childrens Hospital in Washington.

All but one of the participants have intellectual disability. In total, 17 of the participants are suspected or confirmed to have autism and 9 are suspected or confirmed to have attention deficit hyperactivity disorder. All but two have speech delays, and four have had language regression or are minimally verbal.

Mirzaas team found an additional 15 people with mutations in the gene from 12 families. However, the data from these people were incomplete, so the researchers had to exclude them from the analysis. The team has connected with at least 10 other mutation carriers in the six weeks since the study was published in Genetics in Medicine.

The researchers have used their data to classify a new condition. However, it may be premature to call it a syndromic form of autism or intellectual disability, says Holly Stessman, assistant professor of pharmacology and neuroscience at Creighton University in Omaha, Nebraska, who was not involved in the work.

People with ZNF292 variants have a broad spectrum of physical traits. For instance, 11 of the people in the study have growth abnormalities such as short stature; 10 have low muscle tone; and 3 have stiff or mixed muscle tone. The researchers had access to magnetic resonance imaging scans for 17 of the participants: 9 show brain abnormalities such as atypically shaped regions, and 3 of those 9 appear to have blood-vessel injuries in the brain.

Nearly half of the participants also have unusual facial characteristics, including an undersized jaw or eyes that are unusually far apart. Vision problems, such as involuntary eye movement or crossed eyes, affect nine people in the group. Less common facial differences include prominent incisors and protruding ears.

Autism genes are often linked to a wide range of characteristics, says Santhosh Girirajan, associate professor of biochemistry and molecular biology at Pennsylvania State University, who was not involved in the study. Variability has become the rule now, rather than the exception, he says.

Mirzaa says her group plans to study more individuals with variants in ZNF292, and to investigate the genes function.

Link:
Study ties gene active in developing brain to autism - Spectrum

Cancer has been the leading cause of death in Japan since 1981 and this is compounded by the fact that the country has a hyper-aging society, which means that Japan will face a substantial increase in the number of elderly cancer patients, according to a review article by Matsuda and Saika published in the Annals of Cancer Epidemiology in 2018. Prof Yasushi Goto of the National Cancer Center Hospital in Japan shared with MobiHealthNews on some of the latest developments in precision oncology in Japan, the interest of pharmaceutical companies in targeted therapy and a nationwide cancer genome screening project named SCRUM.

Q. Could you tell us more about your role at the National Cancer Center Hospital?

A. National Cancer Center Hospital (NCCH) is based in Tokyo, Japan and is the largest cancer center in the country. The other is national cancer center is located in Chiba, Japan. One of the special characteristics of NCCH apart from the research institute hospital, is that we also do research for every kind of cancer activity in our hospital. We dont only do clinics, but also genetic oncology, rare cancers.

My main work is at thoracic oncology which mainly covers lung cancer. I also am a member of Rare Cancer Center so I also cover, malignant mesothelioma, thymic cancer, neuroendocrine tumors, and all others. Since Japan has launched national genomic project, and National Cancer Center is playing the central role in this project, I am also joining Section of Knowledge Integration in Center for Cancer Genomics and Advanced Therapeutics.

Q. What are your observations on the development of precision oncology in the APAC region? How would you describe precision oncology in the most straightforward manner?

A. Testing for patients with cancer is prevalent in the APAC region. Compared to other countries, people in Asia are generally accustomed to genetic testing for precision medicine. Our capabilities may not be as advanced as the United States for full gene sequencing, perhaps because of cost issues, but we are catching up.

For precision oncology to develop further, more patients should be tested for genetic testing and target therapy. We are looking to putting in place a proper system to support this right now, especially in the rare cancer field.

There was a recent nationwide project in Japan called SCRUM, conducted by the National Cancer Center East Hospital. SCRUM is the first industry-academia collaboration nationwide cancer genome screening project. I believe early access to drugs is partly due to this project.

Q. Medtech or healthtech startups are also getting into the precision medicine space and seeing a lot of interest from investors. For instance, genomic medicine startup Lucence from Singapore recently raised $20 million in Series A funding. What opportunities do you see in these startups in terms of working together with hospitals such as the National Cancer Centre Hospital? Are there any notable startups in Japan in the precision medicine space?

A. In Japan, many pharmaceutical companies are looking at targeted therapy. Prominent companies include Daichi-Sankyo, Chugai, and Takeda. NCCH is currently working closely with Daichi-Sankyo, Takeda and Chugai.

The approval system is different between blockbuster drugs and targeted therapy. If you only have one patient in Japan and globally there are only 20 or so there can be a scenario where the drug is effective, but it is not approved in our country as there is only a single patient. This is why some pharmaceutical companies are looking at precision medicine.

Companies including Sysmex are also actively looking into the testing of panel sequencing. NCCH has also worked with Sysmex to make a cancer sequencing panel.

Q. The high incidence of cancer in modern societies is worrying and also very costly how do you think precision oncology can help tackle some of these challenges?

A. Cost is a global issue, for both the development side (e.g. the pharmaceutical companies) and the consumption side (e.g. governments, individuals). We also need some basic infrastructure for precision oncology, to screen patients. Currently each drug needs its own testing. With many drugs that need to be tested, we need a platform to do panel sequencing in order to annotate any genetic changes in the patients for treatment.

In Japan, we are now trying to make this infrastructure because the government recently approved the panel sequencing in 2019. This means that after standard therapy, every patient is able to test for panel sequencing. As more patients are screened, in this way I think cancer treatment will be improved in the future.

Q. What do you think will be the key developments and breakthroughs in precision oncology in the next 3-5 years?

A. There will be no blockbuster development, but there will be steady progress in the detecting genetic changes earlier in the next 3-5 years. Some of the topics at the ESMO Asia Congress 2019 in Singapore were on advancements in detecting mutations/previously overlooked genes. Since we are able to find these abnormalities earlier, we now have new anti-cancer agents to target them.

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Insights on precision oncology developments in Japan and beyond - MobiHealthNews

Astellas Pharma recentlyagreed to acquire Audentes Therapeutics, a move it expects will result in faster development of potentially best-in-class therapies for rare neuromuscular diseases, including muscular dystrophy (MD).

Audentes vectorized exon-skipping technology which uses a modified adeno-associated virus (AAV) vector to allow cells to skip over mutated sections of genes will complement Astellas own work, Kenji Yasukawa, president and CEO of Astellas, said in a press release.

Recent scientific and technological advances in genetic medicine have advanced the potential to deliver unprecedented and sustained value to patients, and even to curing diseases with a single intervention, Yasukawa said.

Audentes has developed a robust pipeline of promising product candidates which are complementary to our existing pipeline, including its lead program AT132, he added. By joining together with Audentes talented team, we are establishing a leading position in the field of gene therapy with the goal of addressing the unmet needs of patients living with serious, rare diseases.

The technology uses the modified AAV vector to deliver small molecules antisense oligonucleotides complementary to the RNA sequence of a gene of interest, which allow cells to skip over mutated exons while they are producing proteins.

Exons are the coding regions of genes that provide instructions to make proteins.

Audentes had started developing several therapies for Duchenne muscular dystrophy (DMD) based on its exon-skipping technology. These include AT702, AT751 and AT753.

All three treatment candidates use the same AAV delivery vector. However, as they target different DMD gene exons, the potential therapies are intended for distinct subgroups of patients. AT702 is designed to skip exon 2 and is meant for those who either have duplications in exon 2 or mutations in exons 1-5. AT751 is designed for those with mutations in exon 51, and AT753 for people with alterations in exon 53.

Audentes had also started developing and testing AT466, an experimental treatment for myotonic dystrophy type 1.

The acquisition also gives Astellas direct access to AT132, Audentes lead gene therapy candidate for the treatment ofX-linked myotubular myopathy.

AT132 uses an AAV8 viral vector to deliver a functional copy of the MTM1 gene to muscle cells. This enables the production of myotubularin, an important enzyme for the development and maintenance of muscle cells.

Matthew R. Patterson, chairman and CEO of Audentes, said his company is very pleased with the agreement. With its focus on innovative science and a global network of research, development and commercialization resources, we believe that operating as part of the Astellas organization optimally positions us to advance our pipeline programs and serve our patients, he said.

Under the terms of the agreement, Audentes will become an independent subsidiary of Astellas and will have access to scientific resources to accelerate the development and manufacturing of the combined product pipeline. The transaction, worth $3 billion, is expected to take place early this year.

Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells cells that make up the lining of blood vessels found in the umbilical cord of newborns.

Total Posts: 42

Jos is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimers disease.

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New MD Treatments the Main Goal of Astellas, Audentes Merger - Muscular Dystrophy News

SALT LAKE CITY, Jan. 06, 2020 (GLOBE NEWSWIRE) -- Myriad Genetics, Inc. (NASDAQ: MYGN, Myriad or the Company), a global leader in molecular diagnostics and precision medicine, announced that a new analysis of the GUIDED1 clinical trial using the 6-item Hamilton Depression Rating Scale (HAM-D6) was published online in BMC Psychiatry. The key finding is the HAM-D6 scale identified statistically significant improvements in all three clinical endpoints remission, response and symptoms between GeneSight-guided care and treatment-as-usual at Week 8 (Figure 1).

The HAM-D6 scale has been shown to be a better measure of core depressive symptoms than the HAM-D17 scale, said Boadie W. Dunlop, M.D., one of the study investigators and associate professor of Psychiatry and Behavioral Sciences at Emory University School of Medicine. This post hoc analysis provides further evidence that the GeneSight test led to significant and clinically meaningful improvements in clinical outcomes for patients with major depressive disorder relative to treatment-as-usual care.

To view Figure 1: GeneSight Test Significantly Improved Clinical Outcomes by Week 8 (HAM-D6), please visit the following link: https://www.globenewswire.com/NewsRoom/AttachmentNg/980daabb-fd8c-4bbb-b56e-48795fa16bdb

The GUIDED study was the largest prospective study to assess the benefit of pharmacogenomics-guided treatment for depression using the GeneSight Psychotropic test versus an active therapy control arm. All patients in the GUIDED study had the 17-item HAM-D17 questionnaire administered by blinded off-site raters as part of the study protocol. The 6-item HAM-D6 score represents a subset of HAM-D17 questions that have been shown to be more directly linked to depression. For example, questions such as have you had trouble sleeping which could be associated with conditions other than depression are excluded from the HAM-D6 score. Clinical studies have shown that the HAM-D6 score is superior to HAM-D17 at discriminating antidepressants from placebo.

About GeneSight PsychotropicGeneSight Psychotropic is a pharmacogenomic test that analyzes clinically important variations in DNA. The results of the test can inform doctors about genes that may impact how their patients metabolize or respond to depression medications.

About Myriad GeneticsMyriad Genetics Inc., is a leading precision medicine company dedicated to being a trusted advisor transforming patient lives worldwide with pioneering molecular diagnostics. Myriad discovers and commercializes molecular diagnostic tests that: determine the risk of developing disease, accurately diagnose disease, assess the risk of disease progression, and guide treatment decisions across six major medical specialties where molecular diagnostics can significantly improve patient care and lower healthcare costs. Myriad is focused on five critical success factors: building upon a solid hereditary cancer foundation, growing new product volume, expanding reimbursement coverage for new products, increasing RNA kit revenue internationally and improving profitability with Elevate 2020. For more information on how Myriad is making a difference, please visit the Companys website: http://www.myriad.com.

Myriad, the Myriad logo, BART, BRACAnalysis, Colaris, Colaris AP, myPath, myRisk, Myriad myRisk, myRisk Hereditary Cancer, myChoice, myPlan, BRACAnalysis CDx, Tumor BRACAnalysis CDx, myChoice CDx, EndoPredict, Vectra, GeneSight, riskScore, Prolaris, ForeSight and Prequel are trademarks or registered trademarks of Myriad Genetics, Inc. or its wholly owned subsidiaries in the United States and foreign countries. MYGN-F, MYGN-G.

Safe Harbor StatementThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to a new analysis of the GUIDED clinical trial published online in BMC Psychiatry; and the Companys strategic directives under the caption About Myriad Genetics. These forward-looking statements are based on managements current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by forward-looking statements. These risks and uncertainties include, but are not limited to: the risk that sales and profit margins of our molecular diagnostic tests and pharmaceutical and clinical services may decline; risks related to our ability to transition from our existing product portfolio to our new tests, including unexpected costs and delays; risks related to decisions or changes in governmental or private insurers reimbursement levels for our tests or our ability to obtain reimbursement for our new tests at comparable levels to our existing tests; risks related to increased competition and the development of new competing tests and services; the risk that we may be unable to develop or achieve commercial success for additional molecular diagnostic tests and pharmaceutical and clinical services in a timely manner, or at all; the risk that we may not successfully develop new markets for our molecular diagnostic tests and pharmaceutical and clinical services, including our ability to successfully generate revenue outside the United States; the risk that licenses to the technology underlying our molecular diagnostic tests and pharmaceutical and clinical services and any future tests and services are terminated or cannot be maintained on satisfactory terms; risks related to delays or other problems with operating our laboratory testing facilities and our healthcare clinic; risks related to public concern over genetic testing in general or our tests in particular; risks related to regulatory requirements or enforcement in the United States and foreign countries and changes in the structure of the healthcare system or healthcare payment systems; risks related to our ability to obtain new corporate collaborations or licenses and acquire new technologies or businesses on satisfactory terms, if at all; risks related to our ability to successfully integrate and derive benefits from any technologies or businesses that we license or acquire; risks related to our projections about our business, results of operations and financial condition; risks related to the potential market opportunity for our products and services; the risk that we or our licensors may be unable to protect or that third parties will infringe the proprietary technologies underlying our tests; the risk of patent-infringement claims or challenges to the validity of our patents or other intellectual property; risks related to changes in intellectual property laws covering our molecular diagnostic tests and pharmaceutical and clinical services and patents or enforcement in the United States and foreign countries; risks of new, changing and competitive technologies and regulations in the United States and internationally; the risk that we may be unable to comply with financial operating covenants under our credit or lending agreements; the risk that we will be unable to pay, when due, amounts due under our credit or lending agreements; and other factors discussed under the heading Risk Factors contained in Item 1A of our most recent Annual Report on Form 10-K for the fiscal year ended June 30, 2019, which has been filed with the Securities and Exchange Commission, as well as any updates to those risk factors filed from time to time in our Quarterly Reports on Form 10-Q or Current Reports on Form 8-K. All information in this press release is as of the date of the release, and Myriad undertakes no duty to update this information unless required by law.

Media Contact: Ron Rogers Investor Contact: Scott Gleason (801) 584-3065 (801) 584-1143 rrogers@myriad.com sgleason@myriad.com

1 Greden JF, Parikh SV, Rothschild AJ, et al. Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: A large, patient- and rater-blinded, randomized, controlled study. J Psychiatr Res. 2019; 111:59-67.

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New Publication Demonstrates GeneSight Improved All Clinical Outcomes Using HAM-D6 Analysis in Large Prospective GUIDED Study - Associated Press

For all of the hype surrounding gene therapy and gene editing, the precision genetic medicine approach that turned in the best 2019 may have been RNA interference (RNAi). The gene-silencing technique earned its first regulatory approval for a novel targeted delivery method. That may not sound like much to get excited about, but it promises to open up numerous high-value opportunities for RNAi drug developers.

The approval, coupled with promising early-stage clinical results and massive partnership deals, explains why Arrowhead Pharmaceuticals (NASDAQ: ARWR) and Dicerna Pharmaceuticals (NASDAQ: DRNA) erupted higher in 2019. The RNAi drug developers saw their market valuations increase by 450% and 106%, respectively, last year.

While both companies have promise, thepharma stocks are likely to fall in early 2020. What does that mean for investors with a long-term mindset?

Image source: Getty Images.

Shares of Arrowhead Pharmaceuticals had a pretty good first nine months of 2019, but the most impressive gains came in the fourth quarter. The RNAi stock gained heading into the American Association for the Study of Liver Diseases (AASLD) Annual Meeting in November. Investors were eagerly awaiting the results of two drug combinations being developed to treat chronic hepatitis B (CHB) by Johnson & Johnson (NYSE: JNJ) subsidiary Janssen.

The results lived up to the hype. The most impressive data came from a triple combination of an RNAi drug from Arrowhead Pharmaceuticals (now called JNJ-3989), an antiviral drug from Johnson & Johnson (JNJ-6379), and a nucleos(t)ide analog (NA). After 16 weeks of treatment, all 12 individuals in the study achieved at least a 90% reduction in two biomarkers of hepatitis B virus activity.

Investors gobbled up shares of Arrowhead Pharmaceuticals because the triple combination appears to be the industry's best hope for developing the first functional cure for CHB (although it can't be called a functional cure just yet).

Additionally, the RNAi drug candidate in the triple combination is based on a targeted delivery platform called TRiM. The approach is simple: The gene-silencing payload is attached to a special sugar that's absorbed by the liver. Since many RNAi drug candidates need to interact with DNA in liver cells, and the sugars are easily metabolized by the liver (improving safety over prior-generation lipid nanoparticle delivery vehicles), it's a perfect pairing.

It helps that just a few weeks after AASLD, Givlaari from Alnylam Pharmaceuticals (NASDAQ: ALNY)became the first RNAi drug candidate based on a conjugated-sugar delivery method to earn regulatory approval. It also helps that Dicerna Pharmaceuticals landed two massive partnerships in the fourth quarter of 2019 -- both based on its own conjugated-sugar delivery platform. Following those deals, there's now considerable overlap between the pipelines of Arrowhead Pharmaceuticals and Dicerna Pharmaceuticals, which are both all-in on targeted delivery.

RNAi Developer

Partner, Indication

Financial Terms

Arrowhead Pharmaceuticals

Johnson & Johnson, hepatitis B

$175 million up front, $75 million equity investment, up to $1.6 billion in milestone payments, royalties

Arrowhead Pharmaceuticals

Johnson & Johnson, undisclosed

Up to $1.9 billion in total milestone payments for up to three additional drug candidates, royalties

Arrowhead Pharmaceuticals

Amgen, cardiovascular disease

$35 million up front, $21.5 million equity investment, up to $617 million in milestone payments, royalties

Dicerna Pharmaceuticals

Roche, hepatitis B

$200 million up front, up to $1.47 billion in milestone payments, royalties

Dicerna Pharmaceuticals

Novo Nordisk, various liver-related cardio-metabolic diseases

$175 million up front, equity investment of $50 million, an additional $75 million over the first three years, up to $357.5 million per drug candidate, royalties

Data source: Press releases, filings with the Securities and Exchange Commission.

Despite all of the progress from both Arrowhead Pharmaceuticals and Dicerna Pharmaceuticals in 2019, both companies are likely to fall back to Earth a bit following giant run-ups.

Consider that Arrowhead Pharmaceuticals is valued at $6.3 billion at the start of 2020. The company's most advanced drug candidate, ARO-AAT, recently began dosing patients in a phase 2/3 trial in a rare genetic liver disease associated with alpha-1 antitrypsin (AAT or A1AT) deficiency. While that study can be used for a new drug application (NDA), and the drug candidate could achieve over $1 billion in peak annual sales, that alone doesn't support a $6.3 billion valuation.

Meanwhile, the triple combination in CHB could support a market valuation well above $6 billion, especially if it proves to be a functional cure. The drug candidate could eventually earn peak annual sales of over $10 billion in that scenario. But the recent gains were spurred by results in only 12 individuals after 16 weeks of follow-up. A phase 2b trial now underway will enroll 450 patients and follow them for two years. In other words, there's plenty of time for investors to take some gains off the table.

Dicerna Pharmaceuticals is valued a little more reasonably, at just $1.5 billion, but it has only one drug candidate in mid- or late-stage clinical trials. The pipeline programs at the center of recent deals with Roche and Novo Nordisk are still in preclinical development or phase 1 studies; there's little to no clinical data from the programs for investors to survey. While the business will be flush with cash after receiving up-front payments in the coming months, there's a lot of work to be done.

To be clear, both Arrowhead Pharmaceuticals and Dicerna Pharmaceuticals hold a lot of promise. Targeted delivery of RNAi drug payloads into the liver could open up considerable opportunities to treat -- for the first time, in some cases -- rare diseases, viral infections, and cardiovascular ailments. Both companies have even demonstrated early work to target gene-silencing payloads to other cell types, such as muscle tissues, which may open up additional avenues for drug discovery and development.

However, these two RNAi stocks have fallen 10.7% and 12.3%, respectively, since Dec. 3 -- and both are likely to fall a bit further in early 2020. If and when that occurs, investors may want to give each stock, especially Arrowhead Pharmaceuticals, a closer look.

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These 2 Stocks Will Fall After the New Year - Nasdaq

A new, safe and efficient way to coax stem cells into bone cells is reported in a recently published article from STEM CELLS Translational Medicine (SCTM).

DURHAM, N.C., Jan. 6, 2020 /PRNewswire-PRWeb/ -- A new, safe and efficient way to coax stem cells into bone cells is reported in a recently published article from STEM CELLS Translational Medicine (SCTM). The protocol, developed by researchers at the University of Sydney, Australian Research Centre (ARC) for Innovative BioEngineering, could lead to a shift in the treatment of bone regenerative medicine.

Large bone defects and loss due to cancer or trauma can result in scar tissue that impairs the bones' ability to repair and regenerate. The current gold standard therapy, autografting, has inherent drawbacks, including limited availability and donor site morbidity. This leaves researchers seeking an alternative source of bone cells and makes bone tissue engineering a growing field with considerable translational potential.

"The success of induced pluripotent stem cell (iPSC) technology to reprogram fibroblasts into progenitor cells of various lineages offers an exciting route for tissue repair and regeneration," said Zufu Lu, Ph.D., a member of the University of Sydney's Biomaterials and Tissue Engineering Research Unit and a research associate at the ARC for Innovative BioEngineering. He is a co-lead investigator of the SCTM study, along with Professor Hala Zreiqat, Ph.D., head of the research unit and director of the ARC Training Centre for Innovative BioEngineering.

"However, while iPSC technology represents a potentially unlimited source of progenitor cells and allows patients to use their own cells for tissue repair and regeneration thus posing little or no risk of immune rejection the technology has several constraints. Among them are the requirement for complex reprogramming using the Yamanaka factors (Oct3/4, Sox2, Klf4, c-Myc). To add to the complexity, specific stimuli are required to direct iPSCs to re-differentiate to progenitor cells of the lineage of interest.

"In addition," Dr. Lu said, "any remaining iPSCs pose the risk of tumors following implantation."

One potential way around this, as demonstrated by recent studies, is through the direct reprogramming of fibroblasts into bone cells. "Fibroblasts are morphologically similar to osteoblasts. Their similar transcriptomic profiles led us to hypothesize that distinct factors produced by osteoblasts may be capable of coaxing fibroblasts to become osteoblast-like cells," Prof. Zreiqat said.

Previous studies aimed at using fibroblasts to produce various cell types relied on the genetic manipulation of one or more transcription regulators. But just as with iPSCs, reprogramming fibroblasts in this manner has its own inherent technical and safety issues. The Lu-Zreiqat team, however, surmised that an approach employing natural factors might just allow better control over reprogramming and improve the safety.

"Unlike genetic reprogramming, chemical induction of cell reprogramming is generally rapid and reversible, and is also more amenable to control through factor dosage and/or combinations with other molecules," Dr. Lu explained.

The team initially determined that media conditioned by human osteoblasts can induce reprogramming of human fibroblasts to functional osteoblasts. "Next," said Prof. Zreiqat, "our proteomic analysis identified a single naturally bioactive protein, insulin growth factor binding protein-7 (IGFBP7), as being significantly elevated in media conditioned with osteoblasts, compared to those with fibroblasts."

This led them to test IGFBP7's ability as a transcription factor. They found it, indeed, successfully induced a switch from fibroblasts to osteoblasts in vitro. They next tested it in a mouse model and once again experienced success when the fibroblasts produced mineralized tissue. The switch was associated with senescence and dependent on autocrine IL-6 signaling.

"The approach we describe in our study has significant advantages over other commonly used cell sources including iPSCs and adult mesenchymal stem cells," Dr. Lu and Prof Zreiqat concluded.

"Bone tissue engineering is a growing field where cell therapies have considerable translational potential, but current cell-based approaches face limitations," said Anthony Atala, M.D., Editor-in-Chief of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. "The novel observation described in this study could potentially lead to a shift in the current paradigm of bone regenerative medicine."

Story continues

This study was conducted in collaboration with the Charles Perkins Centre and the Children's Hospital at Westmead, University of Sydney.

The full article, "Reprogramming of human fibroblasts into osteoblasts by insulin-like growth factor binding protein 7," can be accessed at https://stemcellsjournals.onlinelibrary.wiley.com/doi/abs/10.1002/sctm.19-0281.

About STEM CELLS Translational Medicine: STEM CELLS Translational Medicine (SCTM), co-published by AlphaMed Press and Wiley, is a monthly peer-reviewed publication dedicated to significantly advancing the clinical utilization of stem cell molecular and cellular biology. By bridging stem cell research and clinical trials, SCTM will help move applications of these critical investigations closer to accepted best practices. SCTM is the official journal partner of Regenerative Medicine Foundation.

About AlphaMed Press: Established in 1983, AlphaMed Press with offices in Durham, NC, San Francisco, CA, and Belfast, Northern Ireland, publishes two other internationally renowned peer-reviewed journals: STEM CELLS (http://www.StemCells.com), celebrating its 38th year, is the world's first journal devoted to this fast paced field of research. The Oncologist (http://www.TheOncologist.com), also a monthly peer-reviewed publication, entering its 25th year, is devoted to community and hospital-based oncologists and physicians entrusted with cancer patient care. All three journals are premier periodicals with globally recognized editorial boards dedicated to advancing knowledge and education in their focused disciplines.

About Wiley: Wiley, a global company, helps people and organizations develop the skills and knowledge they need to succeed. Our online scientific, technical, medical and scholarly journals, combined with our digital learning, assessment and certification solutions, help universities, learned societies, businesses, governments and individuals increase the academic and professional impact of their work. For more than 200 years, we have delivered consistent performance to our stakeholders. The company's website can be accessed at http://www.wiley.com.

About Regenerative Medicine Foundation (RMF): The non-profit Regenerative Medicine Foundation fosters strategic collaborations to accelerate the development of regenerative medicine to improve health and deliver cures. RMF pursues its mission by producing its flagship World Stem Cell Summit, honouring leaders through the Stem Cell and Regenerative Medicine Action Awards, and promoting educational initiatives.

SOURCE STEM CELLS Translational Medicine

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New protocol could signal shift in bone regenerative medicine - Yahoo Finance

6 January 2020

Leading figures in science and healthcare have been recognised in the UK's New Year's Honours list 2020.

Professor Dame SallyDavies received Dame Grand Cross of the Order of the Bath (GCB) for services to public health and research, having previously been made a Dame in 2009. Dame Sally was Chief Medical Officer for England from 2010-2019. Her initiatives included the 'Generation Genome' report (see BioNews908) which recommended widespread adoption of genomic medicine within the NHS, as well as ongoing efforts to combat antimicrobial resistance.

'I am honoured to receive this GCB recognising the efforts of many people across Government, the NHS and beyond, working together on issues ranging through health research and public health to fighting the rise of antimicrobial resistance both in the UK and across the world. We willcontinue to build coalitions for action as this war to save lives is not over' she said.

Professor Lesley Regan who stepped down as President, Royal College of Obstetricians and Gynaecologists (RCOG) in December, was made a Dame 'for services to women's healthcare'.

'I am delighted and honoured to be recognised in the New Year Honours. The progress we have made in women's health at the RCOG is only possible because of the hard work and commitment of the wonderful staff and our wider membership. We have much work to do to achieve the aims set out in the Better for Women report and I look forward to supporting the RCOG and its many key partners to transform healthcare services for women and girls.'

Other honours included a knighthood for Genomics England's former chair, Jonathan Symonds for services to UK life sciences and finance.

Professor Alan Lehmann, Research Professor of Molecular Genetics, University of Sussex received a CBE for services to medical science, patients and families affected by the genetic conditions xeroderma pigmentosum and Cockayne syndrome.

OBEs were awarded to Professor Sheila McLean, the University of Glasgow's Professor Emerita of Law and Ethics in Medicine for services to health and education and to former director of the Academy of Medical Sciences Dr Helen Munn for services to the advancement of medical science.

Nicola Perrin, former head of the Wellcome Trust's Understanding Patient Data programme received an MBE for services to science.

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Professors Sally Davies and Lesley Regan recognised in New Year's Honours - BioNews