StemCell Therapy

A new gene therapy may lessen traits of Angelman syndrome, but its makers may need to limit the dose.

By Giorgia Guglielmi, SpectrumNov. 5, 2020 , 9:30 AM

Originally published onSpectrum

A small clinical trial of a gene therapy for Angelman syndromea rare genetic condition related to autismis on hold after two participants temporarily lost the ability to walk. The safety issue is important to resolve, experts say, given that the therapy otherwise appears to be effective, and the trial could guide treatment strategies for similar brain conditions.

Biopharmaceutical companyUltragenyxin Novato, California, in collaboration with Florida-based biotech startupGeneTx, launched the trial in February to assess the safety of a therapy forAngelman syndrome, a neurodevelopmental condition characterized by intellectual disability, balance and motor problems, seizures, sleep problems and, in some cases, autism.

Angelman syndrome results from the mutation or absence of a gene calledUBE3A. People inherit two copies of UBE3A. Typically, only the maternal copy is active in neurons and the paternal copy is silent. But in people with Angelman syndrome, the maternal copy is mutated or missing, so their brain cells express no active UBE3A protein.

The drug developed by Ultragenyx and GeneTx, called GTX-102, is a short snippet of RNA called an antisense oligonucleotide thatactivates the paternal copy of UBE3Aand aims to restore the protein to typical levels. Three other companiesRoche, Biogen, and Ionisare pursuing similar therapies for the syndrome.

On 26 October, Ultragenyx and GeneTx reported that the clinical trial hadenrolled five individualswith Angelman syndrome, aged 5 to 15. The plan had been to administer to each participant a dose of GTX-102 once a month over four months. Researchers injected the drug directly into the nutrient-rich solution that envelops the brain and spinal cord through a site in the lower back.

The participants were to receive increasing doses, but all started with different amounts: Two began at the lowest dose, two started with the second-lowest dose, and one started at the second-highest dose. The final dose was about 10 times higher than the lowest dose.

After a single dose at the second-highest level, one participant developed leg weakness. The other four participants experienced the same adverse effect after taking the highest dose. The symptoms emerged one to four weeks after the participants last dose.

Two of the patients were not able to support themselves to walk and three were, but they were weaker, saysElizabeth Berry-Kravis, professor of child neurology at Rush University Medical Center in Chicago, Illinois, where the five children were treated.

The side effects appear to be a result of inflamed nerves where the drug was injected, perhaps due to accumulation of the drug in that area. In animal studies, the drug didnt cause similar adverse effects, says Ultragenyx chief executive officer,Emil Kakkis. We do know, though, that antisense oligonucleotides are known to have local toxic effects if given at high concentrations.

The participants all recovered after they received drugs that decrease inflammation, Berry-Kravis says. Even those who couldnt support themselves on their legs are walking around finethey actually are somewhat more coordinated now than they were before the study.

When the researchers evaluated the participants at day 128, all five showed significant improvements in some traits, including communication, sleep, and motor skills, Berry-Kravis says. Within weeks of the initial doses, parents and caregivers reported that the participants had acquired new words and gestures.

Were seeing things like using a fork independently for the first time ever, learning to swim on their own, using their augmentative communication device, being able to play an interactive game with the family, Berry-Kravis says. But, she adds, you cant go on with an adverse event.

Going forward, the companies plan to limit the maximum dose to a range in which the drug appears to improve traits without causing leg weakness. They also intend to change how they administer the drug so it cannot accumulate at the site of injection. The drug solution will be given to the patient with their head down to allow the drug to flow toward the brain more efficiently, Kakkis says.

Before resuming the study, the companies will seek approval from the U.S. Food and Drug Administration, says Scott Stromatt, chief medical officer of GeneTx. We hope dosing will start in the next one to two months, he says. Parents are pretty excited to resume because of the positive changes theyve observed in their children.

All drugs have a side effect at some point, saysMark Zylka, professor of cell biology and physiology at the University of North Carolina at Chapel Hill, who was not involved in the study. It seems like theyre just going to need to dial in the dosage better.

Zylka is working on atherapy for Angelman syndromethat uses the gene-editing technology CRISPR to unmute the paternal copy of UBE3A. The rapid improvement observed in the trial participants is encouraging, he says. It suggests that this idea of turning on the dads copy of the gene really has the potential to help individuals with Angelman.

Others are excited about what the trial results might mean for other brain conditions. One of the biggest questions in the field is how long the therapeutic window remains open in neurodevelopmental disorders like Angelman syndrome, saysTimothy Yu, assistant professor of pediatrics at Harvard University. The preliminary findings from the Ultragenyx and GeneTx trial suggest that the therapy can work even in teenagers.

Its still early days, and we have to be careful, Yu says. But if this result continues to hold true, thats going to be really game-changing.

This article was reprinted with permission fromSpectrum,the home of autism research news and analysis.

Go here to see the original:
Gene therapy for autism-linked condition weakened legs, robbing two people of ability to walk - Science Magazine

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