Paused Angelman syndrome trial to restart | Spectrum
Green light: A gene therapy trial for Angelman syndrome is set to resume after the FDA suspended it last November.
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The US Food and Drug Administration (FDA) has paved the way for the resumption of a clinical trial of gene therapy for Angelman syndrome. The FDA suspended the study last November after children receiving the treatment temporarily lost the ability to walk.
Angelman syndrome is a genetic disorder caused by the absence or mutations in the maternal copy of the UBE3A gene; it is often accompanied by autism. Gene therapy, called GTX-102, aims to activate the paternal copy of the gene, which is typically silenced.
Biopharmaceutical company Ultragenyx in Novato, California is conducting the study in collaboration with Florida-based biotech startup GeneTx. In May and June, regulators in Canada and the UK gave companies the go-ahead to begin testing the drug.
“It’s nice to see we can get started again in the US,” says Timothy Yu, Associate Professor of Pediatrics at Harvard University. Yu is not involved in the study, but says he advised the companies and hopes to open a study center at Boston Children’s Hospital.
In February last year, five children with Angelman syndrome received gradually increasing doses of therapy by injection into the lower back. But in July all five suffered from a weak leg that was so severe in two children that they prevented them from walking independently. The researchers stopped giving doses at that point, says Scott Stromatt, GeneTx’s chief medical officer. The FDA officially suspended the study in November.
All of the children made a full recovery, Stromatt says, and the researchers attribute the problems to inflammation at the injection site caused by higher doses of the drug. They continue to test the children’s blood to confirm this theory. In the meantime, eight new children with Angelman syndrome have been admitted to take lower doses.
“We’ll be leaving shortly,” says Stromatt. “The most important thing is safety and do it carefully.”
In the new study, four children aged 4 to 8 who were not previously treated with GTX-102 will receive four monthly doses of 2 milligrams of the drug. Another four children are not receiving the drug. Both groups are evaluated at the beginning of the study and after 128 days. The control group can also start treatment at this point.
In a second phase, all eight children – if their families so wish – will continue to be treated every three months.
In the previous study, the GTX-102 dosage started at 3.3 milligrams and increased to 20 and in some cases 36 milligrams when the side effects started. (The studies in the UK and Canada use 3.3 milligrams in younger children and 5 milligrams in children ages 8-17.) Researchers also monitor proteins in the children’s blood and cerebrospinal fluid as an extra safety precaution, Stromatt says.
The children in the previous study appeared to show improvements in communication, motor skills, and sleep before they were interrupted, and parents continued to report progress. Children may be slower to respond to the lower doses in the new study, Stromatt says
The restart is “promising,” says Mark Zylka, professor of cell biology and physiology at the University of North Carolina at Chapel Hill, who is not involved in the studies. The lower doses are likely to prevent serious side effects, he says, and while the groups are too small to rigorously evaluate the drug’s effectiveness, any improvements would suggest that these types of gene therapies would be a promising way to treat neurological disorders Developmental disorders are.
“I’m curious what they will find,” says Zylka.
If further studies confirm the drug is effective, it would suggest the brain retains the ability to respond to treatment throughout childhood, Yu says.
“The existence of an open therapeutic window is what the initial study results suggest is really exciting, and that’s why everyone in this area is watching it so closely,” he says. “It has the prospect of being a fundamental truth that is common to many of these neurodevelopmental disorders, and that is the exciting thing about it.”
Quote this article: https://doi.org/10.53053/SOQL5387