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llyson Berent is a specialty veterinarian in New York City. She treats animals that other doctors cannot help. When no good therapies are available, she invents one. Cats and dogs consumed almost all of her time — until six years ago, when her second daughter was born.As a baby, Quincy appeared healthy and happy, smiling at an early age and giggling frequently. But during her first few months of life, she missed many developmental milestones: At 10 weeks, she was not making eye contact. When her parents waved toys in front of her, she stared blankly. She had trouble feeding. And when she was lying on her stomach, she could not lift her head.
Doctors kept telling Berent and her husband to give it time, but the couple insisted on genetic testing: At 7 months old, their daughter was diagnosed with Angelman syndrome, a neurodevelopmental condition that affects as many as 1 in 12,000 people.
Most people with Angelman syndrome have severe intellectual disability. They never talk or live an independent life. They experience seizures, gut issues and sleeping and feeding difficulties. Due to balance and motor problems, they are usually unable or barely able to walk. Many also meet the diagnostic criteria for autism.
Within days of learning her daughter’s diagnosis, Berent set herself a new goal: curing Quincy. With her medical background, she had no trouble parsing the scientific research on Angelman syndrome. She learned that it stems from a missing or mutated copy of a gene called UBE3A, which generates a protein essential for healthy brain activity. People inherit two copies of UBE3A, one from each parent, but the paternal copy is typically silent. In about 70 percent of people with Angelman, the maternal copy is absent, and they produce none of the protein. Many others with the syndrome have a small mutation in the mother’s copy, rendering it ineffective.
Eager to learn as much as she could, Berent set an alert for ‘Angelman’ in her account with PubMed, the medical journal database. Almost immediately, in December 2014, a paper landed in her inbox that suggested a bold path forward: Researchers had found a way, using snippets of RNA that bind to DNA, to activate the silent copy of UBE3A in a mouse model of Angelman syndrome. And activating the paternal copy of the gene had reversed memory problems in these mice. Could the same thing be done for Quincy? “I went out on a mission to say that I was going to ensure that happened for her,” Berent says.
In March of this year, a child with Angelman syndrome received the first dose of a therapy similar to the one used in the mice. The therapy, dubbed GTX-102, comes from a company called GeneTx Biotherapeutics, founded by Berent and other Angelman parents. Berent also works with a foundation to accelerate other therapies aimed at boosting the missing protein at the heart of Angelman.
GTX-102 is one of a fast-growing number of gene therapies coming to market. Gene therapies replace, repair, activate or silence a gene sequence underlying a condition, rather than addressing its traits. Traditionally, the term ‘gene therapy’ applied only to gene replacement, but as a variety of approaches have shown promise, the phrase has come to refer to all treatments that target DNA or RNA.
Gene therapies are now moving into the autism space, and the Angelman trial is a sign of things to come. “A success in this space will completely change the way that we think about genetic testing in autism,” says Timothy Yu, a neurologist and geneticist at Boston Children’s Hospital in Massachusetts. “It will hold out the idea that if you can name the disease, you can actually do something to improve the quality of life for that child.”
Other companies are developing gene therapies for Angelman that are similar to GTX-102. In late August, Roche launched a clinical trial for its Angelman drug, and a therapy from Ionis Pharmaceuticals and Biogen is nearing human testing. The first gene therapy trial for Rett syndrome, another single-gene condition related to autism, could start as early as next year. And a variety of experimental gene therapies for additional autism-linked conditions, including fragile X syndrome and tuberous sclerosis, are under investigation in animal models. These treatments all target conditions involving just one gene, but some of what scientists learn from developing them pertains to a range of related conditions, including autism that results from more complex causes.
The initial trials of the GeneTx treatment, as with other early-stage tests, are arbiters of safety only. The trial, given the cheeky name KIK-AS, will have just 20 participants, and it will take at least until 2022 before the compound reaches large-scale clinical trials in children, at which point it will be evaluated for its efficacy. Even if a drug passes preliminary testing, it still might not work, or it may work only if started at birth or in the womb.
In other words, it might be too late for Quincy. Berent is clear-eyed about the challenges, but optimistic. “I think this could be ground-breaking,” she says.