“There's an enormous amount of heterogeneity in both the underlying biology and clinical presentation of autism, so it has been challenging to develop treatments that are significantly impactful,” Dr. Kolevzon says. “But with the advent of new genetic technologies and the knowledge that autism is primarily genetic in origin, we are now seeing some major advances.”

Targeting Autism-Related Genes

Researchers have identified several hundred genes associated with ASD. Phelan-McDermid syndrome, in which approximately 65 percent of patients are also diagnosed with ASD, is caused by a deletion or sequence variant of a single gene, SHANK3. This monogenic cause makes the disorder a promising one to treat using gene therapy.

Phelan-McDermid syndrome is rare, occurring in an estimated 1 in 10,000 births, and SHANK3 mutations are found in approximately 1 to 2 percent of people with ASD. Although symptoms can vary in severity, individuals with the syndrome experience substantial developmental delays.

“Generally speaking, they tend to be minimally verbal, not toilet trained, and cannot live independently,” Dr. Kolevzon says. “A significant percentage also have regression, losing language and motor skills.”

The JAG201 treatment consists of a one-time infusion into the brain, injected into the lateral ventricle. This first-in-human study focuses on six children between the ages of 2 and 3, since it is likely that young children would see the most gains from the treatment. The researchers are evaluating the safety, tolerability, and clinical activity of the treatment, comparing two different doses.

The trial launched in February 2025 at the Seaver Autism Center at Mount Sinai. Rush University Medical Center in Chicago and Boston Children’s Hospital are study collaborators. The team will follow the patients for five years.

Potential for Functional Improvements

Early safety data have been encouraging, and there is reason to be optimistic that the treatment could result in functional improvements, Dr. Kolevzon says.

In mouse models of Phelan-McDermid syndrome, the delivery of JAG201 resulted in increased gene expression and evidence of behavioral changes. The researchers are hopeful the treatment could lead to measurable gains in cognition, language, sensory sensitivities, motor skills, and behavior for human patients.

While there is no placebo arm in the trial, the Seaver Autism Center, with its genetics-first approach to addressing ASD, has been collecting natural history data from patients with Phelan-McDermid syndrome for more than a decade, providing critical control data for comparison.

“We now have data from several hundred patients as part of a national consortium to understand how Phelan-McDermid syndrome evolves. That important information allows for this type of research to take place,” Dr. Kolevzon says. “The fact that biotech companies are investing in these rare autism-related disorders is due, in part, to the work that the Seaver Autism Center at Mount Sinai has done over the past 15 years. We have natural history data, an engaged patient population, and the infrastructure to support these groundbreaking trials.”

Despite the uncertainties associated with testing a novel therapy, Dr. Kolevzon is excited to offer families a potential treatment for the first time. “Even the smallest amount of change in these kids can be dramatic for their quality of life. Small gains could be profound,” he says. “My hope is that we’ll see disease-modifying effects: kids who will develop language, become toilet trained, and shift their trajectory closer to typical development.”

If the therapy shows promise, the methodology could also be adapted for other genetic forms of autism. “We’ve uncovered hundreds of autism-related genes, many of which affect overlapping pathways related to brain development,” Dr. Kolevzon says. “When I began working with these families, the idea of using gene therapy felt like science fiction. But now it’s quite real, and it’s incredibly gratifying to have something to offer the families who have put their trust in us.”