Two years ago, a small biotech start-up got permission to test a gene therapy for a rare and disabling form of autism. The plan: deliver a gene that’s vital for building and maintaining connections between brain cells, but is deficient in people with the disease.
Endpoints News reports that it would have been a medical first, but that particular trial never started. Instead of testing the treatment in adults first as the FDA wanted, Jaguar Gene Therapy convinced regulators to let it start in young children whose developing brains it believed would benefit most.
“We had to go back and argue that it’s a childhood gene therapy – they’re missing a gene, so the sooner you treat them, the better,” CEO Joe Nolan said.
Jaguar dosed the first child a year ago and has since treated four more, all aged between two and four. The Chicago-based company is currently gauging changes in cognitive, motor and social skills, with preliminary results – at least six months of outcomes from six patients – expected later this year.
The data could be a big moment for autism, a field that’s seen little success in developing new drugs. Jaguar’s approach is different, because it is aimed at a specific sliver of autism known as Phelan-McDermid syndrome, which is caused by a broken or missing gene known as SHANK3.
The condition affects fewer than 1% of people with autism and lies on the severe end of the spectrum, resulting in intellectual disability, poor muscle tone and occasionally seizures.
Many struggle to communicate, don’t become toilet-trained, and can’t care for themselves as adults.
“Very basic tasks can be enormously challenging for these kids,” said Alex Kolevzon, a child psychiatrist at the Icahn School of Medicine at Mount Sinai who is leading Jaguar’s study. “There’s essentially no real established treatment.”
Parents of children with the disease are eagerly awaiting the results.
“We’re super excited,” said Geraldine Bliss, president of the patient advocacy organisation CureSHANK and mother to a 27-year-old with Phelan-McDermid syndrome. Although it’s unclear whether her son could benefit, she has “a huge sense of relief” that progress is being made.
“Any degree of improvement is going to be meaningful change,” Bliss said. “This is such a critical first step to demonstrate that it is going to be possible, or hopefully will be possible, for families’ and patients’ lives to get a little bit better.”
A genetic link to learning
Jaguar was founded in 2019, when excitement for gene therapy was at its peak. That’s the year FDA approved Zolgensma, a life-saving gene therapy for an otherwise fatal neurological condition that affects infants. AveXis, that treatment’s developer, had recently been acquired by Novartis for $8.7bn.
As money flowed into the field, healthcare investment firm Deerfield Management reached out to former AveXis executives, including Nolan, to start a company based on gene therapies licensed from academic labs. The riskiest was a SHANK3 gene therapy from the Broad Institute of MIT and Harvard.
The autism field is littered with failed drugs, and “we had some early people tell us we were basically crazy”, Nolan said. But he had reason to believe this therapy would work.
Scientists have long known autism is highly heritable and over the past few decades, they’ve linked hundreds of genes to the condition. Most have small individual effects, but a few, including SHANK3, play an outsized role.
SHANK3 is found on the receiving end of the synapse, the connection between brain cells. Like a scaffold, it helps hold up other proteins in the synapse, including glutamate receptors that are the major way that brain cells process signals for learning and memory.
“Being able to make and maintain connections between neurons is essential for learning, and if you don’t have enough SHANK3, you’re not able to build and maintain those connections,” said Dan Gallo, Jaguar’s EVP of medical affairs and clinical development.
People normally inherit one SHANK3 gene from each parent. If either copy is broken or missing, they only have half the amount needed. Jaguar’s therapy uses a virus called AAV9, the same one used in Zolgensma, to deliver a modified version of SHANK3 into the brain.
“We’re changing the biology,” Gallo said. “I’m hopeful that we’ll be able to, for some children, get them on a developmental trajectory that looks more unaffected.”
Technical hurdles abound
While the fix for Phelan-McDermid syndrome is simple in theory, the company’s approach faces numerous technical challenges.
For starters, the gene is simply too big to fit inside AAV9 and other viruses commonly used in gene therapy. As a workaround, MIT neuroscientist Guoping Feng has developed an abridged version, stripped of a couple of parts that he believed were non-essential.
“We may not restore everything, but most things, and that should be better than nothing,” Feng said.
Feng’s lab has shown his “minigene” can alleviate behavioural and social deficits in mice missing SHANK3, and the results of a similar study in monkeys are currently undergoing peer review, he said.
Timing is another factor. Patients only get one shot at the therapy because immune reactions to the virus preclude redosing. Jaguar is betting that patients two to four years old are at a Goldilocks age, when a child’s brain is about 80% of the size it will reach as an adult.
Dosing any earlier risks diluting the therapy as the brain grows.
To reach as many neurons as possible, neurosurgeons drill a hole in the skull and infuse the gene therapy into a fluid-filled cavity called the lateral ventricle, which Jaguar hopes will distribute it throughout the brain.
Variability between patients poses another complication. Some people have small genetic typos that disrupt SHANK3, but others are missing the entire gene or even a whole slew of genes along the tip of the chromosome where SHANK3 resides. For its first study, Jaguar has excluded people who are missing more than one gene beyond SHANK3.
“Our goal is to start here, demonstrate proof-of-concept, and then continue to expand,” Gallo said.
Awaiting data
Jaguar dosed the first patient in its Phase 1 trial in February 2025. If the data look good, the company will seek additional funding for a bigger study. But investor appetite for gene therapies has diminished greatly since Jaguar was founded.
“When we started the company, it was not an issue to raise money. But now it is,” Nolan said.
The start-up has undergone major changes in the past five years. Soon after it emerged from stealth in 2021, Jaguar reeled in almost $180m, but it hasn’t announced additional funding since then. It abandoned plans to build its own $125m manufacturing facility, and only 22 full-time employees remain from its peak of about 85.
Nolan said Jaguar’s top four investors – primarily Deerfield but also Eli Lilly, ARCH Venture Partners and Goldman Sachs – have continued support, but he wouldn’t disclose details.
Jaguar’s decision to treat children first was partly because Nolan worried investors might cancel funding for the paediatric work if an initial short study in adults returned inconclusive results.
Even if the paediatric results are positive, longer studies with more people will probably be needed to convince doctors and regulators the treatment is working. That would be a major milestone for autism and could help crack open the door for more targeted treatments.
“My hope is that with gene therapy, you’re going to totally shift the trajectory,” Mount Sinai’s Kolevzon said. “If successful, it paves the way for targeting dozens of other high-impact genes.”
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