NEW YORK – A group of researchers from multiple institutions, including the US National Institutes of Health, are exploring next steps for a gene therapy they've developed that has shown some promise in a first-in-human clinical trial for treating giant axonal neuropathy (GAN).
Their efforts to clinically advance the gene therapy program, which was for a time being sponsored by Dallas-headquartered biotech Taysha Gene Therapies but is currently unsupported by an industry partner, highlight the challenges of advancing therapeutics for devastating but extremely rare conditions like GAN.
There are only about 75 families known to have this chronic and progressive neurodegenerative disorder in which the axons of nerve cells swell and degenerate, resulting in mobility issues and muscle weakness throughout the body. Patients even have difficulty with basic activities like eating and breathing. The neurodegenerative condition is caused by loss-of-function variants in the GAN gene, which encodes gigaxonin, a protein that supports the function of nerves. Symptoms usually begin in childhood, around 3 years of age.
A gene therapy for this disorder, referred to as scAAV9/JeT-GAN, has been more than 15 years in the making, said Steven Gray, associate professor of pediatrics, molecular biology, and neurology at the University of Texas Southwestern Medical Center in Dallas and coauthor of a New England Journal of Medicine paper describing a Phase I clinical trial of the therapy.
"The results seem encouraging," said Gray. "It shows that we're moving in the right direction."
The one-time gene therapy, administered through an injection to the spinal cord, uses an adeno-associated virus serotype 9 vector to deliver a functional GAN transgene to nerve cells in the brain and spinal cord. In the Phase I clinical trial, there were signs that the gene therapy can slow motor function declines, but the researchers cautioned in their NEJM paper that "further studies are warranted to determine the safety and efficacy of intrathecal AAV-mediated gene therapy in this disorder."
Gray started working on this gene therapy in 2008 while he was a researcher at the University of North Carolina at Chapel Hill and continued to develop it with colleagues at UT Southwestern when he joined the university in 2017.
The development program for the GAN gene therapy began in response to outreach from Hannah's Hope Fund, a nonprofit founded in 2008 by the parents of a young girl, Hannah, who had recently been diagnosed with GAN. The organization shares GAN resources, raises funds to support R&D, and encourages patients who suspect they might have GAN to connect with the group to arrange genetic sequencing.
There currently isn't a treatment for GAN, and standard care involves supportive services for managing patients' symptoms.
Back in 2008, Hannah's Hope Fund convened a group of about 20 researchers who had studied GAN for a symposium on the disease and identified gene therapy as a promising therapeutic approach. Hannah's Hope Fund went on to support preclinical research of the scAAV9/JeT-GAN gene therapy, led by Gray, who later approached the NIH about developing a clinical trial protocol and sponsoring a study.
Researchers from UT Southwestern, UNC, Johns Hopkins University, University of Pennsylvania, Stanford University School of Medicine, Children's National Hospital, and multiple NIH institutes participated in developing and studying this gene therapy. "Literally, it took a village," Gray said. "A lot of people stepped in and contributed … to make it happen."
In addition to Hannah's Hope Fund, the Phase I clinical trial received grants from the NIH's National Institute of Neurological Disorders and Stroke (NINDS) and support from Taysha Gene Therapies and Bamboo Therapeutics, which was acquired by Pfizer in 2016. Taysha took over sponsorship of the Phase I trial from NINDS in 2022 and had been advancing the gene therapy program after buying rights to the preclinical data from Hannah's Hope Fund.
However, last year Taysha announced it would discontinue developing the experimental gene therapy after the US Food and Drug Administration recommended it complete another trial. At the time, Taysha said discontinuing the program would extend its cash runway into the end of 2025, allowing it to focus on developing other gene therapy programs, including an investigational candidate for Rett syndrome. Taysha has since transferred the investigational new drug (IND) application and investigational clinical trial materials for the gene therapy back to NINDS.
That means there currently isn't an industry partner involved in this gene therapy program, despite promising Phase I results. "It speaks to a larger issue and challenge," said Gray, who has consulted for Taysha and is also its chief scientific adviser. Researchers are undeterred by the lack of industry sponsorship, however, and are still planning to study the gene therapy in more children in a new portion of the ongoing Phase I clinical trial.
For the first-in-human Phase I clinical trial, an open-label study that launched in 2015, researchers administered one of four doses of the gene therapy to 14 pediatric patients with GAN, ranging from 6 to 14 years of age. The doses were administered to the children at an NIH clinical center in Bethesda, Maryland, and study participants were required to live near the center for one month for follow-up and monitoring after receiving the gene therapy.
In the NEJM paper, researchers reported the experiences of patients, who they tracked for a median of nearly six years following treatment. They will further follow patients in the clinical trial for 15 years.
The investigators were mainly interested in the safety of the gene therapy in this first trial, and they found that the gene therapy was well tolerated.
Of 48 documented serious adverse events, just one was potentially linked to the treatment — fever with vomiting — and resolved in two days. Nearly 130 of the total 682 adverse events patients experienced, or almost 20 percent, were potentially related to the gene therapy, including cerebrospinal fluid pleocytosis and leukocytosis.
Two patients who received the lowest dose of the therapy died during the study from events possibly caused by GAN, and likely not the gene therapy, the researchers determined.
The trial also provided researchers with a first look at the gene therapy's efficacy. The researchers noted positive trends favoring the gene therapy when they compared GAN patients' rate of decline on the Motor Function Measure scale over a year against patients' outcomes in a natural history study. Some patients, they found, even regained sensory nerve responses after getting the gene therapy.
"This means that there is the potential of regeneration of these affected sensory nerves even out of a stage of dysfunction," said Carsten Bönnemann, senior author of the paper and chief of the childhood neuromuscular and neurogenetic disorders section at NINDS. "Regeneration of sensory nerves in a genetic degenerative nerve disease has not been seen before."
However, patients varied in their clinical responses to the treatment. Not all of the doses met prespecified thresholds for efficacy, and the therapy's other effects, such as on neuropathy impairment, were variable.
And although the gene therapy slowed some aspects of GAN progression, it didn't cure patients' mobility issues, suggesting earlier intervention may be beneficial.
It's difficult to prove efficacy in progressive neurologic diseases, Terence Flotte, a pediatrics professor at the University of Massachusetts Chan Medical School, wrote in a commentary in Molecular Therapy about the potential of intrathecal gene therapy administration. Flotte, who also holds a faculty position at UMass Chan's Horae Gene Therapy Center, was not involved in the paper on the GAN gene therapy.
"Since neurons have a limited regenerative capacity, the restoration of gene function by very effective gene therapies may only result in a relative stabilization or slowing of the rate of progression of disease," he wrote. "Turning a progressive fatal disease of childhood into a stable neurologic impairment is a very valuable outcome for affected patients but is difficult to evaluate statistically because of the small numbers of patients."
Beyond the prospects of this particular gene therapy, the Phase I clinical trial is one of the earliest studies to test intrathecal administration of a gene therapy and the NEJM paper contains valuable insights for future programs, according to Flotte. This delivery method could be applied in other central nervous system (CNS) disorders in which target cells are too deep to reach with the more standard intravenous infusions.
In a postmortem analysis of one patient, researchers identified vector biodistribution in the spinal cord, but it was lower than expected in regions of the brain. "There are several key features and results of this trial that may be instructive for other teams pursuing [intrathecal] delivery for other progressive CNS diseases," he wrote.
Researchers developing the GAN gene therapy, meanwhile, are assessing next steps and are hoping to expand the clinical trial to test if the gene therapy can prevent degeneration before it happens in children as young as 2 years of age. Investigators may also enroll patients with a milder form of GAN, Bönnemann said.
"Even though we saw signals for efficacy … we don't think that we have seen the full impact of possible benefit yet," Bönnemann said. "As with any neurodegenerative disease, time is of the essence. … A nerve that is diseased beyond the point of return cannot be recovered and is lost. Hence, the importance of early intervention."
However, the research team would need a commercial partner to garner regulatory approval and market it to patients outside of research studies, he said, since the NIH doesn't commercialize treatments on its own. He's hopeful that investigators will be able to find a partner for registrational activities if the program progresses to that point.
Gray, too, would like to see an industry partner sign on to this gene therapy program, but he acknowledged that it's challenging to commercialize rare disease treatments. Sponsors must draw from a limited patient population when proving safety and efficacy of these treatments in clinical trials, and, if approved, companies can only recoup their R&D investment and make profits by selling their drugs to a small number of patients.
"There's just not a lot of patients," Gray said. "It makes for a tough business model."