RARE Daily

The Making of a Gene Therapy for an Ultra-Rare Disease

April 20, 2021

Daniel S. Levine

Axovant’s high profile 2017 failure of a late-stage clinical trial for an experimental Alzheimer’s drug led the company to an overhaul that gave it a new name, a new strategy, and a new CEO.

When Pavan Cheruvu took over as CEO in early 2018, he brought with him a plan for building a company focused on developing gene therapies for conditions of the central nervous system, a decision that would give new hope to patients with the ultra-rare neurodegenerative condition GM1 gangliosidosis.

“I had a vision of building a very focused gene therapy company where indications we would be pursuing in neurodegenerative diseases like these rare diseases, but also extending the reach of gene therapy to much larger indications,” said Cheruvu.

While the since renamed company Sio Gene Therapies in-licensed one program in Parkinson’s disease, it also in-licensed a pair of gene therapy programs from the University of Massachusetts in GM1 gangliosidosis and Tay-Sachs/Sandhoff disease with the GM1 program being Sio’s lead candidate.

Though gene therapies are advancing rapidly today, the history of the GM1 gangliosidosis program is a reminder of the long path some gene therapies must travel before even reaching a patient in a clinical study. It also shows the critical role of collaboration among academic research, the National Institutes of Health, and industry to advance programs to the point where they can benefit patients.

“This isn’t an overnight success,” said Christine Waggoner, president and co-founder of Cure GM1 Foundation, which contributed more than $400,000 to support research into the development of the gene therapy.

Though Tay-Sachs disease had been first identified in 1881, GM1 gangliosidosis was not recognized as a condition distinct from it until 100 years later. GM1 gangliosidosis is a rare and fatal pediatric lysosomal storage disorder that progressively destroys neurons in the central nervous system and leads to a host of systemic manifestations. The underlying causes of GM1 gangliosidosis are mutations in the gene for beta-galactosidase, an enzyme responsible for the breakdown of toxic molecules known as gangliosides throughout the body, which results in rapidly progressing neurodegeneration. There are currently no approved treatments for the condition.

The clinical trial of the GM1 gene therapy is a culmination of a long-standing collaboration between Doug Martin, professor in the Department of Anatomy, Physiology and Pharmacology in Auburn’s University’s College of Veterinary Medicine and the Scott-Ritchey Research Center, University of Massachusetts Medical School researchers Miguel Sena-Esteves and Heather Gray-Edwards, and Cynthia Tifft, deputy clinical director at the National Human Genome Research Institute, a leading expert in ganglioside storage disorders and the principle investigator of the NIH’s natural history study of GM1. It reflects more than a 15-year effort.

Tifft said GM1 naturally occurs in cats and when cats with the condition had been treated with the systemic gene therapy the results were dramatic. Cats with GM1 that typically need to be euthanized by about seven months, were living four or five years without developing significant disease. While there had been some commercial interest in the program, the researchers didn’t want to license the GM1 program separately from the Tay-Sachs program. They decided to advance the therapy to human clinical trials and set about cobbling together funding to do so.

The researchers had a pre-IND meeting with the U.S. Food and Drug Administration and were preparing to file an application to begin the first human trial when Sio licensed the program. Sio also entered into a Cooperative Research and Development Agreement with the National Human Genome Research Institute, which proceeded with the phase 1/2 study in GM1. Separately, the University of Massachusetts is working on a phase 1/2 study of the Sio gene therapy for Tay-Sachs/Sandhoff disease.

The GM1 phase 1/2 study is focused on patients with the type 2 form of the disease, which is characterized by juvenile onset, although the researchers are expected to push into younger patients with type 1, the infantile form of the disease.

Sio said the relationship with Tifft and NIH has worked well.

“She knows these kids and their families intimately well. What that means for us is that we really have a deep understanding of the clinical progression and the burden of the disease that these families carry,” said Sio’s Cheruvu. “What we bring to the table obviously is our experience in drug development. It’s worked really well from a clinical standpoint. We’ve been able to help from a drug development and regulatory perspective. Combined, we have a great team that’s able to put all those things together.”

Though the gene therapy is intended to be a one-and-done treatment, because Tifft was concerned about the durability of its effects in young children, she worked with Barry Byrne, director of the Powell Gene Therapy Center at the University of Florida to devise a pre-treatment regimen that could allow for redosing if necessary. To prevent patients from mounting an immune response to the AAV9 vector used to deliver the gene therapy, patients in the study are given a three-week pretreatment regimen of rituximab, which has the effect of depleting B cells. They are also given sirolimus, a drug used to prevent transplant rejection for three weeks prior to treatment until six months after to prevent T-cells from mounting a response.

Early results have been positive. At the end of December, six-month interim results showed all of the children in the study had been stable or improved. There were no adverse events attributable to the gene therapy.

“When you think about a disease that only gets worse—the only thing that happens is you’re going to lose ground—anything that impacts the trajectory of the disease is a win,” she said. “I’m not sure given the pathology of the disease that getting back to completely normal is going to be possible, but we’ve seen kids that have stabilized. We’ve seen kids that have made small gains. And we’ve seen some kids that have made pretty good gains.”

Two other competing gene therapy programs are in development. Paris-based Lysogene, which licensed an earlier GM1 program developed from the same University of Massachusetts and Auburn University collaboration, is developing a gene therapy that is injected into the cisterna magna, a fluid-filled space in the back of the head. It is not yet recruiting patients for its study. Passage Bio in January won clearance from the FDA to being a phase 1/2 clinical study of a gene therapy it licensed from the University of Pennsylvania for the treatment of infantile GM1 gangliosidosis. It too is administered into the cisterna magna.

The multiple programs are a point of hope for patient advocate Waggoner, who said its easy for rare disease advocates to put all of their hopes into a single therapeutic candidate.

“I’m hopeful for the future because we don’t have all our eggs in one basket,” she said. It’s hopeful that there are multiple studies targeting multiple parts of the population simultaneously. The hope would be that there will be additional therapies for symptomatic patients or patients who are progressed. Our dream would be to have something for them as well.”

Photo: Cynthia Tifft, deputy clinical director at the National Human Genome Research Institute,

Thanks to Pfizer, Inc., Bluebird, and Novartis Gene Therapies for their support of this article, part of our Platforms of Hope: Advances in Gene Therapy and Gene Editing series.

Stay Connected

Sign up for updates straight to your inbox.