NCATS, FDA Co-Host Workshop on Gene Therapy for Rare Diseases

“We are now at the point of translating the potential of gene therapy — which has been around for a while — into a reality for patients,” said NCATS Director Christopher P. Austin, M.D.

These new advances in gene therapies have truly been a long time in coming. The first human study that involved gene therapy, a type of treatment to replace or fix a defective gene in a patient, began in 1990 at the NIH Clinical Center. Nearly 30 years later, in 2017, the Food and Drug Administration (FDA) approved the first three gene therapies for use in the U.S. One of those three is for an inherited disease; the others alter a patient’s own cells to fight two forms of cancer.

Inspired by this scientific progress, in August 2018, NCATS and the FDA co-hosted a two-day workshop about gene therapy for rare diseases. Many of these diseases are caused by a mutation in a single gene, so gene therapy holds great promise as an effective treatment approach.

Led by NCATS’ Office of Rare Diseases Research and the FDA’s Center for Biologics Evaluation and Research (CBER) staff, the workshop brought together representatives from NIH, the FDA, academia, industry and patient organizations to discuss using gene therapy to treat rare diseases. Discussion topics included recent scientific advances; challenges in manufacturing the viruses, called vectors, that are used to deliver gene therapy products; and how to increase the number of available treatments.

“We really are having this meeting at the right time,” said FDA CBER Director Peter Marks, M.D., Ph.D. He noted that hundreds of potential gene therapy treatments are now entering the clinic for testing in people. In July 2018, the FDA released draft guidance on several topics related to gene therapy, such as manufacturing and long-term follow-up of people who receive these agents.

Advancing the Science

NCATS Director Christopher P. Austin, M.D., at the Growing Promise of Gene Therapy Approaches to Rare Diseases Workshop in August 2018.

Exciting scientific advances discussed at the meeting included research in animal models and studies showing new advances in humans.

Jay Chiorini, Ph.D., of the NIH National Institute of Dental and Craniofacial Research, shared his research on using gene therapy to make salivary glands work better. Most people who have radiation treatment for head and neck cancer temporarily or permanently lose the ability to make saliva. Without it, eating becomes painful, and people may lose their teeth and have other dental problems. Using gene therapy in mini-pigs that were treated with radiation, Chiorini has been able to show some improvement in how the salivary glands worked. This approach has now entered the clinic, and he has so far enrolled 12 people in a study designed to test different gene therapy doses to find out whether the approach is safe in humans.

“We are often faced with the fact that mouse studies don’t translate very well to humans,” said Jerry Mendell, M.D., director of the Center for Gene Therapy at Nationwide Children’s Hospital in Columbus, Ohio. However, for his research on the rare disease spinal muscular atrophy type 1, tests in mice did a good job predicting how the treatment would work in humans. Children with this disease have weak muscles, and without treatment, they never talk or sit unassisted and have trouble swallowing. If left untreated, most children with spinal muscular atrophy type 1 die by the age of 2. When newborn mice were given gene therapy by day 1, however, they behaved normally and survived into adulthood. Based on those findings, Mendell conducted a trial in human infants up to 6 months old. The results were impressive: Of the 12 children who received a high dose of the vector, all have survived past age 3, and all are active. Four can stand, two can walk, and all but one can sit without support.

Addressing the Manufacturing Bottleneck

Panelists at the Growing Promise of Gene Therapy Approaches to Rare Diseases Workshop in August 2018.

Despite these scientific advances, manufacturing is turning out to be a critical bottleneck for the production of gene therapy. Producing the specialized vectors that deliver the treatment is a slow and complex process, and only a few facilities can currently do the work. Representatives from some of these facilities talked to workshop attendees about their operations and plans for expansion.

Manufacturing is also expensive, and academic researchers and private-sector companies currently have to compete for the same limited manufacturing capacity. Attendees emphasized the need to keep manufacturing affordable for everyone, including academic researchers and people with rare diseases.

“How do we make sure we have a pipeline for those products that have a commercial future as well as the ones that don’t — those rare diseases with 10 to 12 patients across the country?” asked Jaysson Eicholtz, M.S., director of the manufacturing facility at Nationwide Children’s Hospital. “How do we get to a point where we can support both types?”

When researchers are thinking about conducting a human trial for the first time, they should already be thinking about manufacturing, said Denise Gavin, Ph.D., chief of FDA CBER’s Gene Therapy Branch. That does not mean that a product must be ready for marketing as soon as the first human trials start. However, Gavin said, “Researchers may want to discuss their product manufacturing with someone who knows enough about manufacturing to help them think about whether the approach they’re taking will work when it is time to market a product.”

Advancing Treatments for Rare Disease Patients

FDA CBER Director Peter Marks, M.D., Ph.D..

The challenge of rare diseases is that there are so many. “We at NCATS are big on ‘It’s great that we made success in an individual disease, but what about the other 6,999?’” Austin said. “How do we advance the next one 10-fold better and the one after that another 10-fold better?”

Only about 300 of the thousands of identified rare diseases have an FDA-approved treatment. With only a few new treatments approved each year, it would take more than 1,000 years to address all of the known rare diseases.

Through a number of programs, including its Rare Diseases Clinical Research Network (RDCRN), NCATS is working to advance research on many rare diseases at once. Together, the RDCRN-supported researchers study more than 200 rare diseases, making discoveries that may apply to multiple disorders. NCATS also addresses rare diseases through a variety of programs and initiatives, including Therapeutics for Rare and Neglected Diseases, the Genetic and Rare Diseases Information Center, the NCATS Toolkit for Patient-Focused Therapy Development and the Rare Diseases Registry Program.

One way to attack multiple diseases at once could be to develop a kind of treatment platform that enables any disease’s relevant gene to be plugged in. The virus used by Mendell and many of the other workshop presenters to deliver their gene therapies could be such a technology, said Steven Gray, Ph.D., an associate professor of pediatrics at the University of Texas Southwestern Medical Center in Dallas.

“I would say that is a type of platform technology that could probably be applied to dozens if not hundreds of diseases,” Gray said. “In the meantime, the best I can come up with is to treat one disease at a time.”

As workshop presenters demonstrated throughout the meeting, gene therapy is at a moment of great potential. The challenge for NCATS, the FDA and other stakeholders is to find ways to keep accelerating progress so that no disease is left behind.

Posted October 2018