The National Institutes of Health and U.S. Food and Drug Administration unveiled a public-private partnership Wednesday aimed at accelerating gene therapies for the roughly 30 million Americans living with a rare genetic disease.
“They’ve waited a long time for something to be focused this way to address the incredibly wrenching stories we see all around us of children and adults with rare diseases where we can do a diagnostic test to tell them what they have but beyond that haven’t had much to offer,” Francis Collins, the pioneering genetics researcher and longtime NIH director, told STAT.
With $76 million over five years, the Bespoke Gene Therapy Consortium, or BGTC, will fund research into improving manufacturing processes and standardizing methods for preclinical testing of gene therapies. The initiative, which includes 10 pharmaceutical companies and five nonprofit organizations, will also support four to six clinical trials, each focused on a different rare disease.
Collins plans to leave his post by the end of the year and return to his lab at the National Human Genome Research Institute. But he was excited to be able to oversee the launch of the initiative, which was a year and a half in the making.
“We’re talking about something that could provide real hope to many of those people,” Collins said, “so that’s going to be great to cheer for wildly from the sidelines.”
There are an estimated 7,000 to 10,000 rare diseases. Most of them are caused by mutations in a single gene. Advances in medical science and biotechnology over the past few decades have led to several approved gene therapies, with hundreds more in clinical development. But it’s slow going, made slower by a lack of standards, access to tools, and economic incentives. At the current pace, researchers estimate it would take more than 2,000 years for beneficial, possibly curative, therapies to be developed for all rare monogenic disorders.
“There have been gene therapy success stories, but they have all been one-offs,” said Joni Rutter, acting director of the National Center for Advancing Translational Sciences, one of the 11 national institutes participating in the consortium. “That’s not the most efficient.”
The BGTC will focus on projects that illuminate the basic biology of the adeno-associated virus, or AAV, one of the most common vehicles, or vectors, for delivering genes to where they’re needed. The effort highlights a longstanding limitation of gene therapy: effectively getting therapeutic genes into target cells.
“We know AAVs are reliable and safe, but they’re still far from optimized,” said Rutter. “Right now you need kind of high doses of AAV, and that may increase immunogenicity and some of the off-target [effects] you don’t want to see. But by better optimizing the vector, we can then reduce the dosage.”
Gene therapy researchers turned to AAVs in the 2000s after a patient named Jesse Gelsinger died from an immune response to an experimental gene therapy that used an adenovirus as a vector. Unlike adenoviruses, AAVs are adept at evading the immune system, making them much less likely to provoke a dangerous response.
In the past few decades, AAV vectors have been administered in an estimated 250 to 300 clinical trials. And though they have largely been proven safe, a few recent exceptions have raised the alarm about how much scientists still don’t know about them.
Last year, two patients in a study of a high-dose gene therapy for a rare muscle disorder died. The clinical trial, sponsored by Audentes Therapeutics, was subsequently placed on hold by the FDA. This was after the agency had paused another trial, of a high-dose gene therapy for Duchenne muscular dystrophy being developed by Solid Biosciences, due to kidney problems in one patient. Studies in non-human primates have also shown that high doses of one AAV gene therapy can lead to serious liver complications.
Rutter said that one of the initial aims of the new consortium is to fund studies that will more fully examine all the different flavors of AAVs. Some target the liver and the central nervous system, others target other organs and tissues. Some are big enough to carry CRISPR genome-editing machinery, others are better suited to smaller genetic payloads, like antisense oligonucleotides. And different AAVs interact with the immune system in different ways. “We think we need to learn a little bit more about the biology,” said Rutter.
One of the goals is to create a catalogue of well-characterized, non-proprietary AAVs in the public domain, complete with details on how to best manufacture them and what sorts of data regulators would expect to review before granting a greenlight for human testing. It would be a shared resource of information that otherwise might take private companies many years and hundreds of billions of dollars to assemble.
“The idea here is to figure out which parts of a gene therapy approach are actually standardizable,” said Collins. “Until this model came along, I had worried that gene therapy would still be out of reach of those very rare diseases for which there’s not going to be commercial interest. But this might be a way to move that forward and de-risk those projects.”
While ultra-rare diseases are the focus of the BGTC effort, having a more streamlined development pipeline and regulatory pathway for gene therapies would likely benefit the advancement of treatments for more common (and therefore lucrative) conditions as well. That’s why it’s unsurprising to see such a long list of drug makers lining up behind it.
Collins credited Pfizer’s chief scientific officer, Michael Dolsten, with leading the industry charge and recruiting others to the cause. In addition to Pfizer, private partners include Biogen, Janssen, Novartis, Regenxbio, Spark Therapeutics, Takeda, Taysha Gene Therapies, Thermo Fisher Scientific, and Ultragenyx.
Several nonprofit organizations are also involved, including the Foundation for the National Institutes of Health, the Alliance for Regenerative Medicine, the American Society of Gene and Cell Therapy, CureDuchenne, the National Institute for Innovation in Manufacturing Biopharmaceuticals, and the National Organization for Rare Disorders (NORD).
“The Bespoke Gene Therapy Consortium is a strong, collaborative initiative centered around patients and families,” Ed Neilan, chief scientific and medical officer at NORD, said in a statement Wednesday. “We look forward to contributing to research and data collection that will truly make a difference for the nearly 30 million Americans living with a rare disorder.”