Rare diseases aren’t so rare. Collectively, up to 30 million Americans, many of them children, are born with one of the approximately 7,000 known rare diseases. Most of these millions of people also share a common genetic feature: their diseases are caused by an alteration in a single gene.
Many of these alterations could theoretically be targeted with therapies designed to correct or replace the faulty gene. But there have been significant obstacles in realizing this dream. The science of gene therapy has been making real progress, but pursuing promising approaches all the way to clinical trials and gaining approval from the U.S. Food and Drug Administration (FDA) is still very difficult. Another challenge is economic: for the rarest of these conditions (which is most of them), the market is so small that most companies have no financial incentive to pursue them.
To overcome these obstacles and provide hope for those with rare diseases, we need a new way of doing things. One way to do things differently—and more efficiently—is the recently launched Bespoke Gene Therapy Consortium (BGTC). It is a bold partnership of NIH, the FDA, 10 pharmaceutical companies, several non-profit organizations, and the Foundation for the National Institutes of Health . Its aim: optimize the gene therapy development process and help fill the significant unmet medical needs of people with rare diseases.
The BGTC, which is also part of NIH’s Accelerating Medicines Partnership® (AMP®), will enable the easier, faster, and cheaper pursuit of “bespoke” gene therapies, meaning made for a particular customer or user. The goal of the Consortium is to reduce the cost of gene therapy protocols and increase the likelihood of success, making it more attractive for companies to invest in rare diseases and bring treatments to patients who desperately need them.
Fortunately, there is already some precedent. The BGTC effort builds on a pilot project led by NIH’s National Center for Advancing Translational Sciences (NCATS) known as Platform Vector Gene Therapy (PaVe-GT). This pilot project has helped to develop adeno-associated viruses (AAVs), which are small benign viruses engineered in the lab to carry a therapeutic gene. They are commonly used in gene therapy-related clinical trials of rare diseases.
Since the launch of PaVe-GT two years ago, the project has helped to introduce greater efficiency to gene therapy trials for rare disease. It’s also offered a way to get around the standard one-disease-at-a-time approach to therapeutic development that has stymied progress in treating rare conditions.
The BGTC will now continue to advance in-depth understanding of basic AAV biology and develop better gene therapies for rare and also common diseases. The consortium aims to develop a standard set of analytic tests to improve the production and functional assessment of AAVs and therapeutic genes. Such tests will be broadly applicable and will bring the needed manufacturing efficiency required for developing gene therapies for very rare conditions.
The BGTC also will work toward bringing therapies sooner to individuals in need. To start, BGTC-funded research will support four to six clinical trials, each focused on a distinct rare disease. While the details haven’t yet been decided, these diseases are expected to be rare, single-gene diseases that lack gene therapies or commercial programs in development, despite having substantial groundwork in place to enable the rapid initiation of preclinical and clinical studies.
Through these trials, the BGTC will chart a path from studies in animal models of disease to human clinical trials that cuts years off the development process. This will include exploring methods to streamline regulatory requirements and processes for FDA approval of safe and effective gene therapies, including developing standardized approaches to preclinical testing.
This work promises to be a significant investment in helping people with rare diseases. The NIH and private partners will contribute approximately $76 million over five years to support BGTC-funded projects. This includes about $39.5 million from the participating NIH institutes and centers, pending availability of funds. The NCATS, which is NIH’s lead for BGTC, is expected to contribute approximately $8 million over five years.
Today, only two rare inherited conditions have FDA-approved gene therapies. The hope is this investment will raise that number and ultimately reduce the many significant challenges, including health care costs, faced by families that have a loved one with a rare disease. In fact, a recent study found that health care costs for people with a rare disease are three to five times greater than those for people without a rare disease . These families need help, and BGTC offers an encouraging new way forward for them.
NIH Support: National Center for Advancing Translational Sciences; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Eye Institute; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Dental and Craniofacial Research; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders; and NIH’s BRAIN Initiative.
Developing a drug takes time and money: on the average, around 14 years and $2 billion or more. More than 95 percent of the drugs fail during development. Even those that go all the way to large and expensive clinical trials in humans frequently don’t make the cut—perhaps because they weren’t quite as effective as they were supposed to be, had undesirable side effects, or didn’t align with the developer’s business priorities. But some of these compounds may have surprising therapeutic properties that have not yet been fully exploited. It would be a wasted opportunity not to take another look at them and test them for effectiveness in other conditions.
For that reason, our National Center for Advancing Translational Sciences (NCATS), with financial support from the NIH Common Fund, launched a pilot program to discover new therapeutic uses for existing molecules. Today we are awarding $12.7 million to nine academic institutions to reexamine a collection of compounds developed by major pharmaceutical companies and test them as treatments for diseases, both common and rare: from alcoholism and Alzheimer’s disease to Duchenne muscular dystrophy and schizophrenia.
The humble laboratory mouse has taught us a phenomenal amount about embryonic development, disease, and evolution. And, for decades, the pharmaceutical industry has relied on these critters to test the safety and efficacy of new drug candidates. If it works in mice, so we thought, it should work in humans. But when it comes to molecules designed to target a sepsis-like condition, 150 drugs that successfully treated this condition in mice later failed in human clinical trials—a heartbreaking loss of decades of research and billions of dollars. A new NIH-funded study  reveals why.