Most public health challenges may seem obvious. The COVID-19 pandemic, for example, swept the globe and in some way touched the lives of everyone. But not all public health challenges are as readily apparent.
Rare diseases are a case in point. While individually each disease is rare, collectively rare diseases are common: More than 10,000 rare diseases affect nearly 400 million people worldwide. In the United States, the prevalence of rare diseases (over 30 million people) rivals or exceeds that of common diseases such as diabetes (37.3 million people), Alzheimer’s disease (6.5 million people), and heart failure (6.2 million people).
Shouldering the Burden of Rare Diseases
As with common diseases, the personal and economic burdens of rare diseases are immense. People who live with rare diseases often struggle for years before they receive an accurate diagnosis, with some remaining undiagnosed for a decade or longer. The diagnostic odyssey includes countless doctor visits, unnecessary tests and procedures, and wrong diagnoses. For people in rural and low-income communities, lack of access to care is an additional barrier to an accurate diagnosis. And a diagnosis often doesn’t lead to better health—only about 5 percent of rare diseases have U.S. Food and Drug Administration–approved treatments.
Collectively, the personal burdens of those with rare diseases impose a significant economic cost on the nation. When quantifying the health care expenses for people with rare diseases, we found that they have three to five times greater costs than those without rare diseases . In the United States, the total direct medical costs for those with rare diseases is approximately $400 billion annually, a figure validated independently by the EveryLife Foundation for Rare Diseases. The EveryLife study also included indirect and non-medical costs, resulting in a higher total economic burden of nearly $1 trillion annually .
What’s even starker is that the true scope and impact of rare diseases actually may be greater because rare diseases aren’t easily visible in our health care system. Many of the diseases are too rare to have a code that identifies them in the electronic health record (EHR).
Speeding Up the Search for Solutions
Each and every day, NIH’s National Center for Advancing Translational Sciences (NCATS) works with patients, advocates, clinicians, and researchers to meet the public health challenge of rare diseases. Driving those conversations are three overarching goals to help people living with rare diseases get the high-quality care they need, faster:
1.Shorten the duration of the diagnostic odyssey by more than half. The diagnostic odyssey for someone with a rare disease takes on average seven years, and there are several ways we can speed the journey. For example, we are designing computational tools to detect rare genetic disorders from EHR data. This work is part of a broader research effort focused on using genetic analysis and machine learning to make it easier for health care providers to diagnose people with rare diseases correctly. Also, connecting patients more quickly with each other and the research community can hasten the search for answers. Check out the resources below to learn about rare diseases, find patient support organizations, and get involved in research efforts.
2. Develop treatments for more than one rare disease at a time. A key strategy is leveraging what rare diseases have in common. Some of our efforts build upon the fact that 80–85 percent of rare diseases are genetic. We can use this knowledge to develop genetic and molecular interventions for groups of rare diseases. Two programs—the Platform Vector Gene Therapy pilot project and the Bespoke Gene Therapy Consortium, which is part of the public-private Accelerating Medicines Partnership®—are streamlining the gene therapy development process. Their ultimate goal is to make gene therapies more accessible to many people with rare diseases. We also have joined in to advance the clinical application of genome editing for rare genetic diseases.
The NCATS-led Rare Diseases Clinical Research Network, which is supported across NIH, brings scientists together with rare disease organizations and patient advocacy groups to better understand common characteristics, which also might speed clinical research. With this in mind, we are adapting a clinical trial strategy used in cancer research to test a single therapy on multiple rare diseases.
3. Make it easier and more efficient for scientists to discover and develop treatments for rare diseases. NCATS develops ways for new treatments to reach people more quickly. Repurposing drugs, for example, is revealing already-approved drugs that may work for rare diseases. Programs such as Therapeutics for Rare and Neglected Diseases and Bridging Interventional Development Gaps move basic research discoveries in the lab closer to becoming new drugs. Ambitious initiatives, such as the Biomedical Data Translator, unite data from biomedical research, clinical trials, and EHRs to find treatments for rare diseases faster.
The COVID-19 pandemic showed us the power of working together to solve public health challenges. Let’s now come together to address the public health challenge of rare diseases. If you want to get involved, please join us at Rare Disease Day at NIH 2023 on February 28. You’ll hear personal stories, learn about the latest research, and discover helpful resources. I hope to see you there!
Note: Dr. Lawrence Tabak, who performs the duties of the NIH Director, has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the 23rd in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.
About 20,000 people in the U.S. live with hemophilia A. It’s a rare X-linked genetic disorder that affects predominantly males and causes their blood to clot poorly when healing wounds. For some, routine daily activities can turn into painful medical emergencies to stop internal bleeding, all because of changes in a single gene that disables an essential clotting protein.
Now, results of an early-stage clinical trial, published recently in the New England Journal of Medicine, demonstrate that gene therapy is within reach to produce the essential clotting factor in people with hemophilia A. The results show that, in most of the 18 adult participants, a refined gene therapy strategy produced lasting expression of factor VIII (FVIII), the missing clotting factor in hemophilia A . In fact, gene therapy helped most participants reduce—or, in some cases, completely eliminate—bleeding events.
Currently, the most-common treatment option for males with hemophilia A is intravenous infusion of FVIII concentrate. Though infused FVIII becomes immediately available in the bloodstream, these treatments aren’t a cure and must be repeated, often weekly or every other day, to prevent or control bleeding.
Gene therapy, however, represents a possible cure for hemophilia A. Earlier clinical trials reported some success using benign adeno-associated viruses (AAVs) as the vector to deliver the therapeutic FVIII gene to cells in the liver, where the clotting protein is made. But after a year, those trial participants had a marked decline in FVIII expression. Follow-up studies then found that the decline continued over time, thought to be at least in part because of an immune response to the AAV vector.
In the new study, an NIH-funded team led by Lindsey George and Katherine High of the Children’s Hospital of Philadelphia and the University of Pennsylvania, tested their refined delivery system. High is also currently with Asklepios BioPharmaceutical, Inc., Chapel Hill, NC. (Back in the 1970s, she and I were medical students in the same class at the University of North Carolina.) The study was also supported by Spark Therapeutics, Philadelphia.
Trial participants received a single infusion of the novel recombinant AAV-based gene therapy called SPK-8011. It is specifically designed to produce FVIII expression in the liver. In this phase 1/2 clinical trial, which evaluates the safety and initial efficacy of a treatment, participants received one of four different doses of SPK-8011. Most also received steroids to prevent or treat the presumed counterproductive immune response to the therapy.
The researchers followed participants for a year after the experimental treatment, and all enrolled in a follow-up trial for continued observation. During this time, researchers detected no major safety concerns, though several patients had increases in blood levels of a liver enzyme.
The great news is all participants produced the missing FVIII after gene therapy. Twelve of the 16 participants were followed for more than two years and had no apparent decrease in clotting factor activity. This is especially noteworthy because it offers the first demonstration of multiyear stable and durable FVIII expression in individuals with hemophilia A following gene transfer.
Even more encouraging, the men in the trial had more than a 92 percent reduction in bleeding episodes on average. Before treatment, most of the men had 8.5 bleeding episodes per year. After treatment, those events dropped to an average of less than one per year. However, two study participants lost FVIII expression within a year of treatment, presumably due to an immune response to the therapeutic AAV. This finding shows that, while steroids help, they don’t always prevent loss of a therapeutic gene’s expression.
Overall, the findings suggest that AAV-based gene therapy can lead to the durable production of FVIII over several years and significantly reduce bleeding events. The researchers are now exploring possibly more effective ways to control the immune response to AAV in expansion of this phase 1/2 investigation before pursuing a larger phase 3 trial. They’re continuing to monitor participants closely to establish safety and efficacy in the months and years to come.
On a related note, the recently announced Bespoke Gene Therapy Consortium (BGTC), a partnership between NIH and industry, will expand the refined gene therapy approach demonstrated here to more rare and ultrarare diseases. That should make these latest findings extremely encouraging news for the millions of people born with other rare genetic conditions caused by known alterations to a single gene.
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.