NINDS Recognizes Rare Disease Day: Shining a Light on the Unknown

Rare and ultra-rare diseases affect millions of people worldwide. Today, roughly 10,000 known rare and ultra-rare diseases affect more than 30 million Americans and their families. The incidence of each disease may be rare, but collectively, rare diseases represent a unique public health challenge. Further, rare diseases disproportionately affect the nervous system, and almost 90% of rare disorders can occur in children. For years, the NIH and NINDS have supported important research efforts and partnerships that aim to better understand, diagnose, and treat rare diseases.

Often described as a journey, getting a diagnosis for a rare or unknown condition can be a long and arduous process, often involving several years of testing and multiple doctors. Even with a diagnosis, very little may be known about the mechanisms underlying the disease, and effective treatments may not exist. Many have heard of the rare neurological disorders amyotrophic lateral sclerosis (ALS or Lou-Gehrig’s disease), spinal muscular atrophy, Duchenne muscular dystrophy, and Huntington's disease. Ultra-rare diseases, which affect as few or fewer than one in fifty thousand people, are less known, or completely undiscovered. In 2021, NINDS launched the Ultra-rare Gene-based Therapy (URGenT) network, a collaborative research program that supports the development of state-of-the-art gene-based therapies for ultra-rare neurological diseases. One of the programmatic goals of URGenT is to support a "platform approach” to the gene therapy development pipeline that if successful, could guide the approach to treatment of other ultra-rare disorders in the future.

Currently, we have two URGenT Network funding opportunities to move promising therapies into the clinic. The URGenT Network Resource Access X01 will provide a framework for investigators to access a network of contract research/medical organizations and subject matter experts to support planning, manufacturing, and some non-clinical therapeutic development resources. And the Translational Efforts to Advance Gene-based Therapies for Ultra-Rare Neurological and Neuromuscular Disorders U01 will accelerate the development of promising gene-based or transcript-directed therapeutics, such as oligonucleotides and viral-based gene therapies, by supporting early drug studies and clinical trial planning. These and other NINDS initiatives help to fill gaps in clinical trial readiness for rare neurological and neuromuscular diseases with new treatments on the horizon.

NINDS also collaborates with our partners to drive innovation in better understanding these rare diseases, including through the Bespoke Gene Therapy Consortium (BGTC), part of the Accelerating Medicines Partnership® (AMP®) program. This public–private partnership with the U.S. Food and Drug Administration (FDA), multiple pharmaceutical and life sciences companies, and nonprofit and other organizations, and managed by the Foundation for the NIH (FNIH), aims to improve current models for developing diagnostics and therapies. The BGTC is establishing therapeutic platforms and standards to speed the development and delivery of customized or “bespoke” gene therapies that could treat millions of people affected by rare diseases, including diseases too rare to be of commercial interest.

In addition, the NIH Common Fund’s Somatic Cell Genome Editing (SCGE) program is working to improve the efficacy and specificity of gene editing approaches to help reduce the burden of common and rare diseases caused by genetic changes. In partnership with the National Center for Advancing Translational Sciences (NCATS), NINDS is supporting the development of targeted delivery systems for the delivery of editors into somatic cells and improved human gene editing tools. Ultimately, our hope is that through these and other efforts, the genetic cause of rare neurogenetic disorders may be corrected.

Since its launch in 2013, NINDS has co-led, along with the National Human Genome Research Institute (NHGRI), the NIH Undiagnosed Diseases Network (UDN), an NIH Common Fund program that brings together clinical and research experts from across the nation to improve the level of diagnosis of rare and undiagnosed conditions. I serve as a co-Chair of the Common Fund UDN, and NINDS program staff serve as Coordinators of the program. The network includes 12 clinical sites, core facilities specializing in genetic sequencing and metabolomics, and a coordinating center. The UDN also provides resources for participants and families to improve their experience in research studies, connect families with each other, and share the UDN with others. After Common Fund support for the UDN ends later this year, NINDS will take the lead in managing the program.

The UDN has led to exciting breakthroughs in recent years. Earlier this month, researchers at the NIH Undiagnosed Diseases Program, part of the UDN, discovered a new neurological condition in three children characterized by issues with motor coordination and speech. The researchers determined that mutations in the ATG4D gene cause the disease, a finding that will enable diagnosis in more individuals as well as research toward developing treatments. This discovery may also help us understand more common disorders with shared biological mechanisms, such as Alzheimer’s disease.

In addition, NINDS supports research consortia within the Rare Diseases Clinical Research Network, a trans-NIH partnership led by NCATS to advance medical research on rare diseases by providing support for clinical studies and facilitating collaboration, study enrollment and data sharing. The RDCRN consists of 20 RDCRN rare diseases research groups (consortia) and a Data Management and Coordinating Center -- NINDS is proud to support 10 of the 20 consortia. Through the network, researchers and their teams work together with over 120 patient organizations (patient advocacy groups) to study nearly 200 rare diseases at clinical centers across the nation and worldwide.

This month, we recognize the researchers committed to solving the mysteries of these devastating conditions, including NINDS-funded neuroscientists Harry Orr, Christopher Walsh, and Huda Zoghbi, as well as Jean-Louis Mandel of France. They were recently awarded the 2022 Kavli Prize in Neuroscience for finding genetic causes of brain diseases including Rett syndrome, spinocerebellar ataxia, and rare forms of epilepsy.  Such discoveries, along with advances in gene editing and other precision medicine technologies, open exciting opportunities for gene-targeted treatments.

More importantly, we also take this opportunity to acknowledge the patients, families, advocacy organizations, medical teams, and many others impacted by rare diseases. As mentioned in our 2021-2026 NINDS Strategic Plan: Investing in the Future of Neuroscience, and in my previous message that outlined the ALS strategic plan, we at NINDS strive to engage people with lived experience of neurological disorders in the research process, including those with rare diseases or who are still searching for a diagnosis.

I encourage you to join us in celebrating Rare Disease Day at NIH today, Tuesday, February 28, 2023. Hosted by the National Center for Advancing Translational Sciences (NCATS) and the NIH Clinical Center, this annual event raises awareness among policymakers and the public about rare diseases and their impact on people’s lives. Speakers and panelists from NIH and partner organizations will highlight rare disease research programs, resources, and collaborations to improve care and advance therapy development for rare diseases. We’ll also hear stories from stories told by people living with a rare disease, their families, and their communities. I’m looking forward to this event, and looking ahead, to the exciting new discoveries and therapies that will offer hope to everyone in the rare disease community.