Here’s how the National Institute of Neurological Disorders and Stroke defines Spinal Muscular Atrophy:
Spinal Muscular Atrophy refers to a group of hereditary diseases that damages and kills specialized nerve cells in the brain and spinal cord (called motor neurons). Motor neurons control movement in the arms, legs, face, chest, throat, and tongue, as well as skeletal muscle activity including speaking, walking, swallowing, and breathing. The most common form of SMA is caused by an abnormal or missing gene known as the survival motor neuron gene 1 (SMN1), which is responsible for the production of a protein essential to motor neurons. This form of SMA has four types:
BETHESDA, MD — For decades, federal grants have provided critical support for research on the causes and potential cures for spinal muscular atrophy (SMA), with ongoing funding from the National Institutes of Health (NIH) and the DoD.
The NIH’s National Institute of Neurological Disorders and Stroke (NINDS) conducts basic, translational, and clinical research on SMA at its own laboratories and through grants to major medical institutions across the country.
Researchers at those labs continue to build the critical understanding of the cellular and molecular mechanisms that cause degeneration of motor neurons in the hope that elucidation of the pathways will point the way to new therapies for SMA and, perhaps, other neuromuscular disorders.
So far, NIH-funded studies have developed multiple models of the disease in animals and cells that reveal the steps involved in the disease process and speed evaluation of potential therapies. The work in this area contributed significantly to the development of and clinical trials for the therapies approved in the last four years that have changed the lives of SMA patients by stopping motor neuron destruction and slowing disease progression. Additional therapeutic candidates targeting other avenues are in the pipeline.
Early funding for animal models of SMA in zebrafish, mice, and pigs, continue to help researchers explore potential therapeutic targets and new therapies for SMA, not just for type 1 disease, but for the older children and adults less severe SMA types 2 and 3. At the same time, longitudinal studies that track pre-symptomatic and recently diagnosed children with SMA and their siblings builds an invaluable foundation for genetic counseling of carriers of the critical mutation underlying the disease and provides objective information on SMA progression, therapeutic advances, and clinical trial opportunities for parents of recently diagnosed children.
NINDS has also created a network of clinical trials, NeuroNext (NINDS Network for Excellence in Neuroscience Clinical Trials), to facilitate investigation of potential therapies for neurological disorders in children and adults. Among its current goals, the network aims to develop early-phase trials focused on identifying biomarkers that can indicate likely severity of SMA in infants and predict responses to new therapies to maximize their benefits while minimize potential harms for adverse events. The natural history data NINDS gained through these efforts has been critical in the approval decisions for SMN-enhancing therapies and continues to improve the design of additional clinical trials in SMA.
In addition, the NIH launched the BRAIN Initiative to bring together discoveries that promise to unravel some of the enduring mysteries of the brain, including the underlying causes of many neuromuscular diseases. Through 2019, the NIH had made 700 awards totaling $1.3 billion to the program.
SMA became an approved research topic in the DoD’s Peer-Reviewed Medical Research Program in 2016, “opening up a whole new level of funding from a completely new source,” said FightSMA Co-founder Martha Slay at the time. That opened up consideration by the DoD’s Congressionally Directed Medical Research Programs.
According to the DoD, “the vision and mission of the PRMRP is to improve the health, care, and well-being of all military service members, veterans, and beneficiaries by encouraging, identifying, selecting, and managing medical research projects of clear scientific merit and direct relevance to military health.” While the funding clearly benefits veterans and beneficiaries who develop SMA, the immediate relevance to military health might be less obvious.
An approved grant to Columbia University in New York succinctly explained the importance of SMA research to the DoD. “Department of Defense investment in this initiative would increase the chances of finding treatments for current members of the armed forces and veterans who otherwise remain paralyzed or die from combat-related conditions,” it said. “Since SMA research focuses on dying neurons, how to keep them alive, and how to stimulate them to regenerate, discoveries in this area should have impact for treatment of traumatic injuries to the brain and spinal cord, and this has specific relevance to the armed forces in Iraq.”
Further, the grant application noted, greater understanding of disease mechanisms and advances in treatment in SMA could be applicable to other degenerative diseases, including Alzheimer’s disease and (ALS). Clinicians anticipate that advances in treatment of SMA will be applicable to other degenerative diseases such as amyotrophic lateral sclerosis (ALS) which appears to have developed at increased rates in veterans who served in the Gulf War.
Federal funding for research in SMA remains critical. While the recently developed SMN-enhancing therapies have transformed the outlook for many newly diagnosed SMA patients and improved the prognosis for many others. Still, a cure remains elusive and not all patients respond equally to the available therapies.
Further, the long-term trajectory of patients with type 1 SMA is just now coming into view and the impact of new treatments on type 2 and type 3 patients over time remains unknown. More critically, the precise details of the pathogenesis of SMA and the disease’s impact on the brain, liver, pancreas and other organs continues to be unclear.
Despite these uncertainties and the continued need for development of therapies that address the non-motor aspects of SMA, many funding organizations and charities in the U.S. and abroad have experienced greater challenges in raising money to continue research since the approval of the disease-modifying therapies.
Ensuring that these therapies can provide maximum benefit and that new ones will be discovered to address unanswered issues, “can only occur with a steady flow of funding from both charities and federal/government funding bodies,” argued Melissa Bowerman, PhD, of Keele University School of Medicine in the UK, in an editorial in Future Neurology. “Thus, while we have changed the course of the disease for the better, it is important that we continue funding fundamental, pre-clinical and clinical SMA research, to keep us on an upward trajectory, in the hopes that one day, no one has to succumb to SMA.”1
- Bowerman M. Funding for spinal muscular atrophy research must continue. Future Neurology. 5 June 2019;14(2). Published online.