More than 40 new grants support new drug development, greater understanding of disease processes and more efficient diagnosis of neuromuscular diseases
The Muscular Dystrophy Association has awarded 44 new grants totaling $13.6 million to advance the understanding and treatment of neuromuscular diseases. The new grants, most of which took effect Feb. 1, encompass a range of diseases covered by MDA’s research program, and they support innovative approaches to basic research and new drug development.
In addition to addressing 16 specific neuromuscular diseases under MDA’s umbrella, the grants also fund research into muscular dystrophy in general, and research into muscle physiology related to neuromuscular disease.
To learn about each new grant, visit the Winter 2013 Grants at a Glance slideshow.
Many of the projects funded by this new round of MDA grants fall into four broad categories:
1. Understanding the relationship between specific genetic mutations and disease manifestations. A number of grants enable researchers to look at specific genes that are known to cause disease and determine what the mutation in that specific gene does.
“MDA-funded research has made amazing advances in identifying genes that relate to diseases, but there is still a lot to be learned about how those genes cause the characteristics of the disease,” said Jane Larkindale, MDA vice president of research. “Gaining this understanding gives us a host of new therapeutic targets — a major part of MDA's research focus.”
2. Early-stage testing of specific therapeutic hypotheses. MDA is funding researchers to screen for and test molecules that might be able to be turned into therapies.
“While basic research gives us hypotheses about how we might be able to treat a disease, these projects test those hypotheses,” said Larkindale. “Is the mechanism important? Is there is a target worthy of building a drug around? The results of these projects could lead to drugs that we can test or to new therapeutic targets.”
3. Understanding the processes of degeneration and regeneration in muscles and in nerves. MDA-supported researchers will closely examine the process of deterioration and regrowth in axons (nerve fibers), muscle and the muscle membrane.
“Most of the diseases under MDA’s umbrella are diseases of degeneration, either because there is too much degeneration, not enough regeneration or both,” Larkindale said. “Studies like these are looking for the mechanisms by which these processes are regulated, and how we can tip the balance in a favorable direction.”
4. Developing more efficient diagnostics for neuromuscular diseases. These grants fund the development of better screening techniques for diagnosing disease, including newborn screening technology for Duchenne muscular dystrophy (DMD).
“One of the advantages to being an ‘umbrella organization’ that covers many types of neuromuscular disease is that we can fund individual research projects that can tell us about several diseases,” Larkindale noted. “For example, our grant to John Manfredi of Sfida BioLogic to investigate small molecules that promote the growth of axons of motor neurons in spinal muscular atrophy also may shed light on other diseases of axon degeneration, such amyotrophic lateral sclerosis and Charcot-Marie-Tooth (CMT) disease. Similarly, Noah Weislander at Ohio State University is taking a drug that’s in development for DMD and applying it to limb-girdle muscular dystrophy.”
Amyotrophic lateral sclerosis (ALS): A number of new grants fund strategies for drug development and the search for new genes that are implicated in the disease. For more on ALS grants, see Grants Support Study of New Genes, New Drug Discovery Strategies for ALS.
Becker (BMD), Duchenne (DMD) and limb-girdle (LGMD) muscular dystrophies: New grants support several research projects aimed at investigating newly discovered repair pathways and giving these pathways a "boost" to try to reduce muscle damage.
In addition, DMD and BMD research projects include:
Charcot-Marie-Tooth disease (CMT): Researchers will study the progression of disease in a mouse model of one form of CMT to learn more about how that mutation causes problems. One focus will be on the effects of the mutation on mitochondria, the cell’s powerhouses, which are believed to be involved in CMT.
Congenital muscular dystrophy (CMD) and LGMD: In many cases of CMD and LGMD, the gene causing the disease is unknown. By analyzing the RNA (a chemical cousin to DNA) in cells, researchers hope to discover new mutations that cause these diseases, leading to better diagnosis and targets for new treatments.
Congenital myasthenic syndrome (CMS): Scientists will use high-resolution imaging technologies to study the mechanisms underlying the dysfunctions seen an animal model of CMS. These images will be used to better understand the defects caused by the gene at the neuromuscular junction, where muscle and nerve interact.
Distal muscular dystrophy (DD): Laing distal myopathy is an inherited muscle disease characterized by early and selective weakness of the lower leg that affects ankle and great toe bending. With time, the disease progresses to other muscles, including those of the neck and face. It is caused by mutations in the gene for a muscle protein that helps create the pulling force that allows muscles to contract. Researchers will explore how the disease-causing mutation prevents normal interaction of muscle proteins, and will create a mouse model in order to better study the effects of mutation and to test potential therapies.
Dysferlinopathies: Dysferlinopathies are a group of muscular dystrophies (including LGMD2B and Miyoshi myopathy) caused by mutations in the dysferlin gene, which carries instructions for the dysferlin muscle repair protein. Researchers will explore how calcium signaling differs between healthy cells and those lacking dysferlin, leading to better understanding of the disease process and options for therapy development.
Friedreich’s ataxia (FA): One project targeting FA will develop new research models and explore new therapeutic approaches for the disease. In this project, the DNA carrying the FA mutation will be “edited” to correct the mutation, using new molecular tools. This will allow comparison of cells with and without the mutation that are otherwise genetically identical. A second project will study ways to overcome the vulnerability of heart muscle in the disease. That vulnerability involves mitochondria, the cell’s energy producers, which may be deficient in their ability to use fats and sugars as fuels. Overcoming that deficiency may be a viable therapeutic strategy.
Facioscapulohumeral muscular dystrophy (FSHD): FSHD is caused by mutations that cause production of a toxic protein called DUX4. One group of researchers will be searching for changes in muscle and blood proteins that occur in FSHD, hoping to find a biomarker (biological indicator) that can be used to track response to therapy in future clinical trials. Another group will use gene-editing tools to correct mutations in patient cells, and compare muscle development between uncorrected and corrected cells, in order to shed light on the molecular mechanisms underlying FSHD.
General muscular dystrophies and muscle physiology: Several new grants fund projects that may lead to insights applicable to many muscle diseases. That may be case for a vitamin A-like molecule that blocks two different pathologic processes in muscle: formation of bone within the muscle and muscle degeneration. Scientists will be conducting experiments to learn more about this molecule’s effects and exploring whether it has potential for treatment of muscular dystrophy. Other scientists will be pursuing a cell transplantation strategy in which skin cells are first transformed into muscle cells. They will be working to optimize cell delivery and survival strategies, as well as exploring whether treating cells before transplantation with a regulatory gene can improve the long-term success of the transplant.
Inclusion-body myositis (IBM): Three groups will be exploring aspects of IBM, and its overlap with ALS. Mutations in a gene called VCP are one cause of both diseases. One group is exploring the possibility that VCP may be involved in a gene regulatory system that fails when the gene is mutated. Another group will be using state-of-the-art gene hunting techniques to find other genes that cause IBM, in order to better understand its causes and potential therapies. A third group will be focusing on the protein aggregates found in both VCP and ALS, which are believed to indicate an ongoing toxic process within the cell, and may be toxic themselves. By studying the aggregation process in yeast, scientists hope to better understand how aggregation leads to disease, and whether the aggregates can be targeted with new therapies.
Myotonic muscular dystrophy (MMD, also known as DM): Two projects will take aim at MMD. One project will develop better diagnostic tools that should allow doctors to offer their patients much more detailed information about the likely clinical course of the disease and the likelihood of it developing in those not yet affected. The other project will test the ability of compounds to target the toxic RNA that causes the disease, an early step in drug development.
Oculopharyngeal muscular dystrophy (OPMD): OPMD is caused by mutations in the PABPN1 gene. Researchers will use a fly model of the disease to understand how the mutation leads to the disease, a crucial step in developing therapy.
Mitochondrial myopathies: In people with a mitochondrial myopathy, some mitochondria are mutated and function poorly, while others are healthy. Researchers will explore whether these diseases can be treated by encouraging cells to degrade their unhealthy mitochondria, thus promoting reproduction and growth of nonmutated mitochondria.
Myasthenia gravis (MG): MG comprises several related diseases, all involving anautoimmune attack on the neuromuscular junction (where signals are passed between nerve and muscle). In autoimmune diseases, the immune system mistakenly attacks the body's own tissues.
One research group will better characterize the immune regulatory system that goes awry in the disease, allowing antibodies to attack the body's own proteins at the neuromuscular junction. A second group will study a new animal model of one form of MG, called anti-MuSK myasthenia (AMM), to understand the progression of the disease and options for therapy. A third group will develop tools for diagnosis of the low-density lipoprotein receptor-related protein 4 (LRP4) form of MG.
Spinal muscular atrophy (SMA): The gene defect in SMA is known, but there is still much to be learned about how it causes disease. Scientists will examine the protein product of the gene to discover how it moves through the cell and identify the other molecules with which it interacts. The long extensions of motor neurons called axons are a particularly important target in SMA because they degenerate before the neuron dies; improving their survival is the goal of another MDA grant. Still other researchers will test whether therapy must be given early in the course of disease to have a beneficial effect, an important unknown question as new treatments are tested.
Details about each of these new grants are given in the Winter 2013 Grants at a Glance slideshow.
Richard Robinson is a freelance medical and science writer based in Sherborn, Mass.