Today, MDA announced the award of 34 new grants totaling $9.9 million for its Summer 2018 grant cycle. These new grants represent a continued commitment by MDA to fund groundbreaking research that will one day lead to treatments and cures for the diseases in its program. Each grant will impact neuromuscular disease research in a different way, from better understanding the underlying mechanisms of a particular disease to uncovering therapeutic targets to building a clinical research network infrastructure that will expedite clinical trials. 
Of note in this latest round of funding are two grants awarded to set up clinical research networks for Facioscapulohumeral muscular dystrophy (FSHD) and Limb-girdle muscular dystrophy (LGMD), respectively. Additionally, a research infrastructure grant was awarded to fund the development of computational tools that can integrate and analyze complex amyotrophic lateral sclerosis (ALS) data sets.
This latest round of funding also includes 24 research grants awarded to established, independent investigators; five development grants awarded to investigators at the beginning of their careers and who are on the brink of becoming independent investigators; one clinical trial travel grant to help alleviate the financial burden on individuals and families traveling to participate in clinical research; and one clinical research training scholarship to a physician in the early stage of their medical career who is interested in pursuing a career in clinical neuromuscular research.
Answering crucial questions to speed therapy development
The Summer 2018 grant cycle builds upon decades of MDA-backed research that has led to several FDA-approved treatments and a clinical pipeline of therapies more robust than ever before, in addition to providing funding for novel discovery research. However, there are still unanswered questions about the underlying mechanisms of many neuromuscular diseases. As technology improves, new techniques are being developed to better diagnose patients on a genetic level and develop therapeutic targets to aid in drug discovery once these mechanisms have been identified.
All of these grants aim to find answers to the important questions that are needed to further our understanding of neuromuscular diseases and aid in the development of therapies targeting these diseases.
Some highlights from this latest grant cycle:
Melissa Spencer, Ph.D., professor of Neurology at the University of California, Los Angeles, was awarded an MDA Research Grant to develop nanoparticles for the treatment of neuromuscular disorders, including Duchenne muscular dystrophy (DMD). This technique is an alternative approach to the delivery of therapies based on gene editing, gene replacement, and gene silencing. Nanoparticle-based delivery has the potential to be more accurate and effective than the adeno-associated virus (AAV) method currently in use in gene therapy trials today.
“One of the biggest barriers to success for gene therapies is the ability to deliver the cargo to the tissue of interest,” says Spencer. “In our case the goal is to reframe (correct) the DMD gene in skeletal muscle and in the heart. By developing a systemically injectable nanoparticle delivery platform, we hope to have a mechanism to use to deliver our CRISPR platform to multiple muscles in the body.”
Francis Sverdrup, Ph.D., associate professor of Biochemistry and Molecular Biology at St. Louis University, was awarded an MDA Research Grant to study drugs targeting DUX4 expression in FSHD. DUX4 protein in skeletal muscle is considered the leading cause of muscle degeneration in FSHD. Dr. Sverdrup’s aim will be to continue work on recently identified compounds to find the most effective way to suppress DUX4, which may one day lead to a treatment for FSHD. This project aims to characterize the effects of two types of compounds, beta-2 adrenergic agonists and intracellular signaling modulators, in FSHD cells and a mouse model to gauge therapeutic potential.
Carlo Rinaldi, Ph.D., associate professor and clinician scientist at the University of Oxford in England, was awarded an MDA Development Grant to study how variants in the gene of the androgen receptor (AR) protein cause spinal-bulbar muscular atrophy (SBMA), and investigate the potential of alternative isoforms as novel therapeutic targets. The results of the study will provide a better understanding of SBMA disease mechanisms, as well as develop a new therapy potentially capable of treating the disease.
This work has potential implications for other diseases of the motor unit as well, including spinal muscular atrophy (SMA) and ALS. This grant is co-funded by the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM).
Ludo Van Den Bosch, Ph.D., principal investigator at VIB in Leuven, Belgium, was awarded an MDA Research Grant to study the role of histone deacetylase inhibitors in mouse models as a potential therapeutic approach for ALS. In ALS patients, the motor axon is the most vulnerable compartment determining survival of the nerve cell and it is thought that by inhibiting histone deacetylse 6 (HDAC6), the motor axon can be preserved. Previous MDA-supported work by Dr. Van Den Bosch has highlighted HDAC6 as a potential therapy for Charcot-Marie-Tooth disease (CMT), currently under development by industry.
Dr. Van Den Bosch is hopeful that his research will one day bring about an effective therapy for ALS: “With our research, we want to contribute to the development of a cure! This proposed strategy can be translated relatively fast into a new therapy as the class of drugs that we are testing have already been tested in patients suffering from other diseases, such as cancer.”
Francesco Muntoni, M.D., chair of Pediatric Neurology in the ICH Developmental Neurosciences Programme at the UCL GOS Institute of Child Health in London, England, was awarded an MDA Research Grant to identify novel gene mutations in congenital muscular dystrophy (CMD) and in congenital myopathy (CMY) using advanced genetic techniques. Around 50% of patients with these two conditions do not have a genetic diagnosis, which affects patient care by limiting a clinician’s understanding and knowledge about disease progression, complications and heritability, along with hampering drug development efforts.
Dr. Muntoni’s research will aim to establish the gene-causing mutation in individuals with these conditions whose initial gene sequencing was not conclusive. This information will help to shed light on the biological pathways leading to congenital muscle diseases and facilitate the development of future therapies.
Samya Chakravorty, Ph.D., postdoctoral research fellow at Emory University, was awarded an MDA Development Grant to study the functional resolution of a subset of unsolved cases from MDA’s LGMD genetic testing platform. The goal is to investigate these gene variants to see if these cases are the result of multi-gene pathogenicity – whether instead of one genetic defect, patients have multiple defects that are causing their symptoms.
“This work will specify what proportion of LGMD multi-genic cases can reach a molecular diagnosis and get enrolled in clinical trials,” says Chakravorty. “Besides the clinical impact, this project will also have a major impact on our basic scientific understanding of how different LGMD sub-types and related diseases such as Pompe disease are related in the muscle genome.”
Michio Hirano, M.D., professor of Neurology at Columbia University Irving Medical Center, was awarded an MDA Research Grant to conduct an open-label expanded access trial of deoxynucleoside therapy for Thymidine kinase 2 (TK2) deficiency, a type of mitochondrial DNA depletion syndrome (MDS). The disease typically affects infants and children and is progressive, causing muscle weakness and for more than half of patients, mechanical ventilation. It is estimated that approximately 400 patients in the U.S. have TK2 deficiency.
With previous MDA funding, Dr. Hirano created a TK2 deficiency mouse model and demonstrated that treatment with deoxynuclosides were effective in extending their lifespan. He then obtained approval for compassionate use of this therapy in TK2-deficient patients. To date, 15 treated patients have shown clinical improvements by diverse measurements across multiple countries with this therapy. With this current funding, a uniform prospective study on the safety and efficacy of this treatment in TK2 patients will be conducted. The results will inform the design of the pivotal clinical trial necessary to obtain FDA approval.
Investing in clinical research infrastructure
In this latest round of grants, MDA has strategically committed funding to invest in clinical research tools and infrastructure that are crucial to better understanding disease pathways and accelerating treatments in ALS, FSHD and LGMD.
MDA awarded two clinical research network grants for FSHD and LGMD. Each grant will support a network of MDA Care Centers with expertise in each disease’s research and clinical care and is targeted to facilitate the development of the tools and infrastructure needed to conduct clinical trials and accelerate treatments. Jeffrey Statland, Ph.D., Principal Investigator at the University of Kansas Medical School will head up the FSHD network and Nicholas Johnson, Ph.D., Associate Professor of Neurology at Virginia Commonwealth University will lead the LGMD network.
MDA also awarded a research infrastructure grant to Jeffrey Rothstein, M.D., Ph.D., at Johns Hopkins University School of Medicine, to fund the development of new data analytics approaches for the Answer ALS research project. These analytics tools will support the integration and analysis of over 20 trillion data points generated by Answer ALS, with the goal of enhancing understanding of ALS disease mechanisms and advancing the discovery of targets for effective therapy.
MDA’s unwavering commitment to finding treatments and cures
The awarding of so many new grants is a recognition of the unprecedented advances that have taken place in technology and drug discovery in the last several years. The opportunity to fund meaningful research that will one day lead to treatments and cures has never been greater than it is today, and MDA remains committed to continuing to fund groundbreaking research to one day make these life-changing therapies a reality.
