"Absence of the protein called collagen VI (COL6), which is important for the integrity and function of skeletal muscle and numerous tissues, leads to several forms of neuromuscular diseases with variable clinical presentation, collectively named COL6-related dystrophies (COL6-RD). They are amongst the most common congenital muscular dystrophy forms throughout the world. Despite our increasing knowledge of these diseases, no curative treatment is available yet."

Valérie Allamand, Ph.D., is a Researcher at Sorbonne Universite-Inserm in Paris, France, has been awarded an MDA Idea Grant totaling $25,000 for one year to use viral vectors to deliver transfer RNAs (tRNAs) to synthesize collagen VI protein.

COL6 mutations that introduce premature stop codons show the most severe clinical presentations. Individuals who are affected by these mutations, about 10% of patients with COL6-RD, typically do not have COL6 synthesized in the extracellular matrix. Dr. Allamand will correct the production of COL6 by using anticodon engineered tRNAs. The findings will provide data for in vivo approaches on treated cells and pre-clinical studies in COL6-RD mouse models with nonsense mutation. Additionally, the technique used in this project can be applied to other neuromuscular diseases caused by nonsense mutations.

"Altered RNA metabolism is a common theme in ALS. Indeed, RNA binding proteins (RBPs) are among the most commonly mutated proteins in inherited forms of ALS. These mutations alter gene expression and change the function of RNA-RBP condensates in the cell."

Frederick Arnold, Ph.D., is a Postdoctoral Scholar at The Regents of the University of California in Irvine, CA has been awarded an MDA Development Grant totaling $220,000 for three years to identify central regulators of RNA metabolism in human motor neurons and understand how it changes in ALS.

The RNA exosome complex is found in all cells and known to be important for the survival of motor neurons. The subunits of the exosome complex interact directly with RBPs implicated in ALS. Dr. Arnold's project will help discover RNA substrates and RBP cofactors of the exosome complex in healthy and ALS human motor neurons which could have broad therapeutic impact in ALS treatment.

"In nearly all cases, the genetic defect is caused by the inheritance of two deleted copies of SMN1, which can rapidly be detected in any genetics laboratory. Instead of inheriting SMN1 gene deletions, a small subset of SMA patients have small DNA changes in the SMN1 gene. In these cases, a nearly identical gene known as SMN2 complicates detecting DNA changes in the SMN1 gene."

Matthew Avenarius, Ph.D., is an Assistant Professor at The Ohio State University in Columbus, OH, has been awarded an MDA Idea Program of $25,000 for one year to detect DNA changes in the SMN1 gene using advance DNA sequencing technologies.

Spinal Muscular Atrophy (SMA) is a group of hereditary diseases affecting motor neurons in the spinal cord and brainstem, which are essential for controlling skeletal muscle activity, causing progressive deterioration and weakness. Individuals with SMA present severe muscle weakness in early childhood with most do not live past the age of 2. Treatment and diagnosis of SMA relies on early detection of mutations in the SMN1 gene. Dr. Avenarius' novel technology to sequence different variants of SMN1 offers the potential to provide a molecular diagnosis of SMA and gain knowledge about these genetic changes.

"Despite the similar initiating cause, DMD patients vary significantly in the progression of the disease. Recent studies pointed at the membrane molecule jag1 as a positive modulator of muscle regeneration capable of conferring a nearly normal clinical phenotype and lifespan in naturally occurring jag1 overexpressing canine models of DMD."

Stefano Biressi, Ph.D., is an Associate Professor at the University of Trento in Provo-Trento, Italy, has been awarded an MDA Idea Grant totaling $25,000 for one year to increase jag1 membrane protein activity by using a novel class of synthetic long non-coding RNAs, also known as SINEUPs.

SINEUPs increase protein synthesis in mammalian cells by binding efficiently to target mRNA. They have been shown to upregulate protein synthesis within physiological levels, which shows an optimal safety profile. Dr. Biressi's work is to develop synthetic SINEUPs that can target the upregulation of jag1 in dystrophic mice. Their work will help speed up the process of developing a new approach to target other therapeutic genes in dystrophic muscle.

"Although research has revealed a number of desirable properties for donor cells, in particular the ability to return to a state of dormancy and a location close to muscle cells, more work is needed to uncover methods to enforce the acquisition of these properties."

Alexandre Blais, Ph.D., is a Principal Investigator at the University of Ottawa in Ottawa, Ontario, Canada, has been awarded an MDA Idea Grant totaling $25,000 for one year to study the genome of muscle stem cells and identify roles of regulatory proteins.

Among the many potential therapies that are being investigated to treat neuromuscular diseases including Duchenne Muscular Dystrophy (DMD), muscle stem cell therapy provides promising approaches. However, there are still many challenges with muscle stem cell therapy that researchers are posed with. A common challenge is that donor cells do not assume the fate of desired cells once transplanted into recipient muscles. Dr. Blais’s research will help identify the molecular mode of action of a regulatory protein that is important for the dormancy of muscle stem cells.

"Charcot-Marie-Tooth disease (CMT) is a genetic neuromuscular disease, causing muscle weakness, foot deformities, and frequent trips and falls or difficulty walking. There is currently no cure for CMT, but promising treatments are on the horizon."

Joshua Burns, Ph.D., is a Professor of Paediatric Neuromuscular Rehabilitation and Associate Dean Research at the University of Sydney in Sydney, NSW, Australia, has been awarded an MDA Idea Grant totaling $25,000 for one year to develop training and resources and accreditation program for clinical evaluators worldwide to help assess patients with CMT.

A robust clinical outcome assessment (COA) is available online, www.clinicaloutcomemeasures.org, for use with individuals with CMT. The online has over 200 clinical evaluators registered worldwide. To avoid evaluator drift and variability in assessment measurements, online training and accreditation systems are significant especially during the COVID-19 era. Dr. Burns's project aims to make eHealth training and resources available and accredit clinicians to use COAs as a reliable measurement for clinical trials and how to use it accurately.

"Neuromuscular diseases result from dysfunction in the spinal cord, nerves or muscles. This dysfunction is often caused by mutations in our genes. Genetic advances have resulted in the discovery of more than 500 genes which cause neuromuscular diseases."

Daniel Calame, M.D., Ph.D., is a Postdoctoral Fellow at Baylor College of Medicine in Houston, TX, has been awarded an MDA Development Grant totaling $220,000 for three years to improve rates of diagnoses expand the knowledge in neuromuscular genetics using RNA-seq and long-read whole genome sequencing.

Despite these advances, more than half of patients with neuromuscular disease still lack a genetic diagnosis. Several factors contribute to low diagnostic rates. Utilization of RNA-seq and long-read whole genome sequencing in a cohort of well-characterized patients with undiagnosed neuromuscular disease will help discover novel mechanisms of neuromuscular disease and create opportunities for new treatments.

"Myotonic dystrophies (DM1 and DM2) represent the most common inherited muscular dystrophies in adults. These diseases are caused by the expansions of CTG and CCTG base repetitions in the DMPK and CNBP genes, respectively. The presence of these repeats triggers the accumulation of long genetic products that form clumps inside the cell and interfere with the production of many other proteins."

Massimo Delledonne, M.Sc., Ph.D., is a Full Professor at the University of Verona in Verona, Italy, has been awarded an MDA Idea Grant totaling $25,000 for one year to optimize properties of DM expansions and understand the relationship based on clinical phenotype.

Formation of clumps inside the cells of DM patients leading to a cascade of effects that interferes with muscle cells functioning properly and ultimately leading to muscle deterioration. However, it remains unclear how expansion sizes affect symptoms and severity of the disease. Dr. Delledonne's research will apply innovative genomic technologies that will help uncover new DM expanded alleles, better way to stratify patients in trials, and potentially improve the types of information needed to establish a diagnosis for other neuromuscular diseases with known repeat expansions.

"Duchenne muscular dystrophy (DMD) is a severe genetic disease that affects about 1 out of 4000 boys. The disease causes progressive muscle loss and weakness, resulting in ambulatory difficulties that are followed by an early death."

Junio Dort, Ph.D., is a Postdoctoral Research Fellow at the Centre Hospitalier Universitaire Sainte-Justine in Quebec, Canada, has been awarded an MDA Development Grant totaling $220,000 for three years to investigate the effects of specialized pro-resolving medicators (SPMs) as a treatment for DMD. SPMs are fatty acids-derived molecules with potent anti-inflammatory effects.

Glucocorticoid drugs are used to help dampen inflammation to partially preserve muscle function in DMD. However, the beneficial effects are time limited and there are detrimental side effects. In this work, Dr. Dort will examine the translational potential of resolving D2 (RvD2), a SPM derived from omega 3 fatty acids, in different models.

"Amyotrophic lateral sclerosis (ALS) affects multiple parts of the body including the muscles that control breathing. Early signs of breathing difficulty can appear during sleep, where they often go unrecognized by patients and physicians alike. Identifying early breathing changes in ALS may improve access to life-sustaining therapies."

Andrew Geronimo, M.Sc., Ph.D., is an Assistant Professor at The Pennsylvania State University College of Medicine in Hershey, PA, has been awarded an MDA Idea Grant totaling $25,000 for one year to measure changes in carbon dioxide (CO2) levels using a medical device that is attached to the skin.

ALS is a progressive neuromuscular disorder that weakens the muscles of respiration, eventually leading to chronic respiratory failure with abnormally high concentration of CO2 in the blood. In ALS clinics, they collect respiratory measurements during the day, but not during the nighttime. Dr. Geronimo's project hopes to show that the use of a medical device that will sense CO2 on the skin during sleep can help identify breathing problems and detect any breathing challenges at an earlier stage. Their study has the potential to inform how early respiratory therapies can improve the quality of life and survival of ALS patients.

"There is an enormous need for a better understanding of the clinical, demographic, and genetic features that underlie the phenotypic variability of ALS."

Jonathan Glass, M.D., Ph.D., Professor of Neurology at Emory University, has been awarded an MDA restricted research grant of $75,517 for one year to continue to provide the ALS research community with data, biofluids, and tissues from deeply phenotyped ALS patients and people without ALS who participate in Emory's Clinical Research in ALS (CRiALS) project.

There is significant phenotypic and genetic heterogeneity observed among persons with ALS, which may partly explain some of the failures in clinical trials. The CRiALS database is considered one of the most valuable resources for ALS research with a large and extremely well characterized patient population. Dr. Glass' work could pave the way for better defined disease features and ultimately clinical trials targeting specific patient populations.

"While enhancing SMN as a means to treating SMA is undoubtedly a major development, the therapeutic strategy has its limitations. Indeed, early clinical results and the outcome of studies in model mice have shown that one major caveat stems from the timing of treatment; unless patients are treated shortly after birth, they tend not to benefit."

Narendra Jha, Ph.D., is a Postdoctoral Scientist at Columbia University Medical Center in New York, NY, has been awarded an MDA Development Grant totaling $220,000 for three years to identify factors that mediate the effects of SMN on the neuromuscular system, specifically muscle and nerve.

Although there have been therapeutic advances developed to address SMA, there is still a need to better understand the basic biology of SMA. The outcome of Dr. Jha's project will help with two potential discoveries: 1) unravel how low SMN protein can lead to SMA and 2) refined treatments of the disease.

"ASO-based approaches have shown promising results in different neurodegenerative diseases and I will test whether the method is efficient in blocking aberrant translation in C9ORF72 ALS/FTD. Overall, this project will not only help us understand the contribution of DPRs in ALS/FTD but will also shed light on a potential therapeutic strategy for C9ORF72-disease."

Xin Jiang, Ph.D., is a Postdoctoral Research fellow at Massachusetts General Hospital in Charlestown, MA, has been awarded an MDA Development Grant totaling $220,000 for three years to investigate the effects of genome editing and antisense oligonucleotides (ASOs) in blocking the synthesis of dipeptide repeats (DPRs).

Accumulation of abnormal proteins called dipeptide repeats (DPRs) are the most common cause for inherited ALS and FTD (Frontotemporal dementia). These DPRs are easy to form protein aggregates in the brain and are toxic to the brain cells. Findings from Dr. Jiang's project will help us understand the effects of DPRs in ALS and Frontotemporal Dementia (FTD).

"Muscular dystrophy-dystroglycanopathies (MDDGs) resulting from fukutin-related protein (FKRP) gene mutations are rare disorders and currently, there is no cure and very few options are available for symptom management."

Qi Lu, M.D., Ph.D., director of the McColl Lockwood Laboratory for Muscular Dystrophy Research at Atrium Health in Charlotte, NC, has been awarded an MDA restricted research grant totaling $162,455.36 over two years to evaluate a combination treatment regimen using gene replacement therapy and a pentose alcohol based product that will enhance and maintain long-term efficacy of therapies for FKRP-related dystroglycanopathy patients.

Heart failure is a common cause of death in people with all types of muscular dystrophy, due to accumulation of fibrosis leading to poor regenerative capacity in the heart muscle, and ultimately heart failure. Dr. Lu's research may provide new hope for all heart failure patients.

"With the advent of multiple approved exon skipping therapies, meaningful disease modifying therapy is now a reality. This therapy results the restoration of dystrophin expression, the protein whose absence causes DMD. However, it is missing both the initial defect, as well as a small portion skipped therapeutically."

Nick Menhart, Ph.D., is an Associate Professor at the Illinois Institute of Technology in Chicago, IL, has been awarded an MDA Idea Grant totaling $25,000 for one year to use the computational tools they developed to understand the impact of edits on dystrophin stability and structure.

Exon skipping can only occur at exon skipping areas, which can lead to protein structure instability. Dr. Menhart's lab discovered that edit-mediated structural disruption did not occur near the edit site, but rather located outside of the edit side and exhibited at domain junctions. With their computational framework they can search for optimal edits on the protein and test the sites with wet lab testing.

"Despite great efforts there is no cure for DMD. In this context, it is reasonable to propose that an effective treatment that could prevent or even delay key aspects of DMD muscle disease would be the next best outcome in place of a cure."

Joseph Metzger, Ph.D., Faculty and Head of the Regents of the University of Minnesota – Twin Cities in Minneapolis, MN, has been awarded an MDA Idea Program of $25,000 for one year to evaluate a new high throughput method to test the stability of shortened dystrophin proteins in human stem cell derived skeletal and cardiac muscles.

Dystrophin serves as a link between the cytoskeleton, muscle membrane and extracellular matrix (ECM). Mutations in dystrophin perturbs its normal function leading to progressive deterioration of cardiac and skeletal muscles. There are several ongoing clinical trials focused on using modified shortened forms of the dystrophin protein. Dr. Metzger's project will be essential in characterizing crucial parameters of dystrophin dosing and function required for the success of active and future genetic based DMD clinical trials.

"ALS begins rarely with only upper motor neuron. We have no scientific data as to how the patient whose disease begins only with upper motor neuron impairment."

Hiroshi Mitsumoto, M.D., Wesley J. Howe Professor of Neurology at Columbia University Medical Center, has been awarded an MDA restricted research grant of $31,112.95 for one year to support continuation of three National Institutes for Health and Centers for Disease Control and Prevention-funded studies, for which MDA has already provided supplemental funding.

Studying the epidemiology associated with ALS is critical for developing a better understanding of the disease. Dr. Mitsumoto will continue to analyze large cohorts of ALS patients to identify potential environmental risk factors in ALS.

"Our unbiased transcriptomics and metabolomics profiles with ALS-specific spinal motor neurons derived from induced pluripotent stem cells (iPSCs) revealed dysregulation in lipid metabolism and its related gene expression. Importantly, pharmacological modulation of one of the disrupted lipid pathways is sufficient to reverse ALS-related phenotypes in ALS iPSC motor neurons, fly and mouse models."

Jeffrey Rothstein, M.D., Ph.D., director of the Robert Packard Center for ALS Research at Johns Hopkins University School of Medicine, has been awarded an MDA restricted research grant of $31,113 for one year for investigator Gabsang Lee, PhD, Associate Professor in the Department of Neurology and Neuroscience, to develop unbiased screening of lipid pathways and lipid metabolites that can reverse ALS-related phenotypes.

Research in Dr. Lee's lab analyzes small molecule substrates left behind by chemical processes and collects a snapshot of the total transcripts in the cell at a given time to examine changes of lipid-related metabolism pathways in ALS spinal motor neurons. Their study aims to understand the connection between mis-regulated metabolism and ALS, which could potentially lead to new therapies.

"Duchenne Muscular Dystrophy (DMD) is a fatal inherited disease, causing boys muscles, including the heart and respiratory muscles, to waste away. Currently, it is incurable and there is an extraordinary need for new medicines to treat the rate and severity of its progression."

Emma Rybalka, Ph.D., is a Senior Fellow and Lecturer at Victoria University in Melbourne, Australia, has been awarded an MDA Idea Grant totaling $25,000 for one year to investigate the re-purposed medicine dimethyl fumarate (DMF) as a treatment for DMD.

Dr. Rybalka's group identified DMF as having a high translational potential because it is a strong anti-inflammatory and immunosuppressant drug, it helps with muscle repair and growth, and it has been approved worldwide to treat Multiple Sclerosis. This project will help identify the efficacy of of MDF as a treatment for DMD.

"Measuring the capacity for exercise and associated physiological responses will be important in determining the functional efficacy of emerging treatments, as well as in establishing guidelines for patients to safely exercise. Currently, the 6-minute walk test (6MWT) is the only FDA-approved outcome and it measures submaximal exercise capacity."

Tanja Taivassalo, Ph.D., is a Research Associate Professor at the University of Florida in Gainesville, FL, has been awarded an MDA Idea Grant totaling $25,000 for one year to use physiological exercises to study functional capacity in patients with Duchenne Muscular Dystrophy (DMD).

DMD is a progressive disease that causes muscle deterioration, which causes children to premature loss of ambulation and death from respiratory or cardiac failure. In the age of discovering disease modifying treatments to improve muscle function and exercise capacity, quantification of exercise intensity and understanding the limitations will become important aspects in determining treatment efficacy and prescribing safe exercise guidelines. Dr. Taivassalo's work will uncover underlying mechanisms that reduces exercise capacity, how physiological exercises help improve exercise capacity in response to therapy, and clinical guidance to DMD patient care.

"For most neuromuscular disorders, genetic diagnosis is currently performed by high throughput screening (HTS). Genetic testing for myotonic dystrophy 1 (DM!), however, lags behind, which presents significant challenges for the field."

Charles Thornton, M.D., Saunders Family Distinguished Professor in Neuromuscular Research at the University of Rochester Medical Center, has been awarded an MDA restricted research grant of $38,725 for one year to make improvements in technology for genetic testing of DM1, a relatively common form of muscular dystrophy.

Current genetic testing methods for individuals with DM1 are expensive, labor intensive, have limited throughput, and lack the precision needed to determine the size of the expanded CTG repeat. Dr. Thornton is developing a novel method of genetic analysis that is simple, amenable to high throughput, and able to determine repeat expansion sizes. This technology could be important to increase patient access to genetic testing and understand the complex diversity of expanded alleles in individuals.

"There is an enormous need for a better understanding of the clinical, demographic, and genetic features that underlie the phenotypic variability of AL Within the cell, mitochondria contain the system responsible to make aerobic energy: the mitochondrial respiratory chain (MRC) and the oxidative phosphorylation system. Any mutation in this machinery produces a mitochondrial disease."

Alba Timón-Gómez, Ph.D., is a Postdoctoral Associate at the Miller School of Medicine of the University of Miami in Miami, FL, has been awarded an MDA Development Grant totaling $220,000 for three years to study the who and how mitochondrial respiratory chain plasticity is regulated in healthy and stress induced cells.

The muscles and brain have high energy demands, which makes them the most affected organs in mitochondrial disorders. Findings from this work could help gain insights into the pathogenesis of mitochondrial encephalomyopathies.

"Loss of dystrophin protein perturbs several cellular components important for maintaining muscle integrity, leading to a debilitating muscle disease termed Duchenne muscular dystrophy (DMD). One of the disturbed cellular processes is autophagy, an essential clean-up system that removes toxic cellular wastes."

Jae-Sung You, Ph.D., is a Postdoctoral Research Associate at The Board of Trustees of the University of Illinois at Urbana-Champaign in Urbana, IL, has been awarded an MDA Development Grant totaling $220,000 for three years to explore the role of autophagy and how it contributes to the pathology of DMD.

Studies have shown that an autophagy suppressor, mammalian target of rapamycin complex 1 (mTOR1), was observed in mouse and human DMD skeletal muscles. It has also been shown that inhibition of mTOR1 by rapamycin or low protein diet that autophagy was rescued and improved dystrophic phenotypes in DMD mice. Dr. You's work will help fill in current knowledge gap in DMD pathology and discover new therapeutic targets for the treatment of the disease.