“Axon degeneration is a central component of irreversible neurological disability in many neuromuscular diseases. There is accumulating evidence that enwrapping glia provide metabolic support to axons, and perturbed metabolic functions in these glia can result in axon degeneration.”

Bogdan Karl Beirowski, assistant professor at the University at Buffalo in Buffalo, New York, was awarded an MDA Research Grant totaling $300,000 over 3 years to study metabolic support of axons by LKB1 signaling in Schwann cells. Dr. Beirowski was the recipient of an MDA development grant in 2012.

Degeneration of long axons is a hallmark in neuropathies and neuromuscular diseases like Charcot-Marie-Tooth (CMT), Friedreich’s ataxia (FA), amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (SMA). Axonal losses lead to the debilitating neurological symptoms in these conditions, but underlying mechanisms are only poorly understood. Axons do not exist in isolation but are intimately associated with Schwann cells (SCs), which provide metabolic support to axons. When metabolic functions in these cells are disrupted, it can result in axon degeneration. In CMT neuropathies, it remains unknown how malfunction in SCs results in axon degeneration.

The Beirowski lab recently showed that SCs support integrity of long axons by virtue of their metabolism. Disruption of metabolic function in SCs from transgenic mice results in progressive axon degeneration, recapitulating a key component of human neuromuscular disease. Using genetic mouse models in his laboratory, together with the application of novel technologies to study SC metabolism, Dr. Beirowski and colleagues plan to identify glial metabolic pathways important for regulation of axon integrity and to investigate if abnormalities in such pathways may contribute to nerve damage and axon demise in CMT neuropathy models.

Michael Benatar, at the University of Miami Miller School of Medicine in Florida, and Jonathan Katz, at California Pacific Medical Center in San Francisco, were awarded a clinical research network grant to support their work on the Clinical Procedures To Support Research (CAPTURE) project, which aims to implement the “ALS Toolkit” within the Epic Electronic Health Record System. The ALS Toolkit provides a mechanism to systematize the collection of clinical data so that it can also be used for ALS (amyotrophic lateral sclerosis) research. The two-year award totaling $300,000 will support work conducted through Clinical Research in ALS and Related Disorders for Therapy Development (CReATe) aimed at lessening the burden on people with ALS to attend both clinical and research appointments. CReATe, a rare diseases clinical research consortium, is a member of the National Institutes of Health’s Rare Diseases Clinical Research Network.

Throughout the course of the disease, people with ALS require input and assistance from multiple health care professionals and, as a result, multidisciplinary clinics such as MDA ALS Care Centers are a key resource for ongoing medical management and care. Visits to care centers take several hours, and a substantial amount of clinical data (such as neurological examination results, quantification of respiratory muscle strength and motor function assessments) are routinely collected — much of it identical to the assessments performed at specialized research visits. However, data from these two types of visits are typically captured separately, necessitating separate appointments for people who, depending on the stage of their disease, may experience profound weakness, disability and difficulty associated with travel.

It has therefore been a longstanding goal of many ALS clinician-investigators to find ways to reduce the burden on patients by finding a way to regularly collect a standard data set at clinical appointments that can be used for research purposes as well.

With increasing penetration of the electronic medical record into academic medical centers, and the recently established collaboration between Benatar and Katz with Epic, a team will now develop and implement a novel ALS Toolkit (set of “smart forms”) within the electronic medical record system that will enable clinicians to collect standardized data that can serve both clinical and research purposes.

If successful, the work will support a fundamental change in practice that will provide people with ALS a simple and straightforward way to contribute to research that can accelerate progress towards treatments and cures. 

Michael Benatar, associate professor of neurology and epidemiology at Emory University in Atlanta, received an MDA grant totaling $525,000 to continue research into the early stage of FALS — familial, or inherited, ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease) — prior to symptom onset.

With funding from MDA, Benatar began his "pre-FALS" study in 2007, tracking a group of 30 people at risk for developing ALS because they harbor a mutation in the SOD1 gene, known to cause some forms of the disease. His team collected a series of physical, functional and neurological data over time in an effort to discern early biological markers ("biomarkers") of the disease process, and established a repository of biological samples collected from the study participants.

In Benatar's new follow-up study, the original group of 30 participants will expand to include presymptomatic individuals with mutations in other ALS susceptibility genes such as TDP43 and FUS.

Study aims include better definition of the presymptomatic stage of familial ALS, identification of environmental factors that might modify the age of disease onset among genetically susceptible individuals, continued development of biomarkers of early disease, and expansion of the existing collection of biological specimens.

Benatar's exploration into the presymptomatic phase of ALS could facilitate earlier recognition and diagnosis of both the familial and sporadic forms of the disease, which in turn could point the way toward therapeutics aimed at prevention or delay of ALS onset, as well as attempts to stop or slow the disease before it causes irreversible damage.

"MDA has shown great foresight in recognizing the importance of this study and the kind of long-term contribution that it can make to our understanding of the disease," Benatar said.

Funding for this MDA grant began August 1, 2010.

“I think the myotonic dystrophy field has made great gains in understanding the mechanisms of this disease, and there a number of exciting therapeutic strategies underway,” Andrew Berglund says. “This includes clinical trials with antisense oligonucleotides that target the toxic RNA as well as other strategies that target other aspects of the disease.” 

Andrew Berglund, professor of biochemistry and molecular biology at the University of Florida in Gainesville, received an MDA research grant totaling $300,000 over three years to develop a therapeutic strategy for both types 1 and 2 myotonic dystrophy (DM1, DM2).

It is thought that the genetic defect underlying DM causes a toxic RNA, which accumulates in the nucleus of the cell and causes protein dysfunction by trapping proteins important for normal cell function. (RNA is the chemical step between DNA and protein manufacturing.) Some therapeutic approaches aim at degrading these toxic RNAs, or prevent them from trapping important cellular proteins. Berglund’s approach is to prevent the toxic RNA from even being produced in the first place.   

With colleagues, Berglund recently published proof-of-principle data supporting the approach they’ve developed, called IMPEDE (inhibition of microsatellite promoted expression of deleterious expansions), which showed that treatment with an FDA-approved drug called actinomycin D reduced toxic RNA production in DM1 cell and mouse models.

Now Berglund’s team is working to further develop this small-molecule approach. Small molecules have some advantages over other types of treatments — such as the ability to be given systemically and to get across the blood-brain-barrier.

If successful, this approach potentially could be used alone or in combination with other therapeutic strategies to treat myotonic dystrophy.

Andrew Berglund, a professor of biochemistry, biophysics and molecular biology at the University of Oregon in Eugene, has been awarded an MDA research grant totaling $253,800 over three years to pursue changing the shape of the abnormal genetic material underlying type 1 and type 2 myotonic muscular dystrophy (MMD or DM).  Berglund and colleagues will conduct laboratory experiments to see whether changing the shape of abnormally expanded genetic material (RNA) in these two forms of MMD can reduce or eliminate their harmful effects.

Funding for this MDA research grant began May 1, 2014.

Harold Bernstein, professor of pediatrics at the University of California, San Francisco, has been awarded an MDA research grant totaling $540,000 over three years. The award will help support Bernstein's study of human muscle development and potential cell-based therapies for treatment of degenerative muscle diseases such as Duchenne muscular dystrophy (DMD).

In his new work, Bernstein and colleagues will study the pathways that different types of muscle stem cells follow as they form new muscle, and identify the particular muscle stem cell types that appear most suited for therapeutic development.

The team will first observe the maturation of human stem cells into muscle cells in culture (in the laboratory), as a means of identifying the stages of normal muscle development. The investigators will then transplant the cells at various stages of development into the leg muscles of mice with a disease resembling DMD and study the process by which these cells become new muscle tissue, how this affects the animals' ability to exercise, and the strength of the treated muscles.

Bernstein's team hopes to fully elucidate the process of normal human muscle stem cell development and, in addition, identify specific stem cell types that may provide therapeutic benefit when transplanted into DMD-affected muscle.

"Funding from the Muscular Dystrophy Association will allow us to extend our research on muscle development and stem cell biology into studies specifically focused on therapy," Bernstein said. "This funding provides important support for research that will directly translate into improved treatment for patients with muscular dystrophy."

Funding for this MDA grant began February 1, 2011.

Sanford Bernstein, a professor of biology at San Diego State University in California, was awarded an MDA research grant totaling $370,311 over a period of three years. The funds will help support Bernstein's research into the underlying molecular causes of, and potential treatments for, inclusion-body myopathy type 3 (IBM-3).

IBM-3 is caused by a mutation in a protein called myosin, the "molecular motor" that drives muscle contraction.

"Our biochemical and ultrastructural studies have shown that IBM-3 myosin is prone to unfolding and to forming clumps called aggregates," Bernstein said. "Further, muscle appears to respond to the mutant protein by producing autophagosomes, cellular bodies designed to encapsulate and degrade protein aggregates."

Bernstein's team will study the components that comprise the IBM-3 aggregates. Then, in an IBM-3 fruit fly research model that they developed, the investigators will test various approaches aimed at hastening the clearance of protein aggregates and ameliorating defective muscle structure and function in IBM-3.

"IBM-3 is a rare disease, and no model that produces the inclusion bodies we see in our drosophila model has been developed," Bernstein said. "Hence, use of this model presents the current best opportunity to develop a better understanding of the basis of the disease or its possible treatment."

Funding for this MDA grant began February 1, 2012.

MDA has awarded a clinical research training grant totaling $180,000 to clinical research fellow James Berry at Massachusetts General Hospital (MGH) in Boston. The grant will support completion of a two-year fellowship during which Berry plans to study the effects of a drug called ISIS-333611 in familial, or inherited, ALS (amyotrophic lateral sclerosis, or Lou Gehrig’s disease).

Familial ALS accounts for 5 to 10 percent of all ALS cases. About 20 percent of those (1 to 2 percent of all ALS cases) are caused by a mutation in the SOD1 gene, which leads to production of abnormal SOD1 protein.

Berry is a member of the study team currently planning a phase 2 clinical trial of intrathecal (into the spinal canal) administration of the experimental drug ISIS-333611 (made by Isis Pharmaceuticals of Carlsbad, Calif.) in people with familial ALS. The trial will be a follow-on study to a phase 1 trial of the drug, currently under way, if results from that trial are favorable.

Previous studies of the drug in rats have shown that it is safe and tolerable, that it reduces mutant SOD1 RNA (the chemical step between DNA and protein synthesis) and protein levels, and slowed progression of the disease. It's thought that decreasing mutant SOD1 levels in humans may confer similar therapeutic benefits.

The planned phase 2 study will test ISIS-333611 over an extended period of time to assess its safety and tolerability. If the phase 2 trial is successful, a phase 3 trial may be planned to test efficacy of the drug.

"MDA funding is critical to my career development and my ability to begin my career as a clinical researcher in ALS," Berry said. "I am incredibly excited to have received this award, and I am looking forward to getting started on the project."

Funding for this MDA grant began February 1, 2011.

MDA has awarded a grant totaling $347,094 over three years to François Berthod, a professor in the department of surgery at Laval University in Quebec City, Quebec, Canada. The funds will help support Berthod's study of the underlying molecular mechanisms and disease process in ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).

ALS is characterized by the degeneration of motor neurons (nerve cells that control muscle movement) in the spinal cord and brain.

Berthod, who has a background in tissue engineering, previously has shown that human motor neurons can differentiate (mature) from a population of stem cells obtained from human skin.

Now, Berthod plans to develop a three-dimensional model of the human spinal cord using neural (nervous system) cells obtained from the tissues of people with ALS. The human tissue-engineered spinal cord (TESC) model is expected to mimic the human disease "in vitro," or in a laboratory setting. Its design will permit testing of the interactions of various neural cell types, including motor neurons and neuroprotective cells such as astrocytes, microglia and Schwann cells, as a means of determining the conditions that induce or aid motor neuron death in ALS.

Findings from Berthod's work are expected to improve understanding of the causes and progression of sporadic ALS.

"MDA funding over the years has been the only source of support for our research on amyotrophic lateral sclerosis," Berthod said, adding that it's been "the strongest encouragement to continue developing innovative in vitro models of this disease."

Funding for this MDA grant began February 1, 2011.

Carmen Bertoni, assistant professor of neurology at the University of California, Los Angeles, was awarded an MDA research grant totaling $300,000 over a period of three years to advance gene-editing strategies forDuchenne muscular dystrophy (DMD).

DMD is caused by a mutation in the dystrophin gene. Standard gene therapy techniques have focused on supplying an unmutated dystrophin gene to muscle cells. An alternative strategy, called gene editing, seeks to correct the mutant gene itself.

“Our research group [with MDA funding] has pioneered the use of gene editing strategies for the dystrophin gene to permanently correct the DNA,” Bertoni says.

The gene-editing toolkit is growing, and in this project, Bertoni will compare the correction efficiency of two different methods. Both specifically target the mutant sequence in the gene, and harness elements of the cell’s own “quality control” system to correct the mutation. The comparison will be performed first using muscle cells isolated from a mouse model for DMD, and then in the mice themselves, to determine the feasibility of using this technology in people.

The repair process is simple to describe, but complicated in practice. The therapy needs to reach many different muscle fibers, cross the dense and protective structure that surrounds every fiber, reach the cell nuclei and ultimately the dystrophin gene, and then direct the gene correction process. Finally, the amount of dystrophin expression achieved after correction needs to be sufficient to sustain muscle function over a prolonged period of time.

“Every one of these steps is necessary to ensure a safe and effective therapy in patients,” says Bertoni. “Altogether these studies have the potential to significantly advance the field of gene correction into a clinical scenario for the treatment of DMD.”

Funding for this MDA grant began August 1, 2013.

MDA awarded $408,915 to Carmen Bertoni, assistant professor of neurology at the University of California, Los Angeles, to continue research into DNA repair strategies in Duchenne muscular dystrophy (DMD).

Bertoni's research group has pioneered a technology that uses small molecules called single-stranded oligonucleotides, or ssODNs, to act directly on the source of the problem in DMD: the "genetic blueprint," or DNA. In people with DMD, the DNA that makes up the dystrophin gene contains errors that lead to missing or nonfunctional dystrophin protein.

"We use ssODNs to let the muscle know of those errors and give the opportunity to each cell that composes muscles to correct the mistake," Bertoni said. The fix is permanent, negating the need for ongoing treatment.

The process involves injection of the oligonucleotide into muscle, where it seeks the flawed region of DNA and highlights the specific error. The cell is alerted to the presence of the genetic defect, and activates the repair process to correct the flaw.

To date, the main limitation of ssODN-mediated gene correction has been the low frequency of gene repair. Bertoni's group aims to increase the strategy's efficiency to generate levels of gene repair that are clinically meaningful as a viable treatment for DMD.

The group will test the oligonucleotides first in muscle cells and then, once investigators have optimized the structure, in dystrophin deficient mice.

"MDA has had and continues to have a pivotal role in the development of this technology for the treatment of DMD," Bertoni said. "Without any question, the advance of clinical applications to DMD using ssODNs heavily relies on the help that continues to be received by the MDA. It is a great honor to be part of the numerous and extremely talented scientists that are supported by the Association."

Funding for this MDA grant began August 1, 2010.

Martha Bhattacharya, a postdoctoral research scholar in developmental biology at Washington University School of Medicine in St. Louis, Mo., was awarded an MDA development grant totaling $180,000 over a period of three years to study how and why axons degenerate.

Axons are the long extensions of motor neurons (muscle-controlling nerve cells) that link up with muscles. Signals are sent down the axon to cause the muscle to contract. When an axon degenerates, it can no longer carry those signals, leading to weakness.

“In neuromuscular diseases where motor neuron dysfunction is the primary cause of disability, such as amyotrophic lateral sclerosis (ALS) and Charcot-Marie-Tooth (CMT) disease, axonal degeneration is a unifying pathological hallmark of disease progression,” Bhattacharya says.

To study axonal degeneration, she and her colleagues developed a fruit fly research model that allows the identification of necessary components of the axonal degeneration cascade. Using this system, she has identified several key steps in the process, including one involving a protein called G-protein coupled receptor (GPCR), and another called protein kinase.

“These receptors are highly desirable drug targets,” Bhattacharya says, and pharmaceutical companies have a great deal of experience designing drugs to influence their behavior. “For the GPCR, we will determine its signaling mechanism in mammalian neurons and test its ability to protect neuromuscular synapses after injury. For the kinase, we will examine the effects of loss of this protein on mouse axons and synapses,” the sites of information exchange between nerve and muscle.

Learning more about the details of axonal degeneration also will help researchers understand more about the entire disease process, potentially leading to other targets for therapeutic intervention.

Funding for this MDA grant began Feb. 1, 2013.

"The mechanism of gene silencing in FA is known as epigenetic silencing. As we dig deeper, we realize that the silencing mechanism is more complex than was initially appreciated. A fuller understanding of the epigenetic silencing mechanism will help yield therapeutic targets and perhaps even biomarkers to track therapeutic response in people with FA."

Sanjay Bidichandani, PhD, professor of Pediatrics at the University of Oklahoma Health Sciences Center, was awarded an MDA research grant totaling $300,000 over three years to study the role of epigenetic silencing of the frataxin gene (FXN) in Friedreich’s ataxia (FA).

In FA, mutations in the FXN gene cause decreased production of frataxin protein, resulting in diminished energy production in cells, including those of the nervous system and heart. MDA funding helped Dr. Bidichandani participate in research that led to the discovery of the FXN gene and its role in causing FA. In past work, Dr. Bidichandani discovered a DNA hypermethylation in FXN of people with FA. However, to identify effective therapeutic targets and biomarkers, a complete understanding of exactly how the silencing mechanism works is needed.

In this project, Dr. Bidichandani will look more closely at the two main mechanisms of FXN gene silencing to see if one mechanism precedes the other, or if they work in parallel. This information will inform if different therapeutic agents can work synergistically or limit the effectiveness of each other. Specifically, he will test the hypothesis that DNA hypermethylation acts as a barrier to efficient gene reactivation in FA, examining cells from people with FA and a humanized mouse model of the disease.

CMRI Claire Gordon Duncan Chair in Genetics and Professor of Pediatrics Sanjay Bidichandani, at University of Oklahoma Health Sciences Center in Oklahoma City, was awarded an MDA research grant totaling $300,000 over three years to address clinically and scientifically important questions regarding the use of existing and novel HDAC inhibitors to increase levels of the frataxin protein in Friedreich’s ataxia (FA). Bidichandani and colleagues recently found that the mechanism of gene silencing in FA involves shutting off the FXN gene promoter, a region of the gene that typically controls when and how much a gene should be turned on. They are now working to identify therapeutic molecules that will effectively reverse FXN promoter silencing in FA, and to determine the precise mechanism by which promoter inactivation and reactivation occurs.

Funding for this MDA research grant began Aug. 1, 2015.

"We are interested in both understanding how exercise affects skeletal muscle in FSHD and identifying the key cellular events contributing to those responses."

Adam Bittel, PT, DPT, PhD, a postdoctoral fellow at Children’s National Medical Center in Washington, DC, was awarded the 2019 SSSI-MDA Fellowship Award. The award, co-sponsored by Strength, Science & Stories of Inspiration (SSSI) and MDA, will provide a total of $40,000 over two years to support Dr. Bittel’s work investigating the cellular mechanisms underlying the effects of exercise in facioscapulohumeral muscular dystrophy (FSHD).

During his doctoral studies, Dr. Bittel explored how exercise influences multi-organ metabolism in metabolic syndromes as well as in Barth syndrome, a genetic disease affecting skeletal and cardiac muscle. While exercise is known to improve muscle health and metabolism in other forms of muscular dystrophy, there are very few studies assessing the effects of exercise in individuals with FSHD. Dr. Bittel is interested in understanding how exercise affects skeletal muscle in a mouse model of FSHD (the FLExDUX4 mouse) and in identifying important cellular events contributing to those responses.

MDA has awarded a research grant totaling $362,295 over a period of three years to Robert Bloch, a professor in the department of physiology at the University of Maryland School of Medicine in Baltimore. The funds will help support Bloch's study of the role of a protein called dysferlin in type 2B limb-girdle muscular dystrophy (LGMD2B) and distal muscular dystrophy (DD, or Miyoshi myopathy).

"Limb-girdle muscular dystrophy 2B and Miyoshi myopathy are caused by mutations in the gene that carries instructions for dysferlin, but the role of dysferlin and its location in muscle cells are controversial," Bloch said.

Bloch and colleagues are working to answer these questions by studying isolated muscle fibers from normal and dysferlin-mutant mice, studying the structure and function of intact muscles from these same mice, and comparing what they observe in mouse muscle to muscles of people with LGMD2B or Miyoshi myopathy.

"The state of research in my area is in considerable flux, largely because of problems that have arisen from attempts to translate studies done in isolated cells to what occurs in muscle tissue in a living animal," Bloch said. "We have been trying to bridge this gap and have been getting results that we did not expect based on earlier work from other laboratories.

"It will take us some time to sort out the differences, but once we do so we anticipate making rapid progress."

Funding for this MDA grant began February 1, 2012.

Gregory Block, senior fellow in pediatrics at the University of Washington in Seattle, was awarded an MDA development grant totaling $179,994 over a period of three years to search for treatment targets infacioscapulohumeral muscular dystrophy (FSHD).

FSHD occurs when a section at the tip of one chromosome, chromosome number 4, is shortened. When that happens, it allows a gene called DUX4 to remain active into adulthood, instead of becoming inactive after early development. The symptoms of FSHD are due to this extended activity of DUX4, so preventing that activity, or blocking its effects, could be therapeutic in the disease. Block has developed a cell-based system to study DUX4 activation, and has found one chemical pathway in muscle cells that can prevent activation. He will continue investigating this pathway to determine if it can be used to develop treatments for FSHD.

“This is an exciting time for FSHD research,” Block says. “Four years ago, there was still considerable debate as to the genetic cause of the disease, and today we are challenged with defining pragmatic approaches for disease intervention. We are hoping the data generated from this project will provide considerable insight into the mechanisms used by cells to silence DUX4.”

Funding for this MDA grant began August 1, 2013.

“My focus is to better understand the role that Cullin-3-related protein degradation may play in the pathological mechanism leading to the development of nemaline myopathy,” Jordan Blondelle says. “It’s important because the underlying mechanisms of this life-threatening disease currently are poorly understood.”

Jordan Blondelle, postdoctoral researcher at the University of California San Diego in La Jolla, was awarded an MDA development grant totaling $180,000 over three years to increase understanding of the underlying mechanisms in nemaline myopathy.

Muscle mass maintenance is tightly regulated by a balance between muscle growth and atrophy, reflecting the balance between protein synthesis and degradation at the cellular level. Accumulation of misfolded proteins or premature degradation of proteins is often associated with diseases such as skeletal muscle myopathies.

The degradation of muscle proteins is accomplished mainly through a cellular “clean-up and disposal system” called the ubiquitin-proteasome system, or UPS. The Cullin family of proteins, a key component of the UPS system, incorporate into complexes after which they are able to bind and mark unwanted proteins for degradation. Recently, mutations in several binding partners of Cullin-3, a Cullin protein family member, were found in people with severe forms of nemaline myopathy. These findings suggest a specific and important function for Cullin-3 targeted protein degradation during muscle development and maintenance.  

Using mutant mice in which Cullin-3 is depleted in muscles, Blondelle and colleagues determined that the protein is necessary for survival, and will now look at how the loss of Cullin-3 affects muscle development, structure and function.

The team expects to find new target proteins of the Cullin-3 complex that would be misregulated in the absence of Cullin-3 and responsible for the myopathy observed in mice. In addition, the team intends to decipher, for the first time, how protein degradation mediated by Cullin-3 is relevant for muscle physiology, and to provide insight into the pathological mechanisms leading to nemaline myopathy in people.

If successful, Blondelle’s work could inform the development of therapies for nemaline myopathy.  

“Our research is aimed at unravelling how myelination is regulated in the PNS and how perturbation of these mechanisms can cause disease in humans.”

Alessandra Bolino, head of the Human Inherited Neuropathies Unit at IRCCS Ospedale San Raffaele in Milano, Italy, was awarded an MDA Research Grant totaling $300,000 over 3 years to study the targeting of phospholipid and cytoskeleton dynamics to ameliorate CMT neuropathies.

Charcot-Marie-Tooth type 4B1 is a very severe demyelinating neuropathy with childhood onset, characterized by myelin outfoldings, redundant loops of myelin in the nerve that degenerate causing axonal problems. Dr. Bolino’s research previously demonstrated that loss of MTMR2 (Myotubularin-related 2) phosphatase is the cause of the disease. MTMR2 acts on phospholipids, important regulators of membrane trafficking, which is a key process in Schwann cells, the glial cells forming myelin in the peripheral nervous system. Dr. Bolino and colleagues also generated in vitro and in vivo models of CMT4B1, which have been instrumental over the years to study the pathophysiology of this neuropathy.

By investigating the mechanism by which loss of MTMR2 leads to altered membrane trafficking and myelin outfoldings in Schwann cells, they identified a novel signaling pathway that regulates the cytoskeleton dynamics and membrane growth within myelin-forming cells. In this project, they will further characterize this novel pathway and test whether this pathway is a good drug target. These approaches can be extended to other forms of CMT that are characterized by myelin outfoldings (CMT4B2, B3, CMT4C, CMT4H).

"Our research will help define the role of satellite cells in muscular dystrophy. The findings from our proposed work will have implications on therapeutics that are currently being tested for Duchenne muscular dystrophy as well as offer new a therapeutic strategy to treat other types of muscular dystrophies."

Justin Boyer, PhD, research fellow at the Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, was awarded an MDA development grant totaling $210,000 over three years to study the role of ERK1/2 signaling in satellite cells of mice models of Duchenne muscular dystrophy (DMD).

Extracellular signal-regulated kinases (ERKs) are proteins that are intricately involved in cell division. Normally, skeletal muscle can repair itself after injury with the help of a specific type of muscle stem cell called a satellite cell (SC). In previous work, Dr. Boyer found that the ERK1/2 protein signaling pathway is an essential mediator of SC survival and function. Silencing this pathway in SCs led to the loss of these cells in skeletal muscle, preventing it from recovering from injury. However, activating the ERK1/2 signaling pathway led to a greater number of SCs.

In this research, Dr. Boyer will further characterize ERK signaling, determine if increasing ERK1/2 activity increases satellite cell numbers, and determine if increased ERK1/2 activity improves muscle regeneration. In doing so, he hopes to further define the role of SCs in muscular dystrophy to better understand how these cells can be targeted for developing therapies to treat this disease.

Andrew Brack, an assistant professor at the Center for Regenerative Medicine at Massachusetts General Hospital in Boston, was awarded an MDA research grant totaling $353,259 over three years. The funds will help support Brack's research into the function of adult muscle stem cells called "satellite cells" in Duchenne muscular dystrophy (DMD) and possibly in other muscular dystrophies as well.

Satellite cells are responsible for tissue maintenance and repair over a lifetime. It's widely accepted among scientists that these cells are sufficient to promote muscle repair; however, it is unknown what is required of them for regeneration of diseased skeletal muscle and whether the number and function of cells in the satellite cell pool can be manipulated as a means of slowing or ameliorating disease progression.

Brack and colleagues plan to use targeted genetic approaches to manipulate the number and function of adult satellite cells in a research mouse model of DMD. From this they hope to gain an understanding of the relative importance of both number and functionality of satellite cells needed for effective muscle repair.

Results from Brack's work may shed light on new therapeutic strategies for slowing disease progression that are based on retaining a functional pool of satellite cells in people with DMD and other muscular dystrophies.

"Without funding through MDA," Brack said, "this project would not have been realized."

Funding for this MDA grant began February 1, 2011.

Paul Brehm, senior scientist at Oregon Health Science University in Portland, was awarded an MDA research grant totaling $351,648 over three years to study the underlying mechanisms of movement disorders in some forms of congenital myasthenic syndromes (CMS).

Brehm’s research team has identified zebrafish research models that carry mutations in the same proteins that are known to cause some forms of CMS in humans. In both fish and humans, these proteins are localized to the neuromuscular junction (the space where signals are transferred between nerve and muscle). Their deficiency results in movement disorders such as use-dependent fatigue (the inability to perform repetitive tasks).

In one model, known as the rapsyn-deficient line (in which the fish have mutations in the gene for the rapsyn protein), Brehm and his team have been exploring the basis of use-dependent fatigue.

Rapsyn deficiency has been associated with problems on the muscle side of the neuromuscular junction. Brehm’s team has found that the absence of an as-yet unidentified signal produced by muscle regulates the motor neuron and that, ultimately, the absence of this signal appears to be accountable for use-dependent fatigue.

Brehm’s team is working to uncover the mechanism underlying the reduced motor neuron activity that precedes use-dependent fatigue, as well as ways in which to rescue the nerve defect.

“The means to study neuromuscular function using the zebrafish system has been unparalleled among the vertebrates,” Brehm says. “The discovery of zebrafish models that carry these mutant proteins now opens the way to addressing directly the consequences in humans.”

Funding for this MDA grant began Aug. 1, 2012.

“We are testing multiple drugs in our animal model,” Robert Bryson-Richardson said. “Some of these, if effective, could be suitable for clinical use. Those that are not suitable for clinical use will help us to identify pathways that could be targeted in future therapies.” 

Robert Bryson-Richardson, associate professor at the School of Biological Sciences, Monash University, in Victoria, Australia, was awarded an MDA research grant totaling $273,962 over three years to investigate potential approaches to treating myofibrillar myopathy (MFM) caused by a mutation in the Filamin C gene.

With colleagues, Bryson-Richardson has generated zebrafish models for MFM caused by a Filamin C mutation that reproduce key symptoms of the disease including accumulation of Filamin C protein into aggregates (clumps) and loss of muscle integrity, leading to muscle weakness. Using the models, the team is investigating two potential approaches to treat the disease: increasing the level of functional Filamin C protein overall so that there is more present in the muscle to compensate for the loss of some of it to aggregates, and removing the protein aggregates to slow down the sequestration of Filamin C.

In addition, the team is using CRISPR/Cas9 gene editing technology to develop new zebrafish models for the disease and screen for drugs that potentially could provide clinical benefit by increasing the level of functional protein or removing protein aggregates.

Izumi Biosciences in Lexington, Mass., was awarded an MDA Venture Philanthropy (MVP) grant totaling $96,360 to fund early-stage development of a type of IZ10023, a type of drug called a “pharmacokinetic (PK) enhancer,” for use in people with ALS (amyotrophic lateral sclerosis) who are taking riluzole. (Riluzole, marketed under the brand name Rilutek, was developed based on MDA-supported research on the neurotransmitter glutamate, and is the only drug approved by the U.S. Food and Drug Administration to treat ALS.)

IZ10023 targets and blocks two proteins in the brain and spinal cord that work to protect the central nervous system (CNS) by acting as pumps that remove foreign or toxic substances. In mouse studies it’s been shown that these pumps remove drugs such as riluzole, reducing levels of the drug in the CNS and thereby limiting its effectiveness.

President and CEO of Izumi Biosciences Antonius Bunt will serve as the principal investigator on the project.

“Blockade of these pumps maintains effective levels of riluzole in the diseased tissues and leads to improved outcomes in animal models of ALS and other brain diseases where multi-drug resistance is a key clinical bottleneck,” Bunt explained.

Confirmation that the pumps’ activity is increased in most ALS patients and demonstration that sufficient blood levels of IZ10023 can be achieved to block their activity are important milestones that must be achieved before moving IZ10023 into clinical trials in patients with ALS, Bunt noted. If the work is successful, Izumi Biosciences intends to open an Investigational New Drug Application and move into clinical trials — possibly as early as 2019.

Robert Burgess, a professor at The Jackson Laboratory in Bar Harbor, Maine, has been awarded an MDA research grant totaling $300,000 over three years. Burgess and co-investigator Scott Harper, associate professor at Nationwide Children’s Hospital Center for Gene Therapy in Columbus, Ohio, will test an AAV gene therapy approach to specifically block the altered form of the GARS gene in a newly developed mouse model for type 2D Charcot-Marie-Tooth disease (CMT). Successful completion of these studies could lead to a new therapy for type 2D CMT and provide a proof of principle for this approach that may be applicable to other types of CMT.

Funding for this MDA research grant began Aug. 1, 2015.

Arthur Burghes, professor of biological chemistry and pharmacology, molecular genetics, and neurology at The Ohio State University Wexner Medical Center in Columbus, was awarded an MDA research grant totaling $188,613 over two years to refine how a genotype can be used to predict the severity of spinal muscular atrophy (SMA). Burghes will develop assays to test whether SMA patients have either intact or defective SMN2 genes, which serve as the backup for the SMN1 gene lost in SMA patients. Since the level of SMN2 determines the disease severity in SMA patients, these assays may be able to better predict how disease may progress in an individual.

Funding for this MDA research grant began Aug. 1, 2015.

“In this proposal we aim to identify the genes that modify the severity of SMA and the changes in them that cause modification of severity. The identification of these changes will improve the ability to predict severity with a DNA test and initiate treatment at the appropriate time. In addition, these modifier genes can be novel therapeutic targets that can act independently of current therapies to increase SMN.”

Arthur Burghes, PhD, professor of Biological Chemistry and Pharmacology, Molecular Genetics, and Neurology at The Ohio State University Wexner Medical Center in Columbus, was awarded an MDA research grant totaling $200,000 over two years to study genes that might have the potential to modify the severity of spinal muscular atrophy (SMA).

In SMA, mutations in the survival motor neuron 1 gene (SMN1) prevent a person from making enough survival motor neuron protein (SMN). Lack of this protein is what causes the loss of motor neurons, muscle weakness, and paralysis that define SMA. In addition to the SMN1 gene, there is also a related SMN2 gene, which functions as a “backup” to producing some amount of SMN protein.

Dr. Burghes was previously awarded MDA funding to study how SMN2 copy number might predict severity of SMA. Currently SMN2 copy number is the best predictor of SMA severity and in general, having more SMN2 copies results in less severe SMA. However, both SMA type 2 and type 3 patients have three copies of SMN2. In this new work, Dr. Burghes will study the DNA of siblings who have three copies of SMN2, but one has SMA type 2 while the other has SMA type 3. He aims to identify new genes with the potential to modify the severity of the symptoms of SMA, which may potentially become novel therapeutic targets.

“I have received other MDA grants which have been critical to these studies,” Dean Burkin says. “This new grant will allow us to move an exciting new integrin-targeting small molecule closer to clinical trials for Duchenne muscular dystrophy patients.”

Dean Burkin, professor of pharmacology and directory of cellular and molecular pharmacology and physiology graduate program at the University of Nevada School of Medicine in Reno, was awarded an MDA research grant totaling $300,000 over three years to test the effects of an existing FDA-approved drug on the function of heart and skeletal muscle in a mouse model of Duchenne muscular dystrophy (DMD).

DMD is caused by mutations in the DMD gene, which encodes the dystrophin protein. Dystrophin forms a molecular “glue” that binds muscle cells together and provides structural integrity, and its loss or deficiency in DMD causes progressive muscle weakness and results in premature death.

A second molecular glue, a protein called alpha7beta1 integrin, is also present in muscle, and studies in transgenic mouse models have shown that increased levels of alpha7beta1 can act as a surrogate for the absence of dystrophin and prevent disease progression.  

In collaboration with the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health (NIH), Burkin and colleagues conducted a muscle cell-based test and screened more than 400,000 compounds to identify drugs that could enhance the activity of alpha7beta1. They identified a novel compound called SU9516 that increases levels of alpha7beta1 integrin protein and prevents muscle disease in the mdx mouse model of DMD.

SU9516 has an FDA-approved analog called sunitinib, and Burkin’s team will now test the effectiveness of this drug in mouse models of DMD. Since sunitinib already is FDA-approved (to treat some forms of cancer), successful outcomes of this study could lead to future clinical trials and rapid translation into a novel class of integrin-based therapeutics for DMD. 

“We hope this laminin-enhancing small molecule will slow muscle pathology and improve muscle strength in a mouse model of laminin-alpha2-related congenital muscular dystrophy. Successful preclinical outcomes from this study will form the basis for potential future clinical trials for patients with this disease.”

Dean Burkin, PhD, professor of Pharmacology at the University of Nevada School of Medicine in Reno, was awarded an MDA research grant totaling $300,000 over three years to study a laminin-enhancing small molecule for treating congenital muscular dystrophy (CMD).

Laminin-alpha2-related congenital muscular dystrophy, also known as merosin-deficient congenital muscular dystrophy (MDC1A), is a muscle disease with no cure or treatment. Children with MDC1A typically die at a young age. MDC1A is caused by mutations in the laminin-alpha2 gene, which lead to a lack of merosin or laminin-211/221 in muscle. Laminin-511 (aka, laminin-alpha5) is another form of laminin found in the muscle of MDC1A patients and is similar in structure and function to laminin-211.

Dr. Burkin has recently identified an FDA-approved small molecule, designated laminin-enhancing small molecule 5 (LEM5), that increases laminin-alpha5 in cultured skeletal muscle cells and improves muscle pathology and function in a mouse model of MDC1A. With this new funding, Dr. Burkin will use a LEM5 analog (a modified version of the FDA-approved drug) to determine optimal dose, safety, and efficacy in reducing symptoms in MDC1A mice.

Dean Burkin, associate professor of pharmacology at the University of Nevada School of Medicine in Reno, was awarded an MDA research grant totaling $308,028 over three years to study laminin-111 protein therapy for Duchenne (DMD) and Becker (BMD) muscular dystrophies.

Burkin and colleagues have shown in previous work that systemic delivery of the laminin-111 protein works as a potent therapeutic in a mouse model of DMD. Laminin-111 treatment in these mice results in stabilization of the muscle membrane and a reduction in levels of an enzyme called creatine kinase, or CK, which is a sign of muscle damage.

It remains unclear, however, whether laminin-111 protein therapy in people with DMD may be able to prevent muscle damage, or reverse it after it's already started.

Burkin is working to test the hypothesis that laminin-111 protein therapy can prevent muscle damage after DMD disease onset in mouse models of DMD and in dogs that have the disease.

To do this, Burkin and colleagues first plan to determine if laminin-111 prevents muscle damage after disease onset in the two animal models. Next, the team will test to see whether laminin-111 prevents heart muscle deterioration (cardiomyopathy) in mouse models of DMD, and finally the group will study whether laminin-111 prevents muscle disease in dogs with DMD.

Favorable results could pave the way for development of laminin-111 as a therapeutic for DMD and BMD.

Funding for this MDA grant began Aug. 1, 2012.

Michele Calos, professor of genetics at Stanford University School of Medicine in California, was awarded an MDA research grant totaling $300,000 over a period of three years to test gene therapy approaches in mouse models of limb-girdle muscular dystrophy (LGMD) types 2B and 2D.

With colleagues, Calos will study a gene therapy approach based on delivering the therapeutic gene — either dysferlin or alpha-sarcoglycan — through the bloodstream. The DNA will be injected rapidly into a vein near the ankle, where it will then be carried by the blood to all leg muscles.

The goal of this work is to demonstrate effective DNA delivery that results in improved condition of muscles and muscle function in the mice. A sequence-specific integration system will specifically target the therapeutic gene into a safe and permanent section of the genome. Because the gene will become a permanent part of the chromosomes in muscle cells, the therapy will act long-term.

These studies will pave the way for larger animal studies and human clinical trials. Success in LGMD types 2B and 2D may demonstrate that a similar approach will work for all 10 forms of recessive limb-girdle muscular dystrophy. Furthermore, this type of approach also may be helpful for other neuromuscular diseases.

Funding for this MDA research grant began Aug. 1, 2016.

Michele Calos, professor in the department of genetics at Stanford University School of Medicine in Stanford, Calif., received a $200,000 MDA research grant to develop a new stem cell-based therapy for Duchenne muscular dystrophy (DMD).

"Funding from MDA is critical for us to develop these new ideas that could lead to novel strategies to combat DMD," Calos said. "A prior MDA grant has allowed us to make progress in the studies, and we are now poised to perform the critical experiments."

The new work involves extraction of stem cells from DMD mice. A good copy of the dystrophin gene, necessary but missing in DMD, will be added to the cells, which will then be returned to the mouse where they are expected to home in on damaged muscle and help create new muscle fibers to replace those damaged by the disease. The investigative team will also conduct experiments using a type of adult human stem cell called "adipose-derived mesenchymal stem cells," which are purified from fat tissue and have been shown to develop into muscle.

Successful results in these experiments eventually may lead to clinical trials and may indicate potential for use of a similar approach in other muscle diseases.

"Progress in the development of stem cell therapies offers major hope for regeneration of muscle mass and strength," Calos said, even for those in whom the disease has progressed.

Funding for this MDA grant began August 1, 2010.

MDA awarded a research grant totaling $375,000 over three years to Kevin Campbell, professor of neurology and internal medicine at the University of Iowa in Iowa City. The funds will help support Campbell's study of a process called protein O-mannosylation in a mouse model of congenital muscular dystrophy (CMD).

O-mannosylation is an important protein modification that occurs in mammals. Diseases caused by O-mannosylation defects include severe muscular dystrophies characterized by profound muscle weakness as well as central nervous system impairment. Despite extensive efforts, the genetic causes of most occurrences of these diseases remain unknown.

The only known O-mannosylated protein is alpha-dystroglycan, which works in skeletal muscle to link connective tissue (the extracellular matrix) with the cellular framework or "scaffolding" known as the cytoskeleton.

Campbell aims to identify proteins that play a role in initiating O-mannosylation and then investigate their function in cell culture models. He also is working to generate a new O-mannosylation-deficient mouse model in which to study any newly identified proteins.

There is a critical need for better understanding of the mechanism responsible for this modification to develop new treatment options for O-mannosylation deficient disease, Campbell says. "Besides direct patient health benefits, identification of new players involved in protein O-mannosylation will open new avenues to understand O-mannosylation deficient muscular dystrophies."

Funding for this MDA grant began Aug. 1, 2012.

MDA has awarded a research grant totaling $404,274 over three years to Stephen Cannon, professor of neurology and associate dean for undergraduate medical education at the University of Texas Southwestern Medical Center in Dallas. The funds will help support Cannon’s research into attacks of paralysis in people with periodic paralysis (PP).

Periodic paralysis is a muscle disorder in which affected individuals have transient attacks of muscle weakness lasting hours to days.

With prior support from MDA, Cannon and colleagues generated a mouse model for hypokalemic periodic paralysis, in which attacks are triggered by low blood potassium levels. Using the new mouse model, the team intends to establish how shifts in potassium level, exercise and stress trigger attacks of weakness.

Preliminary work already has identified several strategies to reduce the risk of an attack or to reduce the severity of weakness, through the use of available drugs or by modifying the level of muscular activity.

“Support from the MDA has been a vital component of our research program on myotonia and periodic paralysis for two decades,” Cannon said. “MDA’s commitment to funding investigation into the fundamental biology of these diseases has yielded many important advances.

“Through the generosity of donors and the wisdom of the MDA Board of Directors, important work on muscle disease has been able to not only continue, but also to flourish.”

Funding for this MDA grant began August 1, 2011.

Steve Cannon, professor of physiology at the David Geffen School of Medicine at the University of California, Los Angeles, was awarded an MDA research grant totaling $300,000 over three years to investigate a new hypothesis about the underlying mechanisms involved in periodic paralysis. New preliminary studies in research models have revealed a profound loss of muscle force within minutes of recovery from exposure to high carbon dioxide levels, which Cannon and colleagues suggest may be a surrogate for the exercise-induced attacks of weakness that occurs in patients. Cannon and his team will investigate the mechanistic basis for exercise-induced weakness in periodic paralysis, will strategically select drugs that may block this process, and will test the potential of these drugs to foreshorten or prevent attacks of periodic paralysis.

Funding for this MDA research grant began Feb. 1, 2016.

“This work will specify what proportion of LGMD multi-genic cases can reach a molecular diagnosis and get enrolled in clinical trials. Besides the clinical impact, this project will also have a major impact on our basic scientific understanding of how different LGMD subtypes and related diseases such as Pompe disease are related in the muscle genome.”

Dr. Samya Chakravorty, postdoctoral research fellow at Emory University in Atlanta, Georgia, was awarded an MDA Development Grant totaling $180,000 over 3 years to study the functional resolution of multi-genic Pompe and limb-girdle muscular dystrophy (LGMD).

LGMD subtypes are a group of genetic disorders with overlapping phenotypes among themselves and with Pompe disease, complicating accurate disease diagnosis. Genetic testing can aid in this process, but some estimates indicate that even after extensive genetic testing, 30% to 40% of neuromuscular disease patients never receive a complete molecular diagnosis. This is likely due to a combination of new disease genes not identified, as well as a combination of genes that can contribute to disease manifestation. Combinatorial functional assays will confirm this finding and reveal how gene networks may impact disease manifestations, which will improve molecular diagnosis.

Dr. Chakravorty and colleagues plan to use a discovery-driven approach to correlate gene networks with disease phenotype using patient muscle biopsy tissue to test the hypothesis that complex genetic pathways contribute to the Pompe and LGMD mechanism with high prevalence, potentially by synergistic effects of multiple genes.

Joel Chamberlain, research associate professor at the University of Washington School of Medicine in Seattle, was awarded an MDA research grant totaling $300,000 over a period of three years to increase understanding of the role of DUX4 protein in facioscapulohumeral muscular dystrophy (FSHD).

In the muscle cells of people with FSHD, too much of a protein called DUX4 is made, leading to cell death. To determine how excess DUX4 results in muscle damage in FSHD, Chamberlain and colleagues will examine DUX4 protein production in a range of human biopsy samples in an effort to determine the cellular location of DUX4 and the protein’s relationship to disease-related changes in the muscle.

In parallel, in studies conducted in a unique mouse model of FSHD developed in Chamberlain’s lab, the team also will examine the toxic effects of expressing very low levels of the DUX4 protein. These studies will help assess how DUX4 initiates a chain of events that cause the slow, progressive muscle damage seen in FSHD. 

Chamberlain’s work may reveal drug targets and inform the development and testing of therapies for FSHD.

Funding for this MDA research grant began Aug. 1, 2016.

Jeffrey Chamberlain, a molecular biologist at the University of Washington, Seattle, was awarded an MDA grant of $328,628 over one year (through Jan. 31, 2014) to develop gene therapy delivery vehicles ("vectors") for gene transfer in Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Chamberlain will develop gene transfer vectors derived from adeno-associated viruses (AAVs). They'll be designed to carry miniaturized versions of the gene for the dystrophin protein, which is missing in DMD-affected muscles and deficient in muscles affected by BMD. The studies are directly related to moving gene therapy for DMD/BMD into clinical trials.

Joel Chamberlain, research assistant professor in the department of medicine at the University of Washington in Seattle, was awarded an MDA research grant totaling $330,780 over three years to study a therapeutic approach called RNA interference (RNAi) for the treatment of facioscapulohumeral muscular dystrophy (FSHD).

"Despite the surprising complexity of the FSHD disease pathway, several lines of research converge to identify DUX4 protein production as the final step in the disease pathway," Chamberlain says.

Now, Chamberlain and colleagues are working to develop a therapy that targets production of DUX4 through interaction with DUX4 messenger RNA, or mRNA. (RNA is a chemical cousin to DNA and is involved in a chain of steps between DNA and cellular protein production.)

"To carry out RNAi, we will use an RNA that specifically binds to the DUX4 mRNA and directs the cell to destroy the target DUX4 mRNA," Chamberlain explains. "Once inside the muscle, the RNA made to carry out RNAi is produced continuously to treat disease and is expected to remain active for many years."

The team also is working to create a mouse model of FSHD that mimics the human disease. The investigators will use the model — as well as new cell and mouse models from collaborating laboratories — to test their DUX4 RNAi approach. They plan to make the model available to other researchers for the testing of additional potential therapies. 

"We have developed this targeted approach, referred to as RNA interferenceor RNAi, to reverse disease," Chamberlain says. "It works well in mouse models of muscular dystrophies, and we are the only laboratory to have succeeded in changing the course of the disease by delivering this therapy to all the muscles of the mouse with a single intravascular (into a blood vessel) injection."

Funding for this MDA grant began Aug. 1, 2012.

David Chan, a professor of biology at the California Institute of Technology in Pasadena, has been awarded an MDA research grant totaling $253,800 over three years, to study mitochondria in mice. Mitochondria are the energy-producing parts of cells, and an aspect of their normal functioning involves fusing together and dividing. Chan and colleagues will study mice with defects in the fusion or division of mitochondria to improve the understanding of mitochondrial myopathies.

Funding for this MDA research grant began May 1, 2014.

Vijayendran Chandran, assistant professor in the department of pediatrics, University of Florida School of Medicine in Gainesville, was awarded an MDA research grant totaling $300,000 over three years to identify biomarkers in Friedreich’s ataxia (FA).

FA is caused by deficiency of the frataxin protein. With colleagues, Chandran has developed a mouse model for FA, that exhibits symptoms similar to those seen in people with the disease and in which he can control the onset and progression of disease.

Now the team will use the new model to identify biomarkers at different stages of disease that could predict disease onset and progression in humans.

If successful, Chandran’s work could help clinicians and researchers measure and predict disease progression, and aid in preclinical development and testing of potential FA treatments.

Funding for this MDA research grant began Feb. 1, 2017.

Postdoctoral research fellow Tathagata Chaudhuri, at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, was awarded an MDA development grant (DG) totaling $180,000 over three years to develop a stem cell therapy for muscular dystrophies, including Duchenne muscular dystrophy (DMD), that will lead to muscle regeneration.

MDA development grants are awarded to exceptional postdoctoral candidates who have the best chance of becoming independent researchers and future leaders of neuromuscular disease research.

Some experimental cell therapies for muscular dystrophies are designed to use cells from healthy human donors, but the successful transplantation of cells from one person to another requires the use of immunosuppressants in order to keep the body from rejecting the new cells.

Chaudhuri and colleagues are working on the development of a cell-based therapy that uses a person's own stem cells — adult mesenchymal stem cells (MSCs), which are taken from bone marrow and coaxed into becoming muscle cells.

The team first plans to demonstrate that MSCs can reliably be differentiated(grown) into muscle cells. They'll then use the cells they produce to study muscle regeneration in animal models of muscular dystrophy.

Next, Chaudhuri and his team will determine the optimum time for transplanting the maturing cells into a recipient. They'll monitor the development of the human MSCs in animal models to determine how well the MSCs integrate with existing muscle fibers and whether they have any effect on muscle repair and regeneration over time.

Treatment with adult stem cells that develop into muscle cells may provide a means to correct skeletal muscle function in muscular dystrophy, Chaudhuri says, noting that this type of therapy for DMD and other dystrophies "is currently becoming an increasingly attractive area of research in the muscular dystrophy community."

Funding for this MDA grant began Aug. 1, 2012.

MDA awarded $330,000 to professor of medicine Ju Chen at the University of California, San Diego, for research into the role of a protein called Cypher in skeletal muscle function and disease.

Mutations in Cypher result in myofibrillar myopathy (MFM) and late-onset distal myopathy, and results from completed studies in people with myotonic muscular dystrophy (MMD, or DM) indentified flawed Cypher isoforms (different forms of the same protein) in skeletal muscle tissues. Cypher activity also has been shown to be significantly decreased in mice exhibiting skeletal muscle atrophy.

"These observations suggest that Cypher plays essential roles in skeletal muscle function and disease," Chen said. "A better understanding of the function of Cypher in its various forms is key to developing therapies for Cypher-based MFM and potentially other myopathies."

In its work to understand the role of Cypher in skeletal muscle function and gain insight into the mechanisms by which mutations in Cypher cause skeletal muscle myopathy, the Chen research team will conduct experiments using three different genetically manipulated mouse models: an adult mouse lacking Cypher in skeletal muscle; mice lacking a short form of Cypher; and mice lacking a long form of the protein. Analysis will include comprehensive biochemical and functional evaluation, as well as evaluation of the microscopic structure of cells in skeletal mouse muscle tissue.

"Without funding from MDA, it would not be possible to perform these important studies," Chen said.

Funding for this MDA grant began August 1, 2010.

MDA has awarded a research grant totaling $321,489 over a period of three years to Elizabeth Chen, an associate professor at Johns Hopkins University School of Medicine in Baltimore. The funds will help support Chen's research into a mechanistic understanding of normal muscle physiology, which will inform potential therapeutic strategies aimed at treating various genetic and acquired degenerative muscle diseases.

Skeletal muscle is composed of large numbers of muscle fibers, each of which is the product of fusion between hundreds or even thousands of immature muscle cells called myoblasts. Myoblast fusion is not only important for skeletal muscle development, but also essential for stem-cell-based muscle regeneration.

Despite a large body of studies over several decades, the mechanisms underlying myoblast fusion in mammals remain poorly understood.

In this study, Chen and colleagues plan to characterize the role of a small type of protein called a GTPase during myoblast fusion in fruit fly (drosophila) muscle development and in a mouse model of muscle regeneration.

"While studies in Drosophila continue to provide novel insights into the molecular and cellular mechanism of myoblast fusion, the fundamental principles revealed by the Drosophila studies are now being tested in the mammalian systems," Chen said. "Such a cross-species approach will provide the basis for enhancing therapeutic efficacy in the treatment of a variety of muscle degenerative disease."

Funding for this MDA grant began Feb. 1, 2012.

“We hope that we can demonstrate good bioavailability of the antisense oligonucleotide (ASO) therapy in muscle cells and high in vivo efficacy in the mouse model, which will allow us to move this forward for drug development.”

Yi-Wen Chen, DVM, PhD, associate professor at the Center for Genetic Medicine Research, Children’s Research Institute (CNMC) in Washington, DC, was awarded an MDA research grant totaling $200,000 over two years to develop an antisense oligonucleotide (ASO) therapy for facioscapulohumeral muscular dystrophy (FSHD).

FSHD leads to progressive degeneration of muscles, with the most pronounced effects appearing in muscles of the face, shoulder blades, and upper arms. FSHD is caused by abnormal expression of double homeobox 4 protein (DUX4), which causes toxicity and muscle cell death. Suppressing DUX4 expression is a primary therapeutic approach for halting disease progression, as it is thought that would prevent or slow down the many detrimental activities of this toxic protein on muscle cells.

As a new MDA grant awardee, Dr. Chen will develop an ASO-based therapy to knock down DUX4 expression using the same backbone chemistry as was successfully used for Spinraza (the first disease-modifying therapy to treat spinal muscular atrophy, approved by the US Food and Drug Administration in December 2016). Dr. Chen will start with previously identified FSHD ASO candidates that showed efficacy in cell culture and see how well they work in FSHD mice, aiming to take these ASOs closer to pre-clinical and clinical trials for treating FSHD.

Martin Childers, a professor at the Institute for Regenerative Medicine in Winston-Salem, N.C., has been awarded an MDA grant totaling $480,000 over three years. The Institute is part of Wake Forest University Baptist Medical Center.

The new funds will help support Childers' research on heart disease associated with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). DMD results from a complete lack of dystrophin protein in skeletal and cardiac muscles, and BMD results from the presence of partially functional dystrophin protein. Both diseases are caused by mutations in the dystrophin gene.

"Many patients with DMD die as young adults from heart failure," Childers said. "The reason for this is that the heart muscle carries a genetic mutation that damages the normal operation of this all-important muscle. Our project will allow for the discovery of new drugs that might reverse or prevent the effects of the disease on the heart muscle."

Childers and colleagues will use two types of new technology to find potential new drugs for heart disease related to dystrophin deficiency. First, they'll use a method called cellular "reprogramming" to create heart cells from the skin cells of DMD patients. "This remarkable new technology will allow us to study how a genetic mutation affects the heart cells of a specific patient," Childers said.

The second method the investigators will employ is a drug-discovery "platform" that can screen thousands of compounds in individual cells.

"By marrying these two incredible technologies, this project will allow, for the first time, the testing of new drugs directly on the heart cells of an individual patient without any risk to the patient," Childers noted.

Funding for this MDA grant began August 1, 2011.

Martin Childers, PhD, DO, chief medical officer at Asklepios BioPharmaceutical Inc. in North Carolina, was awarded an MDA research grant totaling $192,500 over one year to perform pre-clinical studies using an adeno-associated virus (AAV) to deliver a gene therapy for limb-girdle muscular dystrophy type 2I (LGMD2I).

Limb-girdle muscular dystrophies are a diverse group of disorders with many subtypes categorized by disease gene and inheritance. LGMD2I is caused by mutations in the gene encoding fukutin-related protein (FKRP). In gene-replacement therapy for LGMD2I, an AAV vector is used to deliver a normal copy of the missing or mutated FKRP gene to a patient’s cells in order to make up for the inherited, non-functioning copy.

With this funding, Dr. Childers and Asklepios will build upon existing proof-of-concept work to collect the remaining pre-clinical data necessary for a first-in-human gene transfer clinical trial using AAV-FKRP in patients with LGMD2I. Upon successful completion of these studies, Asklepios will submit an Investigational New Drug (IND) application to the FDA, aiming to start a clinical trial in late 2020.

Premkumar Christadoss, a professor in the department of microbiology and immunology at the University of Texas Medical Branch in Galveston, was awarded an MDA research grant totaling $390,000 over a period of three years to study the potential for gene therapy as a treatment in myasthenia gravis (MG).

In MG, an "autoimmune" disease, the immune system attacks the body's own tissues. The attack occurs at the junction between nerve and muscle, and targets the acetylcholine receptor, the part of a muscle cell that receives signals from a nerve cell. Specific functions involved in driving the attack are generated by components (including the proteins C2, C4 and C1) in what is known as the complement system.

In a research mouse model of MG, Christadoss and colleagues will administer what are called small interfering RNAs (siRNAs) designed to block activation of C2, C4 and/or C1. Inhibition of the proteins should shed light on each protein's role in the autoimmune disease process and guide the development of therapies that can target them.

"Successful completion of this project will lead to human complement C2, C4 or C1 siRNA gene therapy for myasthenia gravis," Christadoss said. "Moreover, this complement gene therapy can be applied to other complement-mediated muscle diseases as well."

Funding for this MDA grant began February 1, 2012.

Sebahattin Cirak, pending assistant professor at the Children’s National Medical Center in Washington, D.C., was awarded an MDA development grant totaling $180,000 over a period of three years to hunt for elusive genes that cause congenital muscular dystrophy (CMD) and limb-girdle muscular dystrophy (LGMD).

Though CMD and LGMD are different diseases, they are similar in one respect: Both can be caused by a variety of different mutations in the same gene, and about half the time, the causative mutations are unknown.

New mutation hunting techniques have become available in the past several years that allow researchers to find gene mutations by examining the gene’s “messenger,” called RNA. Genes carry the instructions for making a new protein. To do so, a gene creates a “working copy” of itself using RNA. By carefully analyzing that RNA with a variety of techniques, it is possible to discover new gene mutations.

Cirak will use RNA extracted from muscle biopsies of people with CMD or LGMD. “I hope to uncover these elusive mutations by studying RNA, using the latest available sequencing technology,” he says.

“This research will improve the methods for molecular diagnostics of the muscular dystrophies,” he adds, with the goal of providing more families with the knowledge of the cause of their disease. In addition, the discovery of new genes can reveal new information about the exact causes of the disease, potentially suggesting new avenues for developing treatments.

Funding for this MDA grant began Feb. 1, 2013.

MDA has awarded a research grant totaling $429,983 over three years to Don Cleveland, departmental chair of cellular and molecular medicine; professor of medicine, neurosciences, and cellular and molecular medicine; and member of the Ludwig Institute for Cancer Research in La Jolla, Calif. The funds will help support Cleveland’s research into the connection between mitochondria and ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).

Mitochondria, the intracellular compartments that consume oxygen to produce chemical fuel that supports the cell, have been implicated as targets for toxicity in the inherited, SOD1-associated forms of ALS.

It is not known, however, in which cell types of the nervous system mitochondrial damage occurs, whether the ensuing mitochondrial dysfunctions are a cause or a consequence of neuronal degeneration during the disease and if the effects are the same in SOD1-associated ALS caused by different SOD1 mutations.

Using mice that are genetic mimics of inherited, SOD1-related ALS, Cleveland intends to determine at what disease stage and in which cell types of the central nervous system mitochondrial dysfunction occurs, and whether rescue of individual mitochondrial functions or an increase in mitochondrial activity may alter the ALS disease course.

“This comparative analysis will, in principle, provide a test for whether mitochondria are a common target of toxicity,” Cleveland said.

Funding for this MDA grant began August 1, 2011.