Atsushi Asakura, assistant professor at the University of Minnesota Medical School in Minneapolis, was awarded an MDA research grant totaling $378,531 over three years to study how the system of blood vessels known as the vasculature affects muscles in Duchenne (DMD) and Becker (BMD) muscular dystrophies.

Data from recent studies suggests that dystrophin — the protein deficient in DMD — plays a role in blood vessel health and maintenance. The absence of dystrophin in the vasculature results in vascular deficiency, making it likely that disturbed blood flow also is a cause of DMD-related muscle damage.

Therefore, Asakura says, “Definitive treatment of DMD will require both muscle fiber and blood vessel repair.”

With colleagues, Asakura is working to understand how vasculature affects muscle stem cells and regeneration in muscular dystrophies, and to develop a therapy based on growing new blood vessels. The team will examine the effects of increased blood-vessel growth on muscles in a research mouse model of DMD.

“The hope is that at least some, or combinations of, the vascular-targeted therapies will soon have clinical utility and provide current and future human beings living with DMD or other muscular dystrophies enhanced control over their own destiny,” Asakura says.

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

Mary Baylies, professor in the program of developmental biology at Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center in New York, was awarded an MDA research grant totaling $399,269 over three years to study LMNA gene mutations and the role of a protein called esconsin in Emery-Dreifuss muscular dystrophy (EDMD).

EDMD can result from mutations in the lamin A/C (LMNA) gene, which carries instructions for the lamin A and lamin C proteins. But how mutations in LMNA cause muscle disease is unclear, Baylies explains.

In previous work, Baylies and colleagues have shown that lamin C interacts with ensconsin, which plays a key role in muscle development.

Now, Baylies is working to determine the nature of the interaction of the two proteins and how they regulate muscle function, with the goal of providing new insight into the cellular processes required for optimal muscle function and for different muscle diseases. 

Studies are being conducted in a drosophila (fruit fly) research model, which Baylies says is "particularly well-suited to rapidly finding processes critical for muscle function, due to similarities with mammalian systems at both the genetic and cellular levels." In the model, using time-lapse imaging, Baylies' team gets "an unparalleled view" of cellular processes required for both the development and maintenance of muscle.

“This is an exciting period in muscle biology,” Baylies says. “Imaging approaches continue to evolve and allow us to ‘see’ muscle structure like never before.”

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

Postdoctoral research scholar Bogdan Beirowski, in the department of genetics at the Washington University School of Medicine in St. Louis, was awarded an MDA development grant totaling $180,000 over three years to study how defective Schwann cells lead to nerve-cell damage in Charcot-Marie-Tooth disease (CMT).

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.

Degeneration of axons — fibers that carry electrical signals between the brain and spinal cord and the rest of the body — is a hallmark of CMT and some forms of Dejerine-Sottas disease, and is thought to be responsible for muscle weakness associated with these diseases.

In some forms of CMT, the primary molecular defect localizes to Schwann cells, which normally help nourish and protect axons by wrapping them in a multilayered membrane called myelin. But it's poorly understood how Schwann cell dysfunction causes axon damage.

Data from previous work suggests that removal of defective myelin (demyelination) causes inflammation that results in axon damage, but Beirowski hypothesizes that "defective Schwann cells deprive long axons of metabolic support, thus contributing to axon degeneration."

Beirowski has developed mouse models in which key metabolic regulators are blocked exclusively in Schwann cells, which he now will use to test whether failure of the cells to deliver nutrients to axons could explain axon loss. 

The identification of specific metabolic defects in Schwann cells could lead to the development of CMT therapeutic strategies based on supporting the stability of axons.

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

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.

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.

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.

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.

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.

Adam Engler, assistant professor at the University of California, San Diego, in La Jolla, was awarded an MDA research grant totaling $390,000 over three years to study cell-based therapies designed for Duchenne (DMD) and Becker (BMD) muscular dystrophies and other muscle diseases.

Engler and colleagues are working with adipose-derived stem cells, orASCs (stem cells derived from fat). These cells, Engler says, are readily available, can develop into muscle, and — once they become muscle — can integrate into damaged skeletal muscle tissue. But the ASCs so far have been unable to repair DMD-related damage and restore muscle function.

Now Engler’s team, which has demonstrated the function of ASC-derived muscle in the lab, plans to translate those findings into animal models of muscular dystrophy.

The investigators are using a new method to coax ASCs into turning into mature muscle cells that they say should “better mimic” the conditions in which muscle cells in the body mature. This should make the cells more likely not only to integrate into damaged muscle tissue, but also help repair it.

”Stem-cell-based regenerative applications for muscle diseases, including muscular dystrophy, are showing increasing signs of feasibility in our lab," Engler says. "But our research and others' address critical stumbling blocks that currently prevent successful translation of these therapies in animal models of the disease and in humans."

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

Research associate David Gokhin at the Scripps Research Institute in La Jolla, Calif., was awarded an MDA development grant totaling $180,000 over three years to study the role of a protein called gamma-actin in muscle degeneration and weakness in Duchenne (DMD) and Becker (BMD) muscular dystrophies.

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.

Gokhin plans to determine the role gamma-actin plays in regulating the structure, strength and function of the skeletal muscle sarcoplasmic reticulum (SR), a cellular membrane system that houses the calcium that muscles use when they contract. He'll examine how gamma-actin filaments are linked both to the SR and to myofibrils (the force-generating units in muscle contraction).

Next, he'll study SR structure, calcium transport and SR-myofibril connections in the muscles of healthy mice and in those with altered levels of gamma-actin. Lastly, using a DMD mouse research model, Gokhin will examine how elevated levels of gamma-actin affect the DMD disease course.

Gokhin acknowledges progress made in the development of therapeutics for DMD, but says there still is a "gap" in the understanding of basic disease mechanisms.

"In other words, we don't have a convincing answer to the question 'how does a protein defect at the sarcolemma contribute to the cascade of events that leads to muscle wasting,'" he says. "I hope that my research will spark interest in the idea that communication between intracellular and peripheral membranes is an important, yet underappreciated, facet of muscle biology."

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

MDA awarded a research grant totaling $300,009 over three years to Yosef Gruenbaum, professor and elected chairman at the Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, in Israel. The funds will help support Gruenbaum’s study of proteins called lamins and their role in muscle diseases such as Emery-Dreifuss (EDMD) and limb-girdle (LGMD) muscular dystrophies, and Charcot-Marie-Tooth disease (CMT).

Relatively little is known about the biological pathways that are affected in muscle cells that have lamin defects, and why these changes lead to muscular dystrophy, Gruenbaum says. Now, using a nematode (worm) model of EDMD, Gruenbaum and colleagues are studying those pathways.

The investigators will use a variety of techniques in structural biology, genetics, cell biology and live imaging to investigate the effects of EDMD-linked lamin mutations and determine how those mutations affect the normal health and development of muscles.

Gruenbaum’s work is expected to uncover the underlying mechanisms at work in EDMD and potentially could lead to the identification of new drug targets and the development of new therapies to treat EDMD.

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

Madhuri Hegde, associate professor and scientific director at Emory Genetics Laboratory, Emory University in Atlanta, was awarded an MDA research grant totaling $262,928 over two years to identify genes that, when mutated, cause congenital muscular dystrophy (CMD).

A significant number of CMD-associated genes have been identified, but in approximately 30 to 40 percent of occurrences of the disease the causative gene remains unknown.

“As understanding of disease mechanisms and the function of the genes involved in the pathology of CMD grows, new cutting-edge therapies may be developed for the cases in which causative genes are currently unknown,” Hedge says.

Hegde and colleagues are working to identify more genes associated with CMD, using a variety of both traditional and next-generation methods designed to determine a person’s entire genetic makeup, such as whole-genome genotyping and whole and targeted next-generation genomic sequencing.

The team also is focusing on understanding the genotype-phenotyperelationship (the correlation of clinical differences with particular mutations) and developing a map of the CMD muscle genome (complete set of DNA),transcriptomes (the set of all molecules of RNA, a chemical cousin to DNA), and proteosomes (protein complexes).

“Next generation sequencing has revolutionized our ability to find new disease-causing genes, but it has not yet been widely applied to neuromuscular diseases,” Hedge says. “Research on new therapies is moving at a rapid pace, so it is important to identify the molecular defect in patients.”

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

Veronica Hinton, associate professor of clinical neuropsychology at Columbia University in New York, was awarded an MDA research grant totaling $397,596 over three years to study cognitive problems in children with dystrophinopathies, which include Duchenne (DMD) and Becker (BMD) muscular dystrophies.

"Children with dystrophinopathies are at risk for having delayed language development, poor academic achievement and limited social skills in addition to muscle weakness,” Hinton notes. “This cognitive and behavioral profile puts them at increased risk for poor quality of life, but the profile can be modified and improved with early detection and proper intervention.” 

Hinton is working to better understand the specific nature of the cognitive problems that children with dystrophinopathies may experience — information that is vital to minimizing and ameliorating the learning and behavior challenges that many children and families experience. 

With colleagues, Hinton is using neuropsychological tests to examine cognitive and behavioral performance in a diverse group of children. The children participate in tests that involve answering questions, solving picture riddles and doing computer-administered puzzle tasks. Parents and teachers complete rating forms about each child’s daily life behavior.

Hinton’s study is designed to do an in-depth assessment of executive function (the higher thought processes that include making or following complicated plans, solving complex problems, following a series of directions and making sound judgments) and verbal working memory skills, and provide information about how these skills affect “real life” outcomes in school, socialization and quality of life.

"Research in this area has been limited, yet effective in raising awareness and understanding about the cognitive and behavioral risks associated with a diagnosis of dystrophinopathy,” Hinton says. “With that knowledge has come much improved care for the individuals affected.”

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

MDA awarded a research grant totaling $398,532 over three years to Michio Hirano, professor of neurology and chief of the neuromuscular division at Columbia University Medical Center in New York. The funds will help support Hirano’s study of “molecular bypass therapy” for a mitochondrial myopathy called thymidine kinase 2 (TK2) deficiency.

Cellular “energy factories” called mitochondria generate the energy that fuels cells. Defects in mitochondria, which have their own DNA, are the causes of numerous human diseases that typically affect muscle and the brain.

One such disease, TK2 deficiency, usually begins in infancy. The disease also can manifest as adult-onset eye and limb muscle weakness. An enzyme (type of protein) called TK2 is required to synthesize the molecular building blocks of mitochondrial DNA.

With a previous MDA grant, Hirano and colleagues generated a research mouse model that has severely decreased TK2 activity and that develops muscle weakness similar to that of people with the infantile-onset form of TK2 deficiency.

In preliminary studies, administration of compounds to bypass the defective TK2 enzyme slowed the progression of the disease and doubled the life spans of the mice. Now, Hirano’s team is working to optimize the molecular bypass treatment in the TK2 mice.

Intensive research has revealed more than 200 genetically distinct mitochondrial diseases as well as novel therapeutic approaches for them, Hirano says. If successful, his new work could lead to the development of therapies for human TK2 deficiency and related diseases.

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

MDA awarded a research grant totaling $253,812 over two years to Dwight Koeberl, associate professor in the department of pediatrics at Duke University Medical Center in Durham, N.C. The funds will help support Koeberl’s research on the development of gene therapy for acid maltase deficiency (AMD, or Pompe disease).

Koeberl is investigating a new therapy for Pompe disease, using a drug that improves the response to gene therapy. The drug, called a beta2-agonist, increases the amount of acid maltase (the enzyme that’s deficient in Pompe disease) taken up by muscle cells during gene therapy.

Koeberl and colleagues also are studying ways to stop the immune system from mounting a response and interfering with gene therapy.

Experiments are being conducted in a research mouse model of Pompe disease. The mouse, which lacks the gene for acid maltase, responds to therapy in a similar way to people with Pompe disease.

Favorable results in Koeberl’s study could lead to a new design for gene therapy in Pompe disease.

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

Andrew Lieberman, assistant professor of pathology at the University of Michigan Medical School in Ann Arbor, was awarded an MDA research grant totaling $405,000 over three years to study a new therapy approach for spinal-bulbar muscular atrophy (SBMA).

SBMA is an inherited degenerative disorder of lower motor neurons (nerve cells) that is caused by a mutation in the androgen receptor (AR) gene. The mutant protein causes toxicity associated with the male hormonetestosterone, resulting in muscle weakness and atrophy in men.

Previous work established that the mutant AR protein is the cause of this toxicity, suggesting that strategies aimed at more efficient degradation of the protein should diminish disease severity.

Lieberman and colleagues found that degradation of the AR protein is tightly controlled by cellular machinery consisting of the heat shock protein 70 (Hsp70).

The investigators now are testing genetic and pharmacologic (drug-related) methods to see whether increasing the stability of Hsp70 will help it more efficiently bind the mutant AR protein and promote its degradation.

“It is our expectation that this work will help define a new therapeutic approach to SBMA and other protein aggregation disorders where degradation of the mutant protein is controlled by Hsp70,” Lieberman said.

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

Feng Lin, associate professor in the department of pathology at Case Western Reserve University School of Medicine in Cleveland, Ohio, was awarded an MDA research grant totaling $390,000 over three years to study a potential new cell-based therapy for myasthenia gravis (MG).

MG is part of a large class of diseases known as autoimmune diseases, in which the body's immune system attacks its own tissues.

In MG, the attack occurs at the neuromuscular junction (NMJ)  — the space where signals pass between muscle and nerve.

Symptoms include weakness in muscles that control the eyes, face, neck and limbs; partial paralysis of eye movements; double vision and droopy eyelids; and weakness and fatigue in the neck and jaws with problems in chewing, swallowing and holding up the head.

In previous work, Lin and colleagues developed a new method for generating a special group of cells that are highly effective at suppressing the immune system.

"Pilot studies in our labs found that this group of cells concurrently inhibited both T and B cell responses that lead to myasthenia gravis," Lin says.

Now Lin is testing the effectiveness of the special cells in treating MG in an animal model of the disease.

"Results from this project could help to develop these cells as a new, effective treatment for myasthenia gravis," Lin says.

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

MDA awarded a research grant totaling $390,000 over three years to Lin Mei, professor and director of the Institute of Molecular Medicine and Genetics at the Medical College of Georgia, part of Georgia Regents University. The funds will help support Mei’s research on the role of a protein called LRP4 in myasthenia gravis (MG).

MG is an autoimmune disease — a disease that occurs when the immune system attacks the body's own tissues. The attack occurs at theneuromuscular junction (NMJ), the space where signals pass between muscle and nerve. 

Symptoms include weakness in muscles that control the eyes, face, neck and limbs; partial paralysis of eye movements; double vision and droopy eyelids; and weakness and fatigue in the neck and jaws with problems in chewing, swallowing and holding up the head.

Most MG occurs when the immune system uses special proteins calledantibodies to target either the acetylcholine (ACh) receptor, or muscle-specific kinase (MuSK), a protein that helps organize ACh receptors on the muscle cell surface. But approximately 10 percent of people with the disease are seronegative for antibodies to the ACh receptor or MuSK, meaning the antibodies aren't detectable in their blood.

In preliminary studies, Mei and colleagues have identified an antibody against a protein called LRP4 in people with seronegative MG. (LRP4 is known to play a role in formation and maintenance of the NMJ.)

Now the group is studying the possible role and mechanisms of LRP4 in seronegative MG. 

"Such information should contribute to a better understanding of seronegative MG and development of novel diagnostic and therapeutic means for this devastating disease," Mei says.

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

MDA awarded a research grant totaling $237,868 over two years to Joseph Metzger, professor and chair of integrative biology and physiology at the University of Minnesota in Minneapolis. The funds will help support Metzger's work in development and testing of copolymer molecules, or "membrane sealants," for Duchenne (DMD), Becker (BMD) and other muscular dystrophies.

DMD and BMD are caused by an absence of dystrophin, a protein that helps keep muscle cells intact. Dystrophin deficiency causes muscle membranes to be fragile, with structural and functional abnormalities. These weakened cellular membranes make the muscle tissue highly susceptible to contraction-based injury and eventual destruction.

Metzger and colleagues are utilizing cutting-edge techniques in the fields of physiology (the study of chemical and physical processes involved in a living organism), chemistry, and chemical engineering to develop membrane-protective molecules as a therapeutic approach to treat muscular dystrophy. 

"Molecular 'Band-Aids' for muscle membrane protection have the potential to spark a revolution in novel therapeutics for diseased striated muscles in muscle dystrophy," Metzger says.

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

Daniel Michele, associate professor in the department of molecular and integrative physiology at the University of Michigan in Ann Arbor, was awarded an MDA research grant totaling $364,965 over three years to study the underlying mechanisms of muscle weakness and muscle fatigue in Duchenne (DMD) and Becker (BMD) muscular dystrophies. Michele's work could have implications for other dystrophies as well, including limb-girdle muscular dystrophy (LGMD) and congenital muscular dystrophy (CMD).

"Recent work by a number of laboratories has shown that patients and mouse models with DMD show early muscle fatigue, particularly when muscles are active, such as during exercise," Michele explains. "This early fatigue is thought to be primarily due to disruption of the production of nitric oxide in muscle, which helps dilate blood vessels in muscle and increase blood flow during exercise."  

Michele notes that there are several forms of the enzymes that produce nitric oxide in muscle, and "it's not exactly clear how nitric oxide production is regulated in muscle during exercise and exactly what causes dysfunction in muscular dystrophy." 

With colleagues, Michele is working to determine how nitric oxide production is regulated in muscle and if the normal regulators of nitric oxide production can be targeted to improve muscle blood flow and reduce muscle fatigue during exercise. The team will work primarily with the mdx mouse model (a DMD research model), but also will look at mouse models of other forms of genetic muscular dystrophy and muscle injury.   

"Overall, we hope to show that manipulation of the regulators of nitric oxide production will provide potential therapeutic benefit to prevent muscle fatigue," Michele says.

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

MDA awarded a research grant totaling $357,366 over three years to Jeffrey Milbrandt, professor and head of the department of genetics, and professor of pathology & immunology, medicine and neurology at Washington University School of Medicine in St. Louis.

The funds will help support Milbrandt's work in determining how Schwann cells contribute to nerve damage (neuropathy) in neuromuscular diseases such as Charcot-Marie-Tooth disease (CMT) and Friedreich's ataxia (FA).

Neuropathies and neuromuscular diseases like CMT and FA are associated with poor function of mitochondria, the energy producer in cells.

In previous work, Milbrandt and colleagues found that mice with mitochondrial deficits in Schwann cells develop a progressive neuropathy. (Schwann cells are a type of support — or glial — cell in the nervous system outside the brain and spinal cord; they support the function and maintenance of nerve fibers, or axons.)

Milbrandt's new project focuses on determining how Schwann cells obtain their energy when their mitochondria are damaged, and the mechanisms by which Schwann cell metabolism causes damage to the peripheral nerves (bundles of nerve fibers that run between the spinal cord and the muscles). He also plans to test whether pharmacological interventions to manipulate Schwann cell metabolism will help restore normal peripheral nerve function.

"For these studies, we will use a mouse model in which mitochondria are dysfunctional specifically and exclusively in Schwann cells," Milbrandt explains. "These mice, called Tfam-SCKO mice, are a good model for these studies because they develop many critical features of human neuromuscular disease and peripheral neuropathy."

Millbrandt notes: "Peripheral neuropathy research is entering a new era as we learn more about how axons are dismantled and the role of glia in maintaining axon health. There are unparalleled opportunities now to develop new treatments for this debilitating condition that is reaching epidemic proportions worldwide."

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

MDA awarded a research grant totaling $231,300 over three years to Alex Parker, assistant professor in the department of pathology and cellular biology at the University of Montreal Hospital Research Center in Montreal, Quebec (Canada). The funds will help support Parker's study of cellular stress response in neurodegeneration associated with amyotrophic lateral sclerosis (ALS).

Mutations in the genes for TDP43 and FUS proteins have been linked to ALS, Parker notes, "and they cause persistent cellular stress that ultimately overwhelms the neuron’s [nerve cell's] coping mechanisms, leading to cell death."

With colleagues, Parker is working to better understand a critical cell survival mechanism known as the endoplasmic reticulum stress response, which is known to reduce the toxicity caused by mutant TDP43 and FUS proteins. (The endoplasmic reticulum is a cellular compartment involved in the transport of proteins and other biological substances within cells.)

Using a C. elegans (nematode, or roundworm) model of ALS, Parker aims to identify small molecules that modify the ER stress response to help neurons overcome protein toxicity and stave off cell death.

Parker's work potentially could led to the identification of therapeutic targets and development of therapies for people with ALS.

"There are very few drugs available to treat neurodegeneration, and they are not very effective," Parker says. "We hope our findings accelerate drug discovery and development for ALS patients."

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

MDA awarded a research grant totaling $390,000 over three years to Rita Perlingeiro, associate professor in the Department of Medicine at the University of Minnesota in Minneapolis. The funds will help support Perlingeiro's study of genetic correction and muscle regeneration in Duchenne (DMD) and Becker (BMD) muscular dystrophies.

"The practical and ethical problems associated with the use of embryonic stem cells have been eliminated with the revolutionary discovery of reprogramming somatic cells, such as skin, to a pluripotent state (iPS cells)," Perlingeiro explains. "This enables the generation of patient-specific induced pluripotent stem cells that could be used for transplantation." (Pluripotent cells can mature, or differentiate, into any cell type and can be expanded indefinitely in the lab.)

Perlingeiro and colleagues have invented and continue to refine a method to efficiently generate immature skeletal muscle cells from iPS cells. In addition, they have shown that, once transplanted, the cells integrate with existing skeletal muscle cells in an iPS cell model of DMD, and in cells taken from healthy mice and healthy humans.

Now, Perlingeiro is working to determine the efficiency with which genetically corrected iPS cells can increase muscle regeneration in DMD mice.

Perlingeiro's work could lay the groundwork for clinical development of pluripotent stem cells for muscular dystrophy.

"Because disease progression for DMD takes over a decade, there is sufficient time to generate and test iPS cells," Perlingeiro says, "making DMD an ideal candidate for early-stage iPS cell therapy clinical trials."

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

JianRong Sheng, assistant professor in the department of neurology and rehabilitation at the University of Illinois at Chicago Medical Center, was awarded an MDA research grant totaling $317,058 over three years. The funds will help support Sheng's study of potential therapeutic treatments for myasthenia gravis (MG).

MG is an autoimmune disease — a disease that occurs when the immune system attacks the body's own tissues. The attack occurs at theneuromuscular junction (NMJ), the space where signals pass between muscle and nerve.

Most MG occurs when the immune system uses special proteins calledantibodies to target either the acetylcholine (ACh) receptor, or muscle-specific kinase (MuSK), a protein that helps organize ACh receptors on the muscle cell surface.

"Current major therapies for MG produce general, nonspecific suppression of the immune system and are associated with significant long-term risk of infection and malignant tumors, and are therefore not optimal for treatment," Sheng explains. "There is a need to develop more focused treatments that only target those immune cells responsible for causing diseases without otherwise affecting the remainder of the immune system."

In previous studies, Sheng has shown that a growth factor called GM-CSF prevented development of a disease resembling MG called experimental autoimmune myasthenia gravis (EAMG). The treatment increases numbers of T cells and B cells, and Sheng showed that the T cells suppressed MG-associated antibodies.

Now, Sheng and colleagues are working on discerning the function, mechanisms and therapeutic potential of B cells in EAMG, and evaluating new medications aimed at mobilizing the cells for the treatment of MG.

Sheng's work potentially could change the fundamental approach to the treatment of MG from general, nonspecific immune suppression to focused, individualized and more specific therapy. 

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

Melissa Spencer, professor of neurology at the David Geffen School of Medicine at University of California, Los Angeles, was awarded an MDA research grant totaling $390,000 over three years to study the role of an enzyme called calpain 3 in type 2A limb-girdle muscular dystrophy (LGMD2A).

With colleagues, Spencer has demonstrated that characteristics and disease processes of LGMD2A are different from those seen in other dystrophies.

In Duchenne muscular dystrophy and other types of LGMD, the muscle cell membrane is weakened from the genetic mutation and the muscle cells die, Spencer explains. "In LGMD2A, muscle membranes remain intact, a finding which has left researchers without an explanation for the underlying mechanism of disease."

LGMD2A is caused by mutations in the CAPN3 gene, which carries genetic instructions for building a protein called calpain 3. Over the last decade, Spencer's team has generated numerous research mouse models that have provided insight about the biological function of calpain 3 in muscle development and muscle growth, but it's remained unclear how CAPN3 mutations lead to muscle dysfunction.

The team discovered that muscles lacking calpain 3 have severe deficits in the signaling pathways responsible for muscle growth — particularly thecalcium calmodulin kinases (CaMK) pathway.

Now Spencer is working on determining the relationship between calpain 3 and CaMK signaling.

Spencer's work could uncover the underlying defects for LGMD2A and lead to therapeutic targets for stimulating muscle growth in the setting of muscle degeneration. It also could shed light on other related muscular dystrophies, such as multiminicore disease.

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

Tom Thompson, associate professor in the department of molecular genetics, biochemistry and microbiology at the University of Cincinnati in Ohio, was awarded an MDA research grant totaling $330,000 over three years. The funds will help support Thompson's study of potential therapies based on blocking a protein called myostatin for Duchenne (DMD) and Becker (BMD) muscular dystrophies.

"In our bodies, a protein called myostatin inhibits the size and mass of muscle, so therapies aimed at inhibition of myostatin are in high demand," Thompson explains. One potential concern, however, is that myostatin inhibitors need to be specific in order to limit potential side effects.

Humans have proteins that naturally inhibit myostatin. Thompson and colleagues are using a technique called X-ray crystallography to determine, at the atomic level, how these naturally occurring inhibitors bind to and neutralize myostatin. Their focus is on a protein called GASP1, which binds myostatin with high specificity.

The investigators plan to identify the mechanism by which GASP1 binds to myostatin.

In addition, the team will study another inhibitor called follistatin, which helps degrade myostatin by binding with cell surface molecules calledheparin.

This knowledge may make it possible to leverage the body's own system to inhibit myostatin, or develop other strategies to block it, Thompson says.

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

Charles Thornton, professor of neurology at the University of Rochester in New York, was awarded an MDA research grant totaling $308,935 over three years. The funds will help support Thornton's work to expedite the development of effective treatments for type 1 myotonic muscular dystrophy (MMD, also known as DM).

MMD1 is caused by a repeat expansion mutation — an expanded section of DNA — in the DMPK gene, located on chromosome 19. Expanded DNA leads to the creation of expanded and toxic RNA, which causes problems for cells mainly because it traps and disables important proteins. Therefore, an important goal in MMD research is to free these cellular proteins — particularly one called muscleblind 1 or MBNL1 — so that they're able to perform their crucial functions.

One treatment approach that recently has emerged involves the use of small molecules to restore the activity of MBNL proteins, either by increasing their production or by blocking their interactions with toxic RNA. Another approach involves antisense oligonucleotides (AONs) that neutralize RNA toxicity or stimulate the clearance of toxic RNA.

"The model systems that are needed for preclinical testing of these respective approaches are somewhat different," Thornton explains. "Until now, the testing of small molecules has mainly been performed in HSALR transgenic mice, due to advantages of cost and efficiency; however, this model has limitations."

Thornton and colleagues are working to generate new mouse models that better reproduce the muscle weakness and degeneration that are characteristic in human MMD1. In addition, the team plans to design a model that will facilitate the testing of AONs.

Such mouse models could be used in the development and testing of potential new drugs to treat MMD.

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

MDA awarded a research grant totaling $260,000 over two years to Rossella Tupler, research assistant professor in the program of molecular medicine at the University of Massachusetts Medical School in Worcester. The funds will help support Tupler’s search for the molecular cause of facioscapulohumeral muscular dystrophy (FSHD).

FSHD has been associated with a reduction (eight or fewer) in the number of D4Z4 elements (alleles) and the subsequent expression (gene activity) of DUX4, Tupler explains. “However, studies of families in Italy, Brazil and the United States suggest that D4Z4 reduction and DUX4 expression are not sufficient to cause disease.”

In Italian families, a study of 253 unrelated people with FSHD revealed that 204 (80.6 percent) carry D4Z4 alleles with 1-8 units, 19 (7.5 percent) have D4Z4 alleles with 9-10 repeats, and 30 (11.8 percent) carry D4Z4 alleles with 11 repeats or more.

In the United States, family members with identical D4Z4 repeat lengths included members who did not have the disease and members with classical FSHD; not all had DUX4 activity. 

“Collectively, these results indicate that those DNA anomalies are not sufficient to cause FSHD and additional factors are necessary to disease development,” Tupler says.

With colleagues, Tupler is working to identify genetic elements that can cause FSHD disease onset. The team is using a technique called whole-genome sequencing to study the DNA of 12 families from Italy, Brazil and the United States in which D4Z4 reduction does not correlate with the presence of disease.

“A profound rethinking of the genetic disease mechanism and modes of inheritance of FSHD is now required,” Tupler says, “and entirely new models and approaches are needed.”

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

MDA awarded a research grant totaling $358,242 over three years to Christine Vande Velde, research assistant professor in the department of medicine at the University of Montreal Hospital Research Center in Montreal, Quebec (Canada). The funds will help support Vande Velde’s study of the role of TDP43 and the stress granule mechanism in amyotrophic lateral sclerosis (ALS).

Vande Velde and colleagues are looking at the interplay between genetic susceptibility and environmental exposures to toxins that are thought to be relevant in ALS. It’s known that cells exercise a variety of mechanisms to mediate recovery following exposure to environmental stress, one of which is the formation of proteins and RNA molecules into clumps called stress granules.

In previous work, Vande Velde’s team has indicated that TDP43 plays an important role in stress granule formation.

“In particular, this grant focuses on TDP43 and its regulation of an important cell survival mechanism: the formation of stress granules,” Vande Velde explains. Her team will use a combination of cellular and rodent models to dissect the stress granule mechanism in which TDP43 operates and determine the impact of ALS-causing mutations on this pathway.

“This is an exciting area for ALS research,” Vande Velde says, “as demonstrated by a recent convergence on this topic by many groups.”

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

MDA awarded a research grant totaling $301,614 over three years to Marc Weisskopf, associate professor of environmental and occupational epidemiology in the departments of environmental health and epidemiology at Harvard School of Public Health in Boston. The funds will help support Weisskopf’s search for nongenetic risk factors for amyotrophic lateral sclerosis (ALS).

“The search for nongenetic risk factors for amyotrophic lateral sclerosis (ALS) has progressed slowly over the past decades,” Weisskopf explains. “Although numerous hypotheses have been proposed, outside of age and male gender, no risk factor has emerged as a consistent and accepted predictor of risk.” 

Weisskopf says that the lack of rigorous population-based studies of ALS with exposure data collected prospectively (before the onset of ALS) probably is one reason why scientists still have a poor understanding of very basic, fundamental aspects of the distribution of ALS in the population — for example, the distribution by race, ethnicity or socioeconomic status.

With colleagues, Weisskopf is studying the relationship between race/ethnicity, education and specific occupations, and the risk of developing ALS. The team is using the National Longitudinal Mortality Study (NLMS), a cohort study of almost 2.4 million men and women who completed the Current Population Survey (CPS) of the U.S. Bureau of the Census between 1973 and 2002.

"Our analytical approach is to examine how the factors determined at baseline relate to subsequent risk of death from ALS,” Weisskopf says. For this the investigators are using the National Death Index, which provides data on the causes of nearly all deaths in the United States since 1979.

“We have already identified 713 deaths from ALS, which, even as a minimum of the eventual total we will have, makes this study not only one of the largest of the few cohort studies with prospectively collected data, but also the only one that is representative of the U.S. population,” Weisskopf notes.

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

Thurman Wheeler, assistant professor in the department of neurology and Center for Neural Development & Disease at the University of Rochester, New York, was awarded an MDA research grant totaling $396,000 over three years to identify potential therapies aimed either at slowing down the progression of muscle degeneration or improving muscle health in type 1 myotonic muscular dystrophy (MMD1, or DM1).

The mechanism responsible for progressive muscle degeneration in MMD1 in humans is unknown.

Wheeler and colleagues have developed novel therapies that correct most aspects of myotonic dystrophy in mice with mild muscle degeneration. It’s unclear, however, whether the therapies will be as safe and effective in mice with advanced muscular dystrophy similar to MMD1 in humans.

Now the team is working with muscle cell cultures, muscle tissue and research mouse models of MMD1 to determine why progressive muscle degeneration occurs, and to identify therapeutic agents that slow progression of muscle degeneration or improve muscle pathology.

One of the therapeutic agents being tested by the team is antisense oligonucleotides (ASOs), administered by subcutaneous (under the skin) injection to mice with a disease resembling MMD1. The safety and efficacy of ASOs in mice with advanced muscle disease may help predict the safety and therapeutic response in people with MMD1 ahead of clinical trials.

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

Ryan Wuebbles, a postdoctoral fellow in pharmacology at the University of Nevada School of Medicine in Reno, was awarded an MDA development grant (DG) totaling $180,000 over three years to study the potential use of a protein called laminin-111 as the basis of therapies for Duchenne (DMD) and Becker (BMD) muscular dystrophies.

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.

In a research mouse model with a disease resembling DMD, treatment with laminin-111 has been shown to prevent muscle damage and improve resistance to exercise-induced muscle injury. The proteins' large size, however, makes it difficult to manufacture, so Wuebbles and colleagues are working to determine whether a small part of the protein is capable of producing the same effects.

Wuebbles plans to test different parts of laminin-111 in cells cultured from DMD research mice and from people with the disease. The most promising of these will be tested in a DMD research mouse model, where any effects can be compared to those generated by the full-length protein.

"Protein therapeutics are emerging as some of the strongest Duchenne muscular dystrophy therapeutic candidates," Wuebbles says. "Exciting new protein treatments such as laminin-111 offer a directed natural approach compared to traditional small chemical compounds."

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

Stephen Züchner, associate professor of human genetics and neurology at the University of Miami Miller School of Medicine in Florida, was awarded an MDA research grant totaling $390,000 over three years to identify genes responsible for Charcot-Marie-Tooth disease (CMT).

"Genetic research over the past 25 years has identified more than 50 different CMT genes,” Züchner explains. “While the subtype CMT1 is largely explained by these genes, CMT2 and a number of other subtypes of CMT are less well-understood.”

It’s thought that many more genes need to be found to explain the majority of CMT found in people with the disease, but a new generation of DNA sequencing machines — called next-generation sequencers — is making that endeavor much easier and cheaper

“We have been pioneering the application of these new instruments for neuromuscular and other diseases,” Züchner says, “and have already identified and published multiple novel genes using this approach in a number of diseases.”

In his new work, Züchner and colleagues are focused on identifying additional genes that cause CMT.

“We believe that the more genes we know, the better will be our understanding of gene networks that work together in a process that leads to disease,” Züchner says. “Instead of focusing on a single gene, there will be benefits in understanding the entire disease process.”

Such understanding may lead to development of therapies that, instead of targeting a specific gene, influence gene networks or pathways — meaning a single treatment could help people with mutations in different genes.

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