“One of the main roadblocks for ALS drug development is the lack of markers that tell us about drug efficacy in patients,” Nazem Atassi says. “With the recent science explosion and the exciting potential ALS treatment targets, we now need efficient tools that will allow us to quickly test many treatments.” 

MDA has awarded a human clinical trial grant totaling $750,000 to ALS ONE to explore the potential for a type of imaging called positron emission tomography (PET) to measure inflammation in the brain that could serve as a biomarker for ALS.

ALS ONE is an alliance between four institutional leaders in ALS treatment development: Massachusetts General Hospital (MGH), ALS Therapy Development Institute (ALS TDI), University of Massachusetts Medical School, and Compassionate Care ALS (CCALS). The partnership was formed with the goal of speeding the discovery of treatments for ALS and developing new approaches to improve care for individuals living with the disease.

The new project, led by Nazem Atassi, M.D., MSSc, will use PET imaging to track inflammation in healthy people who carry a known ALS gene and in symptomatic people with early-stage ALS. Atassi is a member of the ALS ONE science team, associate director for the Neurological Clinical Research Institute at Massachusetts General Hospital and associate professor of neurology at Harvard Medical School. 

Early data from previous studies conducted by Atassi and colleagues have shown significantly increased inflammation in the motor regions in people with ALS. The team also found that ALS patients who have more inflammation tend to have more advanced disease and worse functional status. Implementing PET technology potentially could reduce both the duration of future trials as well as the number of participants required to enroll. This would add enormous efficiency to ALS drug development. 

“This project is poised to change the paradigm of ALS drug development and have a direct impact on the design of future treatment trials for both familial and sporadic ALS,” Atassi says. 

MDA awarded a research grant totaling $336,503 to William Atchison, professor of pharmacology/toxicology and acting dean for research at Michigan State University College of Veterinary Medicine in East Lansing. The funds will support Atchison's research into the biological mechanisms underlying Lambert-Eaton myasthenic syndrome (LEMS).

In LEMS, the immune system mistakenly mounts an attack, targeting proteins called "types P and Q calcium channels" located at the neuromuscular junction, the place where motor neurons (nerve cells) and muscles meet. These proteins regulate the release of acetylcholine, the chemical messenger that carries signals between the motor neuron and the muscle.

In previous MDA-supported work, Atchison found that mice treated with plasma taken from people with LEMS reacted to an attack on the P/Q calcium channels by recruiting members of other classes of calcium channels (types L and R) in an effort to compensate for loss of the P/Q types.

In his new work, Atchison plans to study the compensation strategy and determine how muscle-controlling nerve cells try to maintain their function via recruitment of the L and R types of calcium channels.

Atchison's work could pave the way to a gene therapy strategy based on increasing the availability of compensating proteins as a means of preventing disruption of the chemical messenger.

"MDA funding has been crucial in that it has allowed us to study a relatively rare neuromuscular disease, but one that has very severe consequences, and that affects the quality of life and its length in patients with LEMS," Atchison said. "It has also allowed us to focus on aspects of this disease that might help increase general understanding of how the neuromuscular system tries to compensate for damage in other forms of autoimmune disease."

Funding for this MDA grant began February 1, 2011.

Paul August, at Sanofi, was awarded an MDA research grant totaling $298,500 over a period of three years to develop a neuron-muscle contraction unit on a chip. On the chip, developed using cells derived from people with amyotrophic lateral sclerosis (ALS), motor neurons will cause muscle cells to contract. The development of this innovative tool provides for a complete muscle-nerve unit, which could be used to test drugs and better understand the mechanisms behind motor neuron death in ALS. 

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

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

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

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

Tomoyuki Awano, a postdoctoral research scientist in the department of pathology and cell biology at Columbia University Medical Center in New York, was awarded an MDA development grant (DG) totaling $180,000 over a period of three years to search for genes that modify the onset and disease course of spinal muscular atrophy (SMA). (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.)

SMA is caused by the deletion of the SMN1 gene and a resulting deficiency of functional SMN protein. In humans, a nearly identical gene called SMN2 produces some partially functional SMN protein. Typically, the greater the number of copies a person with SMA has of the SMN2 gene, the less severe the disease.

But sometimes the SMN2 copy number doesn’t predict a person’s disease course.

This has been demonstrated in families, where multiple members are missing the SMN1 gene and have the same number of copies of SMN2, but whose SMA turns out drastically different. In previous work, Awano and colleagues have confirmed that this inconsistency is observed also in mouse models of SMA. A possible explanation is "modifier genes" that influence the disease course via the modulation of different biological pathways.

"Identifying modifier genes will not only reveal a potential target for cures, but will also shed light on the unknown disease mechanisms of SMA," Awano said.

Funding for this MDA grant began February 1, 2012.

Elisabetta Babetto, a postdoctoral research scholar at Washington University in St Louis, was awarded an MDA research development grant totaling $152,280 over three years to study the possible role of a protein called PHR1 in degeneration of nerve fibers in Charcot-Marie-Tooth disease (CMT).  In experiments in mice with a CMT-like disorder, Babetto will see whether manipulating the biochemical pathway associated with the PHR1 protein can improve the health of nerve fibers. “These experiments will improve our understanding of axonopathy [nerve fiber abnormalities] and have the potential for novel treatments in CMT patients,” she says.

Funding for this MDA grant began May 1, 2014

Mariah Baker, a research associate at the University of Texas Health Science Center at Houston, has been awarded an MDA development grant totaling $152,073 over three years to study how the release of calcium molecules is triggered in muscle cells. Improved understanding of this process could have implications for treating a variety of muscle disorders.

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

MDA awarded a development grant (DG) totaling $170,873 over three years to Celine Baligand, a postdoctoral associate at the University of Florida College of Medicine in Gainesville. The funds will help support Baligand's research into the use of various imaging techniques to help determine the natural progression of Pompe disease (acid maltase deficiency or AMD). (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.)

The current therapeutic approach for Pompe disease, enzyme replacement therapy or ERT, has improved outcomes for people with the disease. Alternatives to ERT, such as gene therapy, are under development.

Baligand and colleagues plan to develop tools, including magnetic resonance (MR) spectroscopy and other imaging techniques, for use in the noninvasive study of the natural course of Pompe disease in a mouse model. Such tools will facilitate the development of second- and third-generation treatment strategies for the disease.

"The development of MRI technology is crucial to improving the treatment of muscle diseases," Baligand said, noting that the development and validation of appropriate procedures for MRI could inform the preclinical testing of drugs and gene therapy in Pompe mouse models, potentially speeding the development of treatments for people with the disease.

Funding for this MDA grant began February 1, 2012.

Robert Baloh, associate professor-in-residence in the department of neurology at the University of California, Los Angeles, has been awarded an MDA research grant totaling $300,000 over three years to study the molecular mechanism of type 2A Charcot-Marie-Tooth disease (CMT) due to mutations in the Mitofusin 2 (MFN2) gene. Baloh has developed a new mouse model that he will use in his research to test whether gene therapy with a gene called MFN1 could serve as a therapeutic approach.

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

Ayan Banerjee, a postdoctoral researcher in biochemistry at Emory University in Atlanta, Ga., was awarded an MDA development grant totaling $180,000 over a period of three years to study the protein defects that cause oculopharyngeal muscular dystrophy (OPMD).

OPMD affects the muscles that control the eyelids, the swallowing muscles and other muscles. It typically occurs in the fourth or fifth decade of life. The gene that, when defective, causes OPMD encodes a protein called nuclear poly (A) binding protein 1 (PABPN1).

“Although we know that the PABPN1 gene is altered in this disease,” says Banerjee, “we do not understand why this change causes a muscle disease, and we also do not currently have any treatment for this disease.”

Banerjee’s goal is to better understand how the PABPN1 protein is regulated, in order to develop a better understanding of how the gene mutation causes disease. His work will include experiments in cell culture and in a fly model of OPMD. “The fly model is very useful for these studies because we can analyze PABPN1 function in the muscle of a living organism quickly and with limited cost, as compared to genetic mouse models,” he says.

Banerjee will be focusing on structural changes made to the protein after it is created (called post-translational modifications), which are known to help regulate the function of the final protein. One of these modifications, called phosphorylation, may be especially important, as errors in phosphorylation are associated with other forms of muscular dystrophy.

“Drugs correcting these defects result in an improvement in the disease in animal models,” Banerjee points out, suggesting a possible therapeutic target for OPMD as well. “If we can understand how the function of PABPN1 can be modulated, we may be able to develop new therapeutic approaches to treat OPMD.”

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

Ellen Barrett, professor of physiology and biophysics at the University of Miami (Florida) Miller School of Medicine was awarded an MDA grant totaling $297,102 over three years. The funds will support Barrett's study of the disease process and potential therapies in familial, or inherited, ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).

It has been observed in some cases of ALS that motor nerve terminals (the part of the motor neuron, or nerve cell that conveys signals from the brain to muscles) deteriorate prior to the death of the motor neuron cell body.

In previous studies, Barrett and colleagues have demonstrated that motor nerve terminal health relies heavily on the proper function of cellular "energy factories" called mitochondria. The team also has found that mitochondrial function in motor nerve terminals is impaired in presymptomatic mice with an ALS-like disease, and that it worsens as the mice age and begin to show symptoms.

In her new work, Barrett will test various mitochondria-protective drugs in a research mouse model of ALS and then observe whether more motor terminals remain intact and functional in mice that receive treatment versus mice that do not.

Results from this work may point the way toward a therapeutic strategy involving a combination of treatments: some designed to protect mitochondria and preserve motor nerve terminals, and others targeted toward preservation of motor neuron cell bodies.

"MDA funding has been critical to research progress in our laboratory," Barrett said. "We have especially appreciated MDA’s (1) willingness to support basic as well as clinical research with relevance to neuromuscular diseases; (2) support for pilot projects investigating new research directions; and (3) excellent reviewers, who have always read our grant applications carefully and offered valuable suggestions."

Funding for this MDA grant began February 1, 2011.

“Better understanding of the cellular and mitochondrial processes leading to COX assembly is expected to have a significant impact on health and neuromuscular disease. Our project will test therapeutic interventions involving copper delivery to mitochondria, which could be extremely useful to patients.”

Antonio Barrientos, PhD, professor of Neurology and Biochemistry and Molecular Biology at the University of Miami Miller School of Medicine, was awarded an MDA research grant totaling $300,000 over three years to study the relationship between genetic mutations and copper delivery to mitochondrial cells in the pathology of mitochondrial myopathies.

Mitochondria produce much of the energy that cells require to function, and an important component of that process is an enzyme called cytochrome c oxidase (COX). Without a properly assembled COX complex, cellular energy production is severely compromised; this affects the brain, muscles, and other organs with high energy demands. Previously, MDA awarded Dr. Barrientos funding to study the underlying molecular mechanisms of COX deficiency in some forms of mitochondrial myopathy as well as defects in mitochondrial protein complex assembly, which are a frequent cause of inherited mitochondrial myopathies.

The mitochondrial protein COX1, which is one of the proteins that make up the COX protein complex, requires copper in order to function and produce cellular energy. In this proposal, Dr. Barrientos will use patient-derived cells to study the proteins that help deliver copper to mitochondria, how their function is disrupted by mutations causing mitochondrial myopathies, and why this dysfunction is specific to certain tissues. Additionally, he will test various therapeutic strategies to enhance copper delivery.

MDA has awarded a research grant totaling $346,500 over three years to Antoni Barrientos, an associate professor in the departments of neurology and biochemistry and molecular biology at the University of Miami (Florida) Miller School of Medicine. The grant will help support Barrientos' study of the underlying molecular mechanisms in some forms of mitochondrial myopathy.

In the mitochondrial myopathies, commonly caused by the deficiency of an enzyme called cytochrome c oxidase (COX), cellular energy production is severely compromised, affecting brain, muscle and other organs with high energy demands. A complete understanding of COX synthesis is essential for uncovering the molecular basis underlying these diseases.

Barrientos and colleagues recently identified in a yeast research model two "chaperone" proteins responsible for helping assemble the COX enzyme.

Now, Barrientos plans to study the human equivalents of the two yeast proteins to determine whether their functions in humans are comparable. To do this, his team will use a gene silencing technique to "turn off" the genes that carry instructions for production of the chaperones, essentially inhibiting the proteins' production and enabling the investigators to identify what happens (or what doesn't happen) in their absence.

Barrientos' previous MDA-funded work has resulted in significant contributions to scientists' understanding of factors involved in COX assembly and regulation of the COX biogenetic process. Now, findings from his new work potentially may lead to therapeutics based on targeting the genes that carry instructions for the two COX assembly chaperones.

"MDA support is extremely important to our laboratory," Barrientos said, adding, "I have been working on cytochrome c oxidase assembly for the last 12 years, beginning with my postdoctoral studies at Columbia University, always with the support of MDA."

Funding for this MDA grant began February 1, 2011.

Antoni Barrientos, professor of neurology and of biochemistry and molecular biology at the University of Miami Miller School of Medicine in Miami, Fla., was awarded an MDA research grant totaling $300,000 over a period of three years to address a knowledge gap about mitochondrial protein complex assembly defects, which are a frequent cause of inherited mitochondrial myopathies. This project will not only improve our understanding of a process fundamentally central to mitochondrial processing, but also explore interventions that improve functioning and disease phenotypes.

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

Gary Bassell, professor of cell biology and neurology at the Emory University School of Medicine in Atlanta, Ga., was awarded an MDA research grant totaling $405,000 over a period of three years to discover new functions of the SMN protein in spinal muscular atrophy (SMA).

SMA occurs when the gene for SMN (survival motor neuron) is mutated, leaving too little SMN protein to perform its normal functions. While some of those functions are known, Bassell expects there are others that have yet to be described.

SMN binds to a molecule in cells called messenger RNA (mRNA), which carries genetic instructions from the nucleus, where they are stored, to the cytoplasm, where they are used to build proteins. Researchers know that SMN interacts with mRNA in the nucleus, but there is also evidence that the two pair up outside the nucleus, in the cytoplasm, as well. Exactly how SMN functions in this role, and exactly where in the cell the pair are located, is unknown.

“Our central hypothesis is that SMN protein plays a critical role in facilitating regulation of mRNA transport in motor neurons,” Bassell says, particularly the long extensions of these cells called axons, which carry nerve impulses to the muscles.

Bassell will use a mouse model of SMA to study the movements of SMN in cells. Using high-resolution fluorescence microscopy and imaging, he will directly visualize those movements within live nerve axons. His goal is to understand the adverse consequences for mRNA regulation when SMN protein is lost.

“We also will use these state-of-the-art methods to investigate whether specific compounds can correct defects in mRNA regulation in motor neurons from SMA mice,” he says, potentially pointing the way for development of new therapies.

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

Linda Baum, professor and vice chair of pathology and laboratory medicine at the Geffen School of Medicine at the University of California, Los Angeles, was awarded an MDA research grant totaling $405,000 over a period of three years to study molecules on the muscle surface that regulate important aspects of cellular communication and survival.

All cells, including muscle cells, are coated with an elaborate set of molecules called glycoproteins. These perform multiple critical functions, including: attaching cells to one another, relaying messages between cells, and ultimately, helping the cell survive. While animal models replicate important aspects of muscle diseases such as Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), the glycoproteins on animal cells differ from those of human cells. These differences may mean that mouse models of DMD do not completely represent the disease that affects people, Baum says.

The precise functions of many of the different glycoproteins on human muscle cells are unknown. Baum’s research will include characterizing the entire set of human muscle glycoproteins, determining the function of a subset of them, and screening for compounds that improve muscle function through their effect on these glycoproteins.

Because she is interested in human-specific glycoproteins, Baum will be studying human cells derived from skin biopsies of boys with DMD and their parents. She will “reprogram” these cells in the lab to become muscle cells, which can then be used for drug screening.

“By using these human muscle cells to screen drug libraries to identify compounds that improve cell function, our aim is to rapidly target therapeutic agents that will be efficacious in patients with Duchenne and Becker muscular dystrophies,” Baum says.

Her results also may be applicable for individuals who have forms of congenital muscular dystrophy, such as Walker-Warburg syndrome, that result from defects in cellular glycosylation (the process of creating glycoproteins).

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

MDA has awarded a research grant totaling $387,228 over three years to Lisa Baumbach, associate professor in the departments of neurology, pediatrics and biochemistry at the Miller School of Medicine at the University of Miami. The funds will help Baumbach continue to search for disease-causing genes responsible for infantile (either X-linked or type 1) spinal muscular atrophy (SMA).

X-linked SMA is one of a group of disorders with a wide spectrum of overlapping characteristics that involve the muscle-controlling lower motor neurons. As a group, these diseases are known as infantile lower motor neuron diseases (ILMD). They manifest just prior to birth or in the newborn period, and generally are lethal.

The only identified causal gene for X-linked SMA is UBE-1, but it's suspected there may be others that have yet to be identified in the ILMD group.

Baumbach's new research focuses on finding additional disease genes and biological pathways responsible for causing X-linked SMA and the ILMD group of disorders, and on identifying potential genetic modifiers of the causal genes.

Favorable results could have implications for improving early disease detection and paving the way toward potential therapies.

"We are indebted to MDA staff, MDA supporters and the Board of Directors for their ongoing support," Baumbach said.

Funding for this MDA grant began August 1, 2011.

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.

MDA awarded a grant totaling $303,438 to Kurt Beam, professor in the department of physiology and biophysics at the University of Colorado School of Medicine in Denver, for research into a process called excitation-contraction coupling responsible for the contraction of muscle cells necessary for voluntary movement and breathing.

"Excitation-contraction coupling is a fundamental process in skeletal muscle that is not yet well-understood," Beam said. "Additionally, mutations of the key proteins involved in excitation-contraction coupling cause serious human muscle diseases, including periodic paralyses, malignant hyperthermia and central core disease."

The process is initiated by electrical impulses which move along the membrane that separates the inside and outside of each muscle cell, and depends, at least in part, on two proteins called DHPR and RyR1.

In completed studies, Beam and his group have shown that mutations of either DHPR or RyR1 affect the behavior of both proteins. In their new work, the investigators will study cultured mouse muscle cells as they attempt to uncover the molecular mechanism for communication between DHPR and RYR1.

"The importance of MDA to neuromuscular research cannot be measured in dollars alone. In particular, MDA has been at the forefront in promoting basic and applied research directed toward understanding normal muscle function, mechanisms of muscle disease and development of therapies for these diseases," Beam said. "An especially important role that MDA plays is to provide funding during early career stages and at times when funding from other sources becomes scarce. I do not believe that I would have been able to establish and maintain my neuromuscular research had it not been for funding from MDA at crucial points in my career."

Funding for this MDA grant began August 1, 2010.

Kurt Beam, professor of physiology and biophysics at the University of Colorado at Denver, was awarded an MDA research grant totaling $300,000 over a period of three years to study two proteins that, when they malfunction, cause central core disease (CCD).

Muscle contraction in response to a nerve signal involves the interaction of two proteins: the dihydropyridine receptor (DHPR), which “senses” the electrical signal, and the ryanodine receptor (RyR1), which controls the release of calcium ions. Mutations in either one lead to CCD, as well as other muscle disorders. Beam will introduce the genes for these proteins into mouse muscle and nonmuscle cells. For both cell types, he says, researchers will measure the tiny electrical currents (less than a billionth of an ampere) produced by the DHPR. Fluorescence microscopy and calcium indicator dyes will be used to monitor movements of calcium inside individual cells; and confocal microscopy used to determine whether DHPRs and RyR1s are close to one another in the cells. The structure of these proteins then will be analyzed at a higher resolution by means of electron microscopy.

“Using these techniques, we hope to identify exactly what parts of the two proteins touch one another,” and how these sites of interaction and the overall shapes of the two proteins are affected by disease-causing mutations, Beam says.

“Although we have known for upward of 20 years that the DHPR and RyR1 are crucial for muscle contraction, we still do not understand the mechanism of their interaction, or exactly how disease-causing mutations affect this interaction,” says Beam. His research will attempt to better understand those interactions in order to define possible therapeutic targets for CCD and related muscle diseases.

Funding for this MDA grant began August 1, 2013.

Joseph Beavo, professor of pharmacology at the University of Washington in Seattle was awarded an MDA research grant totaling $412,500 over a period of three years to study how the drug sildenafil acts to improve the function of heart muscle in animal models of Duchenne muscular dystrophy (DMD).

Sildenafil is best known as the brand-name drug Viagra, used to treat erectile dysfunction. But it also can help protect muscles from damage in models of DMD and other diseases. One of the most important muscles researchers hope to protect is the heart muscle.

“At present, there are no effective treatments for most of the cardiac pathology in DMD patients,” Beavo says. Recent work from his group and others strongly suggests that sildenafil improves much of the dysfunction seen in older mdx mice (an animal model of DMD), “potentially opening a new therapeutic treatment for the cardiac pathology seen in muscular dystrophy,” he says.

“In these early studies, it is not clear how this drug works at a molecular level to improve cardiac function,” Beavo says. While much is known about how the drug affects a cell-signaling molecule called PDE5, evidence is accumulating that this is not the route through which sildenafil benefits the heart. Instead, a less-well-known molecule called PDE1C may be the real target of the drug — a hypothesis that Beavo will test in mice.

The identification of the real target (or targets) for sildenafil is particularly important, as clinical trials of the drug in DMD or Becker muscular dystrophy (BMD) are already in progress. Learning how the drug acts on the heart will help researchers understand the results of those trials.

Until there are effective treatments for DMD and BMD, “it is important to effectively treat the symptoms of the disease,” Beavo says. Agents such as sildenafil that have the potential to influence cardiac muscle health may help lengthen and improve the quality of life for people with either DMD or BMD.

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

Aaron Beedle, at Binghamton University – SUNY, in New York, was awarded an MDA research grant totaling $300,000 over three years to conduct preclinical studies of a potential therapeutic strategy for limb-girdle muscular dystrophy (LGMD) and congenital muscular dystrophy (CMD).

Dystroglycan-related muscular dystrophies are caused by abnormal processing of the protein alpha-dystroglycan. The abnormal processing impairs alpha-dystroglycan function, causing muscular dystrophy with variable involvement of the heart, brain and eyes. Dystroglycan-muscular dystrophies are caused by mutations in many different genes, making it difficult to develop gene therapy strategies because there are so many gene targets.

With colleagues, Beedle aims to test a pharmacological approach to inhibit a common intracellular pathway for growth and survival that involves a protein called mTOR. The team will conduct studies in a mouse model to test whether treatment with an mTOR inhibitor can improve muscle function, reduce pathology and extend lifespan, without causing adverse drug effects in the mice.

There preclinical studies will determine if inhibitor drug therapy can reduce disease severity in dystroglycanopathy mice, and translation of positive findings to the clinic could be quick since several FDA-approved drugs in this pathway are already in use in other diseases, including in some pediatric populations. 

Funding for this MDA research grant began Feb. 1.

Asim Beg, assistant professor at University of Michigan in Ann Arbor, was awarded an MDA research grant totaling $300,000 over a period of three years to study the role of a protein, EphA4, in amyotrophic lateral sclerosis (ALS). High levels of EphA4 correlate with rapid disease progression in ALS patients. Beg and colleagues will work on the development of a strategy to reduce EphA4 levels. This work will provide insight into the molecular mechanisms of motor neuron degeneration and will facilitate new strategies to slow ALS disease onset and progression.

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

Alan Beggs, a professor of pediatrics at Harvard Medical School and director of the Manton Center for Orphan Disease Research at Children's Hospital Boston, has been awarded an MDA grant totaling $396,990 over three years. The funds will help support Beggs' research on the molecular genetics of congenital myopathies.

These are a diverse group of inherited neuromuscular conditions that include myotonia congenita, paramyotonia congenita, central core disease (CCD), nemaline myopathy, myotubular myopathy (MTM) and other centronuclear myopathies (CNM), periodic paralysis (PP), and others, including some that have not yet been identified.

They all result from defects in skeletal muscle that lead to weakness or abnormalities of muscle contraction of variable onset and severity.

Beggs and his colleagues have built an extensive data registry and repository of samples from patients and their families, supported in part by MDA.

"This repository has led to the identification of the underlying gene defect for many individuals," Beggs said. "However, the responsible genes for up to half the cases remain unknown."

Beggs has now started screening for congenital myopathy-causing mutations in zebrafish and has discovered mutations in several genes that may be related to human neuromuscular diseases.

In this new project, Beggs and colleagues will determine the nature of these new gene mutations and their relationships to the muscle defects seen in the fish. They'll then use this information to identify people with analogous muscle findings, in whom they will analyze the genes identified in the zebrafish.

The affected fish also will allow the investigators to test drugs and other interventions to treat congenital myopathies.

"In 1996, MDA provided my very first grant to study muscle development and function," Beggs said, "and ever since then, it has been a constant source of support and encouragement for my efforts to understand and treat congenital myopathies."

Funding for this MDA grant began August 1, 2011.

Alan Beggs, professor of pediatrics at Children’s Hospital Boston, was awarded an MDA research grant totaling $300,000 over a period of three years to uncover new genes that cause nemaline myopathy in patients and families where the underlying cause has not yet been identified. To better understand the biological pathways that lead to disease and to aid the search for effective therapies, Beggs will then develop zebrafish, mouse and dog models containing the newly uncovered mutations.

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

Alan Beggs, PhD, professor of Pediatrics at Harvard Medical School and director of the Manton Center for Orphan Disease Research at Children’s Hospital Boston, has been awarded an MDA research grant totaling $300,000 over three years to continue his previous research on the molecular genetics of congenital myopathies.

Congenital myopathies are a diverse group of inherited neuromuscular conditions caused by defects in skeletal muscle and include central core disease (CCD) and other core myopathies, nemaline myopathy, myotubular myopathy (MTM) and other centronuclear myopathies (CNMs), congenital myopathies with fiber-type disproportion (CFTDs), and others (some of these have not yet been identified). In previous MDA-funded work, Dr. Beggs built an extensive data registry and repository of samples from patients and their families. His screening for congenital myopathy-causing mutations in zebrafish led to the discovery of mutations in several genes that may be related to human neuromuscular diseases. His further analyses determined the nature of these mutations, their relationships to the muscle defects seen in zebrafish, and their relationships to the same genes in humans with analogous muscle findings.

In this new project, Dr. Beggs will use whole genome sequencing methods to discover the disease genes and genetic mutations that cause congenital myopathy in patients and families where the underlying cause has not yet been identified. Then, to better understand the biological pathways that lead to disease and search for effective therapies, Dr. Beggs will develop animal models with these mutations, which he will be able to use in validation studies (to test if the mutation actually causes the disease) and screening assays (to test small molecule libraries to identify new drugs to treat these conditions).

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.

“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.

"A holy-grail of physician-investigators engaged in both ALS patient care and research has been the efficient and effective use of clinically-derived data for research purposes. To address this critically unmet need, we have partnered with Epic (the maker of the most widely used electronic health record [EHR] system) to build the ALS Toolkit. This resource will permit broad sharing of de-identified clinical data in a regulatory-compliant manner."

Michael Benatar, Professor of Neurology at the Miller School of Medicine of the University of Miami, was awarded an MDA Clinical Research Network Grant totaling $916,261 over three years to support the multicenter deployment of the ALS toolkit, a module built into the Epic EHR that aims to facilitate structured data collection for research and improve quality of care.

Clinics are critical to ALS patient care, leading to improved quality of life and prolonged survival. Clinic visits can take several hours with substantial clinical data collected; however, these data have limited utility for research purposes because of the unstructured way in which the data are collected. The ALS toolkit will provide a platform for standardized data collection across clinical sites, which could obviate the need for separate research visits and reduce the burden on patients and physicians.

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.

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.

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.

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.

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

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

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

"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.

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

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

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

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.