Matthew Alexander, a postdoctoral research fellow in genetics and pediatrics at Harvard Medical School in Boston, Mass., was awarded an MDA development grant totaling $180,000 over a period of three years to study the role of microRNAs in Duchenne muscular dystrophy (DMD).

MicroRNAs (miRNAs) are molecules that interact with genes, including the dystrophin gene. (Mutations in the dystrophin gene are the cause of DMD.) Those interactions help control a wide range of processes in cells.

When the dystrophin gene is mutated, the amount of a miRNA called miR-486 is greatly reduced. This causes changes in a system that regulates muscle growth and development.

“Currently, very little is known about the secondary signaling pathways that are altered as a consequence of dystrophin deficiency, and the roles that micro RNAs play in muscle disease,” Alexander says. His work will explore the effects of reducing miR-486 in the context of dystrophin deficiency in the mdx mouse, a research model of DMD. The goal is to gain a better understanding of the problems for muscles caused by loss of miR-486 in order to develop therapies to avoid or compensate for these problems.

“MicroRNA-based therapeutics, unlike traditional single-gene based drug treatments, are capable of manipulating the expression of entire signaling pathways,” says Alexander. In addition, “they can be delivered in a dose-dependent fashion, and can reach the damaged muscle via intravascular or intramuscular injections,” all potential advantages for developing effective treatment.

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

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.

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.

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.

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.

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

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

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

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

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

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

Benoit Coulombe, director of the Proteomics and Gene Transcription Laboratory at the University of Montréal in Quebec, Canada, was awarded an MDA research grant totaling $377,067 over a period of three years to study the regulation of a protein whose gene, when mutated, can cause amyotrophic lateral sclerosis (ALS) and inclusion-body myositis (IBM).

Valosin Containing Protein (VCP) helps clear misfolded proteins so that they do not cause damage within cells. Mutations in the VCP gene that interfere with this function are one cause of both ALS and IBM.

VCP is a type of protein called a molecular chaperone. “Building a detailed understanding of the mechanisms by which molecular chaperones play a role in the onset and development of neuromuscular disorders is important for the design of new tools to better diagnose and treat some of these conditions,” Coulombe says.

Recently, his group discovered that a set of proteins called methyltransferases regulates the activity of VCP, raising the possibility that this regulatory system may go awry when VCP is mutated. By studying the activity of methyltransferases and VCP in both healthy and diseased cells, Coulombe hopes to learn more about the regulation of chaperones and how it is affected by disease-causing mutations.

The goal is to examine the full range of changes brought about by methyltransferase activity, using state-of-the-art tools to capture and characterize the set of protein modifications in cells. Coulombe also will explore whether changes in VCP and the proteins with which it interacts can serve as a “biomarker,” helping to identify diseased cells and following their response to treatment.

“Characterizing these newly discovered enzymes will help us understand the molecular bases of these disorders and accelerate the development of diagnosis and therapeutic tools relevant to their treatment,” he says.

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

Radbod Darabi, assistant professor of medicine at the University of Minnesota in Minneapolis, was awarded an MDA research grant totaling $380,049 over a period of three years to develop methods to use cells derived from skin to regenerate muscle tissue in a model of Duchenne muscular dystrophy (DMD).

A promising strategy to repair damaged muscles in DMD is to transplant healthy cells into the muscle. One source for such cells is from stem cells, which can be grown in a laboratory dish and treated to become muscle cells. In addition, stem cells can generate muscle satellite stem cells, which are normally found in healthy muscle and are necessary for long-term muscle regeneration.

Recent developments in stem cell biology have allowed researchers to generate induced pluripotent stem cells (iPS cells) from skin cells. Darabi has demonstrated that human skin-derived iPS cells are able to differentiate into muscle and can be successfully transplanted into mice that model DMD. The mice are able to accept the new cells, and the cells produce the dystrophin protein. Lack of dystrophin causes the symptoms of DMD.

“This strategy opens a new window of opportunity to use patient-specific pluripotent stem cells for disease modeling as well as cell therapy for muscular dystrophies,” Darabi says.

His work will include optimizing cell delivery and survival strategies, as well as exploring whether treating cells before transplantation with a regulatory gene can improve the long-term success of the graft. The gene, called PAX7, is a master regulator of muscle satellite stem cells.

Darabi says his research is aimed at making cell transplantation a viable treatment in DMD. “Answering these questions will be crucial for the evaluation of the therapeutic potential of human iPS cells, and consequently moving this strategy one step closer to future clinical trials in muscular dystrophy patients.”

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

Dame Kay Davies, Dr. Lee’s Professor of Anatomy in the department of physiology, anatomy and genetics at the University of Oxford in the United Kingdom, was awarded an MDA research grant totaling $207,566 over a period of two years to conduct a drug screen for molecules that can increase levels of a protein called utrophin, which can be developed for clinical trials in Duchenne muscular dystrophy (DMD).

DMD is caused by a mutation that prevents formation of normal dystrophin protein. “Utrophin is very similar to the missing dystrophin protein,” Davies says, and it is unaffected in DMD. Increasing the amount of utrophin has been shown to be beneficial in a mouse model of DMD, indicating the potential for utrophin-increasing drugs in humans. Drugs may offer benefits that other treatment strategies don’t, she says, since they reach every muscle in the body (which has been a challenge for some other strategies), including the heart and the diaphragm.

Davies' drug development efforts (supported by a previous MDA research grant) already have led to an MDA-supported phase 1 safety trial of a compound called SMT C1100, and further trials are planned. At the same time, Davies wants to develop drugs that do the same job better. “We aim to develop ‘best in class’ drugs to follow on from this,” she says. “We have developed a new, more sensitive screening assay and have already found new hits [drug candidates] that work better than the original drug in tissue culture.” Those now will be tested in mouse models, and tinkered with to optimize their performance.

“We are at an exciting point in this research, and we are optimistic that we will be able to find a drug which will increase levels of utrophin to provide substantial clinical benefit,” Davies says.

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

Christine DiDonato, assistant professor of pediatrics at Northwestern University in Chicago, Ill., was awarded an MDA research grant totaling $405,000 over a period of three years to test treatment strategies for spinal muscular atrophy (SMA).

SMA is due to the loss of SMN protein, caused by a mutation in the SMN1 gene. Replacing the SMN1 gene, or increasing production from a usually silent "backup" copy of the gene called SMN2, both hold promise for treatment. However, DiDonato says, “it is currently unknown how late in the disease process such therapies can be beneficial, in terms of either improving function or halting disease progression.”

Her research will address that question in a mouse model of the disease by determining the latest time at which SMN protein can be re-introduced and still have effect after disease onset in milder forms of SMA.

In addition, DiDonato says the project “will specifically determine if therapies that only increase SMN within the nervous system can correct all deficits in milder forms of SMA. This research has important implications for SMA therapy development,” since diagnosis of the disease often occurs months or years after birth.

DiDonato will measure strength, endurance and gait in mice that begin SMN protein production at various time points. Using these techniques, she will ask “whether we can halt, slow or reverse disease progression when SMN is returned after symptoms are clearly evident, and at advancing points of disease.”

She notes that “great strides have been made in SMA research and therapeutic development. There are now several drugs that have entered clinical trials for SMA, so it is a very exciting time. Our research will provide important information for SMN-based therapies for milder forms of SMA.”

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

Matthew Disney, associate professor of chemistry at The Scripps Research Institute in Jupiter, Fla., was awarded an MDA research grant totaling $362,724 over a period of three years to test the ability of compounds he has developed to target the toxic RNA in myotonic dystrophy type 2 (MMD2, also known as DM2).

MMD2 is caused by an abnormally expanded section of DNA on chromosome 3, which leads cells to make an abnormally long segment of RNA from it. This expanded RNA folds into a structure that traps certain cell proteins, preventing them from doing their normal jobs.

Disney’s research group has designed small molecules that bind specifically to this expanded RNA. If these, or molecules like them, can reduce the amount of protein the RNA can trap, they may be useful as therapy for MMD2. Disney will be testing these molecules for that ability, and also determining the three-dimensional structure of the MMD2 RNA.

“If we are successful in these endeavors we will be able to better understand how DM2 RNA binds to and inactivates proteins,” he says. That should provide the foundation for development of better and more specific molecules that can be tested as drugs in people with MMD2.

“This is very much a developing field, and a lot of work is needed to establish if small molecules can be designed to target RNA and have therapeutic utility,” Disney says. “These studies are critically important because biologists are doing such a phenomenal job in identifying the biochemical mechanisms of disease. The major question is whether we can leverage this mechanistic information into small-molecule therapies.”

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

Heather Durham, professor at the Montreal Neurological Institute of McGill University in Quebec, Canada, was awarded an MDA research grant totaling $355,936 over a period of three years to study the consequences of mutations in the FUS gene for muscle-controlling nerve cells called motor neurons.

Mutations in FUS are known to be a cause of amyotrophic lateral sclerosis (ALS), a disease that involves the death of motor neurons. The FUS protein binds to RNA, which cells use to bring protein-making instructions from the nucleus to other parts of the cell. FUS joins up with other proteins to do this. FUS mutations can disrupt the protein's ability to move through the cell and bind properly to other cell components to make these transport complexes.

“In neurons, the distribution of these RNA-containing complexes is particularly important for maintaining connections with other neurons, and for responding to the level of neuronal activity and stress,” Durham says. Her research will study the details of how mutations affect trafficking of FUS and its partners, including RNA, and how these abnormalities relate to or affect cellular adaptive responses. Understanding these important changes may shed light on how these and other ALS-causing gene mutations lead to the death of motor neurons.

“This is a very exciting time in ALS research,” she says. “The recent discoveries of new genes associated with ALS point us toward the commonalities and differences in the multiple disorders we call ALS. Those commonalities will not only help us to identify targets for therapy, but will establish the best preclinical models in which to evaluate their efficacy.”

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

Mohamed Farah, assistant professor of neurology at Johns Hopkins University School of Medicine in Baltimore, Md., was awarded an MDA research grant totaling $375,000 over a period of three years to test drugs in models of amyotrophic lateral sclerosis (ALS).

In ALS, muscle-controlling nerve cells called motor neurons become dysfunctional before they die, and that period of dysfunction may represent an important window in which new therapies could rescue them. “The overall goal of this grant is to investigate whether the capacity of motor nerves to regenerate after insult or disease can be enhanced to a degree that results in functional recovery,” Farah says.

He will be testing whether drugs originally designed for Alzheimer’s disease can offer benefit in animal models of ALS by increasing neuronal regeneration and restoring neuromuscular function when given in the early stages of disease.

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

Vera Fridman, at Massachusetts General Hospital in Boston, was awarded an MDA clinical research training grant totaling $180,000 over a period of two years to the effects of Serine in people with a form of Charcot-Marie-Tooth (CMT) disease called hereditary sensory and autonomic neuropathy type 1 (HSAN1).

CMT is the most commonly inherited neurological disorder, affecting 1 in 2,500 people worldwide. It is a slowly progressive disorder, causing degeneration of the peripheral nerves that control sensory information coming from the limbs. HSAN is a rare genetic neuropathy that causes severe numbness, weakness and ulceration of the feet and hands.

Two abnormal lipids (fat-like substances) have been identified in the blood of both humans and mice with HSAN1. It has been shown that levels of these lipids can be reduced by administering the amino acid serine, and that mice treated with serine have better motor and sensory function.

Fridman’s goal is to determine the effect of serine on symptoms of people with HSAN1 in order to assess whether serine supplementation may be an effective therapy for the disease.

Funding for this MDA grant is effective July 1, 2013.

Madhuri Hegde, executive director of the genetics laboratory and associate professor of human genetics at Emory University School of Medicine in Atlanta, Ga., was awarded a one-year MDA research grant totaling $84,924 to advance methods for newborn screening (NBS) for Duchenne muscular dystrophy (DMD).

Recently, a two-step NBS process was developed for detecting DMD in newborns, with a very high detection rate at relatively low cost. In the first step, a drop of blood is analyzed for the presence of the protein creatine kinase. A high level of this protein is associated with muscle damage. In the second step, newborns with a high protein level receive a genetic test for the mutated gene responsible for DMD.

Detection of a DMD-causing mutation provides families with information for future planning, and as new treatments are developed, allows the earliest possible treatment for their child. “Therefore, it is in the best interest of the patients, families and the nation to provide an efficient newborn screening method for DMD to reduce further burden,” says Hegde.

Her project will further refine the two-step screen, using new gene detection techniques to speed analysis. “Our study will help establish a high-throughput, low-cost screening method which can be implemented in NBS programs to efficiently rule out the false positives detected by the creatine kinase level testing,” she says. “The project is aimed to ultimately reduce DMD disease burden.”

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

Eric Hoffman, director of the Research Center for Genetic Medicine at Children's National Medical Center in Washington, D.C., was awarded an MDA research grant totaling $321,659 over a period of three years to study whether a process called asynchronous repair contributes to muscle degeneration in Duchenne muscular dystrophy (DMD).

Normal muscle repairs itself following injury, Hoffman points out, and that repair is a coordinated process within the muscle, taking place over about two weeks. “Our model is that muscle repair in DMD is asynchronous: Different regions of DMD muscle start the repair process at different times, and neighboring regions of the muscle get disoriented as to which time point in the two-week time frame of repair they are in. This results in inappropriate signals and failed regeneration.”

The implication of that model is that resynchronizing the repair process should provide therapeutic benefit. Hoffman has data suggesting that corticosteroid drugs, such as prednisone, which are effective in DMD, are “re-synchronization” agents for muscle repair. In this way, he thinks, they act similarly to some of the body’s own hormones that synchronize sleep/wake cycles and other time-related events in the body.

His work will further study this phenomenon and explore its implications for development of drugs that offer the same benefits as corticosteroids with fewer side effects. He thinks there also may be a role for using the clock to schedule dosing of current drugs, timing their delivery to improve efficacy and reduce side effects.

“It is an exciting time for development of therapeutic approaches in Duchenne muscular dystrophy and other neuromuscular diseases,” Hoffman says, noting that the growing understanding of the biology of the dystrophin gene and the effects of the dystrophin protein’s loss in muscle is leading to novel therapeutic approaches, and the focus on moving those new approaches to clinical trials has sped up the development of promising therapies.

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

Fenghua Hu, research scientist at Cornell University in Ithaca, N.Y., was awarded an MDA research grant totaling $360,000 over a period of three years to study the effects of TDP43 gene mutations in a model of amyotrophic lateral sclerosis (ALS).

Mutations in the TDP43 gene have been shown to cause ALS in some instances. Even in individuals with ALS who do not have TDP43 mutations, the TDP43 protein usually clumps together abnormally, forming aggregates within muscle-controlling nerve cells called motor neurons. “This suggests that the misbehavior of TDP43 protein could cause neurodegeneration,” Hu says.

The TDP43 protein found in the aggregates is often just a piece of the whole protein, indicating it has been cleaved. It is also often “tagged” with a smaller protein, called ubiquitin, used by the cell to mark a protein for destruction and recycling. “However, the role of TDP43 fragments and ubiquitination in disease progression is still not clear,” Hu says.

She plans to develop a model of ALS using zebrafish, a small and fast-growing fish used as a lab model for the study of many diseases. In the fish, she will study how TDP43 protein fragments induce toxicity and cause neurodegeneration, which should help researchers develop better targets for therapy in ALS.

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

Masahiro Iwamoto, research scientist at the Children’s Hospital of Philadelphia and associate professor of pediatric orthopedics at the University of Pennsylvania School of Medicine, was awarded an MDA research grant totaling $405,000 over a period of three years to study new ways to reduce muscle degeneration.

“The active form of vitamin A, called retinoic acid, plays an important role in numerous organs, including musculoskeletal systems,” says Iwamoto. His team has recently discovered that a molecule similar to retinoic acid, called an RAR-gamma agonist, blocks two different pathologic processes in muscle: formation of bone within the muscle and muscle degeneration.

Iwamoto will now build on that work to learn more about RAR-gamma signaling and how it contributes to the repair and maintenance of skeletal muscle. He will test whether a specific RAR-gamma agonist, called R667, which has shown some promise in the lab and has been tested in humans for other conditions, has potential for treatment of muscular dystrophy in mice.

“We will determine whether these drugs can in fact block or even reverse muscle degeneration in mouse models of muscular dystrophy,” he says, potentially leading to a novel means of therapeutic intervention.

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

Hong Joo Kim, a postdoctoral fellow at St. Jude Children’s Research Hospital in Memphis, Tenn., was awarded an MDA development grant totaling $180,000 over a period of three years to study new genes for a newly recognized disorder called multisystem proteinopathy (MSP).

MSP causes symptoms that are seen frontotemporal dementia (FTD) and Paget’s disease of bone (PDB), and in two diseases covered by MDA — amyotrophic lateral sclerosis (ALS) and inclusion-body myositis (IBM). “Patients with this rare, inherited multisystem disease may experience isolated IBM, FTD, ALS or PDB, which can be indistinguishable from other familial and sporadic cases of these disorders, or the disease may manifest in multiple tissues in the same patient,” Kim says.

While a gene has been discovered that causes MSP, this gene is not responsible for the disease in other families. That led Kim and colleagues to use modern gene-hunting techniques to search for other potential candidates.

They found two such genes, called heterogeneous nuclear ribonucleoproteins (hnRNPA2B1 andhnRNPA1), which bind to a cellular messenger called RNA. Alterations in binding and transport are increasingly seen as likely causes of multiple diseases in the nervous system. “Studying the genes that cause this rare multisystem syndrome represents a unique opportunity to identify a fundamental molecular defect that underlies multiple common age-related diseases,” Kim says.

The disease-causing mutations they have found appear to increase the likelihood that individual units of protein will clump together, a feature of many other neurodegenerative diseases. Kim plans to generate fly and mouse research models that contain either the normal or mutant forms of hnRNPA2B1 and A1, in order to study their effects. “We seek to recapitulate the full spectrum of MSP, to elucidate the molecular mechanism of pathogenesis, and to identify target genes that are misregulated in hnRNPA2B1- and A1-associated diseases,” she says, which may lead to new strategies for treating MSP and other diseases.

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

Deok-Ho Kim, assistant professor of bioengineering at the University of Washington in Seattle, was awarded an MDA research grant totaling $390,000 over a period of three years to develop better techniques for growing muscle for use in transplantation into a mouse model of Duchenne muscular dystrophy (DMD).

Muscle is a highly ordered tissue, with cells oriented in specific directions. Blood vessels and other muscle components must also take up specific positions in muscle for it to perform properly. Kim’s work is focused on developing materials that serve as scaffolds for growing muscle from stem cells in the laboratory, which then can be transplanted into living organisms to replace damaged muscle. These scaffolds work at the cellular scale to promote optimal growth of muscle in the most tissuelike patterns.

“This work aims to generate a functional muscle patch capable of providing long-term muscle strength and regenerative capacity, and to improve morbidity [symptoms] in DMD patients,” Kim says. “The optimal conditions will be utilized to create a robust muscle replacement with adequate force generation capacity. Since DMD is essentially a disease of deficiency of mature muscle cells, stem cell therapy presents an attractive route to cure the disease.”

His group also is working to integrate a muscle signaling molecule, calledS1P, into the growing muscle, to promote muscle stem cell proliferation and differentiation, and to help blood vessels grow properly in the muscle.

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

Michael Kyba, associate professor of pediatrics at the University of Minnesota in Minneapolis, was awarded an MDA research grant totaling $358,227 over a period of three years to study muscle developmental deficits in facioscapulohumeral muscular dystrophy (FSHD). The new grant complements previous MDA-funded work by Kyba to identify and test experimental therapies in FSHD.

FSHD is caused by aberrant expression (activity) of a gene called DUX4, which is usually silenced in adult muscle tissue. DUX4 turns on other genes, and activity of these genes is believed to cause disease by multiple mechanisms, including direct toxicity, interference with normal cell function and provoking the immune system.

“The mechanism of muscle degeneration in FSHD is enigmatic,” Kyba says, since unlike other muscular dystrophies, there is apparently neither ongoing muscle fiber damage, nor ongoing regeneration. “The mechanism of how genetic changes actually lead to deteriorated muscle is still very unclear.”

To answer some of those questions, he has generated muscle cells from patient skin cells in order to study the effects of the mutation that causes FSHD. He will now use newly developed “gene-editing” technology to correct the FSHD mutation, and to compare muscle development between uncorrected and corrected cells.

“This project will shed light on the molecular mechanism underlying FSHD, and will provide tools for genetic correction of the FSHD mutation in cells in culture,” says Kyba. “Understanding the genetic mechanism is essential to developing rational pharmaceutical therapies for FSHD. In addition, with a view toward future cell therapies, having methods to correct the genetic mutation that causes FSHD will facilitate autologous (self) transplantation of genetically corrected cells.”

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

Leslie Leinwand, professor of molecular, cellular and developmental biology at the University of Colorado in Boulder, was awarded an MDA research grant totaling $338,775 over a period of three years to study the causes and treatment of Laing distal myopathy (MPD1).

MPD1 is an inherited muscle disease characterized by early and selective weakness of the lower leg that affects ankle and great toe bending. With time, the disease progresses to other muscles, including those of the neck and face. MPD1 is caused by mutations in a gene called MYH7, which encodes a protein called myosin heavy chain-ß. This protein works in heart and skeletal muscle to create the pulling force that allows muscles to contract, Leinwand says, “but how these mutations lead to disease is unknown.”

Her goal is to learn more about how mutations in MYH7 cause the cellular defects that are at the root of MPD1. Specifically, she is interested in determining the effects of mutations on the ability of multiple myosin proteins to link together, which they must do to function properly. She thinks it’s likely that a defect in that linking ability may reduce the stability of sarcomeres, the basic unit of muscle that exerts the pulling force.

She also will create a mouse model of MPD1 in order to better study the effects of mutation and to test potential therapies. “We hope that our experiments will expose the pathogenesis of the disease and will lead to a successful molecular treatment for MPD1, for which there is currently no treatment,” says Leinwand.

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

Ronald Liem, professor of pathology and cell biology at Columbia University Medical Center in New York, N.Y., was awarded an MDA research grant totaling $318,264 over a period of three years to study the progression of disease in a mouse model of type 2E Charcot-Marie-Tooth (CMT) disease.

CMT is the most commonly inherited neurological disorder, affecting 1 in 2,500 people worldwide. It is a slowly progressive disorder, causing degeneration of the peripheral nerves that control sensory information coming from the limbs. CMT2E is caused by mutations in the gene for a protein called neuronal intermediate filament light (NFL). NFL provides stability to axons, the long extensions of muscle-controlling motor nerve cells called motor neurons that allow them to control muscle contractions.

Liem’s lab has created a mouse model of CMT2E by introducing a mutated copy of the gene. Their preliminary results indicate the mouse develops many of the same features as people with the disease, including deficits of movement and hearing. “We believe that this new mouse model is likely the best model of CMT type 2E and will allow us to study the progression of the disease at a level that is not possible in human subjects. We expect that the mouse model will also be useful for testing therapeutic compounds when they become available,” Liem says. 

Liem will be performing detailed developmental and anatomic studies to follow the progression of the disease in mice, and to learn more about exactly how the mutation causes problems. One focus will be on the effects of the mutation on mitochondria, the cell’s "powerhouses," which are believed to be involved in CMT.

“These studies will give us a better understanding of the mechanisms by which nerve damage occurs as a result of this mutation,” Liem says. “We expect that the mouse model also will be useful for testing therapeutic compounds when they become available.”

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

Michael Linhoff, a postdoctoral fellow at Oregon Health and Science University in Portland, Ore., was awarded an MDA development grant totaling $119,944 over a period of two years to study neuromuscular junction defects in congenital myasthenic syndrome (CMS).

A common cause of CMS is mutation of the RAPSN gene. This gene encodes a protein, rapsyn, that helps other proteins assemble properly on the surface of the muscle at the neuromuscular junction (NMJ). The NMJ is where the motor neuron from the nervous system contacts the muscle. The neuron releases chemicals that cause the muscle to contract.

Linhoff and colleagues have shown that a RAPSN mutation causes defects not only on the muscle, but also on the neuron where it contacts the muscle. Mutation reduces the effectiveness with which the neuron releases its chemicals, reducing muscle contraction and causing weakness.

He is studying this effect in zebrafish, a well-characterized lab model for the study of the interaction between nerve and muscle. “Our lab previously identified a mutant fish line [with a mutation in the RAPSN gene], called twitch once, that exhibits use-dependent fatigue similar to patients with CMS,” Linhoff says.

He will be using high-resolution imaging technologies to study the mechanisms underlying the dysfunctions seen in the twitch once fish. Using the images, he will develop three-dimensional models of the zebrafish neuromuscular junction to discover the details of the neuronal defect caused by the mutation.

“Determining the molecular mechanisms underlying this dysfunction may yield potential therapeutic targets to correct use-dependent fatigue in patients with congenital myasthenias,” Linhoff says.

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

Gordon Lynch, head of the department of physiology at The University of Melbourne in Victoria, Australia, was awarded an MDA research grant totaling $405,000 over a period of three years to study the potential of heat shock proteins for treatment of Duchenne muscular dystrophy (DMD). Heat shock proteins help cells fold other proteins properly, and deal with stresses from a variety of sources. The new grant complements previous MDA-funded research by Lynch into strategies aimed at improving muscle function in DMD.

“Muscle wasting and weakness are major symptoms of many muscular disorders, including Duchenne muscular dystrophy,” Lynch says. “Although considerable efforts are being directed to the development of gene therapies for DMD, these techniques are far from perfected. In the interim, alternative therapies need to be developed, and research directed to preserving muscle fibers, enhancing muscle regeneration and promoting muscle growth.”

Recently, Lynch discovered that increasing the levels of heat shock proteins in muscle fibers can reduce the damage that occurs in mouse models of DMD.

"There are important and unresolved questions regarding the potential of heat shock proteins for clinical application to DMD and related disorders,” Lynch says. He will be studying whether increasing the levels of these proteins, specifically one called Hsp72, in older dystrophic mice can offer the same benefits as seen in younger ones, and whether beneficial effects are seen in the heart, an important target in the treatment of DMD. He also will study the potential of increasing the levels of these proteins in other forms of muscular dystrophy.

“Elucidating the full therapeutic potential of Hsp72 induction in the skeletal and cardiac muscles of various models of muscular dystrophy will facilitate the development of a novel treatment to improve both skeletal and cardiac muscle function and quality of life for patients with muscular dystrophy,” Lynch says.

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

Giovanni Manfredi, professor of neurology and neuroscience at Weill Medical College of Cornell University in New York, N.Y., was awarded an MDA research grant totaling $355,317 over a period of three years to study whether calcium imbalance in nervous system support cells called astrocytes contributes to amyotrophic lateral sclerosis (ALS).

The death of muscle-controlling nerve cells called motor neurons cause the symptoms of ALS, but in recent years it has become clear that astrocytes contribute to the death of motor neurons. Astrocytes normally help motor neurons; and how and why they harm them in ALS is unknown.

“We have developed a novel hypothesis to explain the mechanisms of astrocyte toxicity in familial ALS, which involves intracellular calcium signaling,” Manfredi says. Calcium serves as an internal sensor for regulating many cellular functions. “All cells, including astrocytes, have to keep calcium levels in check at all times.”

His work has suggested that changes within the astrocyte lead to impaired calcium regulation and secretion of toxic molecules, which in turn cause motor neuron death. He plans to further test this hypothesis by manipulating the amount of oxidative stress to which astrocytes are exposed, both in cell culture and in animal models, and studying how they handle calcium in response. His preliminary work has identified a protein that may be centrally involved in regulating calcium in astrocytes, and he will further study this protein to determine if it is a potential target for therapy.

“Numerous exciting reports have emerged in ALS research in the past few years, strongly suggesting that ALS is the product of the combined action of multiple cell types in the nervous systems, including neurons and glial cells,” Manfredi says. (Astrocytes are a type of glial cell.) “These new developments in ALS research will accelerate the understanding of the disease and the development of effective therapies.”

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

John Manfredi, chief scientific officer at Sfida BioLogic in Salt Lake City, Utah, was awarded an MDA research grant totaling $161,995 over a period of two years to study the potential of new compounds for treatment of spinal muscular atrophy (SMA). The new grant complements previous MDA-funded research by Manfredi into potential therapeutics for SMA.

SMA is caused by the loss of muscle-controlling nerve cells called motor neurons. These neurons have long extensions, called axons, which must remain in communication with muscle in order to promote normal movement. Manfredi and colleagues have identified several small molecules that promote the growth of axons of motor neurons. They have shown that these compounds can improve movement in flies with movement defects, and also have shown their potential in a fish model of SMA. They will now move on to test them in a mouse model of SMA.

“Importantly,” says Manfredi, “previous tests of the compounds in healthy adult rats and mice showed that the chemicals are nontoxic, metabolically stable, capable of entering the central nervous system” and remain active for a long time. All these are important for a compound to become a useful drug. Testing the ability of these compounds as potential treatments for SMA is the next step.

“Given the drug-like characteristics of the compounds, positive results in the SMA mice will nominate the compounds for clinical development,” Manfredi says. They also may shed light on whether these or similar compounds have potential in other diseases of axon degeneration, including amyotrophic lateral sclerosis (ALS) and Charcot-Marie-Tooth (CMT) disease.

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

Darren Monckton, professor of human genetics at the University of Glasgow in Scotland, was awarded an MDA research grant totaling $273,892 over a period of two years to develop new diagnostic tests for myotonic muscular dystrophy type 1 (MMD1, also known as DM1)

MMD1 is caused by expansion of part of the DNA code in the DMPK gene. Normally, this gene has a small number of repeats of the DNA “letters” CTG. But in people with MMD1, the number of repeated CTG units is 50 or more, and can be over 1000. Furthermore, the number of repeated units in the genes can grow over the lifetime and may differ between different cells.

“In the standard diagnostic test, this genetic instability is ignored,” Monckton says, “and only an average number of repeats is measured.” But the variation may contain important clues to when the disease is likely to begin, and so may provide valuable information to families and individuals with the MMD1 repeat about the future course of disease.

“Using specialized research techniques, we can measure the number of CTG repeats in many cells, then use a computer model to calculate the number of CTGs the patient had at birth,” Monckton notes. “This number much more accurately predicts when symptoms are likely to start. In addition, the CTGs are sometimes interrupted by other groups of three letters, such as CCG, usually leading to milder symptoms,” and later onset in future generations. “Unfortunately, the current genetic test does not take account of age-dependent changes in the number of repeats or detect the presence of these interruptions.”

Monckton will collaborate with genetic testing laboratories to develop new diagnostic tests that will allow the detection of both these important features. In addition to benefits for individual families, the new tests should help make the interpretation of clinical trial results more accurate, since any effects of treatment can be measured against the severity of the genetic mutation.

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

Marek Napierala, assistant professor of molecular carcinogenesis at the MD Anderson Cancer Center of the University of Texas, Smithville, was awarded an MDA research grant totaling $320,451 over a period of three years to develop new models of Friedreich’s ataxia (FA) and explore new therapeutic approaches for the disease.

FA is caused by an increase in the number of short DNA sequences, termed GAA repeats, within a gene that encoded for the frataxin protein. This reduces the amount of frataxin that can be made in cells, a problem especially important in neurons (nerve cells) and heart muscle cells. These cells die during the course of the disease, leading to the symptoms of FA.

Napierala studies DNA-editing enzymes called zinc finger nucleases (ZFNs) that can target specific DNA sequences and, operating like a pair of molecular scissors, cut out disease-causing mutations. He will develop cell lines from patients with FA, and then use this technology to repair the gene within the cells.

“Editing the genome of FA cells via excision of the pathogenic expanded GAA repeats,” Napierala says, “will generate a perfect model system: ‘Patient neurons’ can be compared to ‘corrected patient neurons’ derived from the same individual, thus eliminating troublesome variability associated with analyses of patient/control pairs from separate, genetically different individuals.”

The technique will allow him to explore how cells respond when the defect is corrected, and to look for new targets for therapeutic intervention in the disease. In addition, it will establish methods that may be used for similar purposes in other repeat diseases, including myotonic muscular dystrophy (MMD or DM).

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

Li Niu, professor and chair of chemistry at the State University of New York at Albany, was awarded an MDA research grant totaling $405,000 over a period of three years to develop new drugs as potential therapies for amyotrophic lateral sclerosis (ALS).

One mechanism believed to be involved in ALS is overactivity of a protein called the AMPA receptor on the surface of muscle-controlling nerve cells called motor neurons. Too much receptor activity leads to too much excitation of the neuron, and eventually the neuron dies.

“Finding inhibitors to control the excessive receptor activity has been a long-pursued strategy for developing ALS drugs,” says Niu.

Niu is developing AMPA receptor inhibitors made from a cell chemical called RNA. These inhibitors, called RNA aptamers, have been shown to prevent receptor activity, but are vulnerable to cellular enzymes that break them down. Niu plans to chemically modify the aptamers to make them resistant to these enzymes. “That is the first step to translate these powerful AMPA receptor aptamers into clinically useful drugs,” he says.

He has already developed several chemically modified aptamers, and will now test their neuroprotective effectiveness in ALS cellular and animal models. “These studies are key preclinical experiments to advance these RNA inhibitors as a new ALS drug,” he says.

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

Mark Payne, professor of pediatrics and medical and molecular genetics at the Indiana University School of Medicine in Indianapolis, was awarded an MDA research grant totaling $298,048 over a period of two years to study ways to overcome the vulnerability of heart muscle in Friedreich’s ataxia (FA).

Heart muscle is especially vulnerable in FA, leading to the possibility of severe heart failure and early death. The reason, Payne says, appears to relate to how mitochondria, the cell’s energy producers, obtain their own cellular fuel. “It appears that the mitochondria in the heart, which normally produce energy for the heart to beat, are not capable of using certain fuels (fats and sugars) to make energy. The result is that the heart does not have enough energy to withstand stressful situations.”

Payne will study this phenomenon further in a mouse model of FA, to understand altered mitochondrial function in the heart that may contribute to the development of heart failure. “In particular, we will determine if the mitochondria are capable of using fats and sugars from the diet in an appropriate manner to make energy,” he says, using a variety of advanced molecular biology and imaging techniques. He also will study whether supplying a good copy of the mutated gene responsible for the disease can reverse the faulty metabolism of the heart.

“The goal of this project is to understand the basic mechanisms of heart failure in this disease, and then develop approaches to improve heart function and save lives,” Payne says.

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

Sunitha Rangaraju, a postdoctoral research scientist at the Scripps Research Institute in La Jolla, Calif., was awarded an MDA development grant totaling $180,000 over a period of three years to determine whether compounds that slow certain aspects of aging may be therapeutic in amyotrophic lateral sclerosis (ALS).

The biggest known risk factor for ALS is advancing age, suggesting that the processes that contribute to aging also may contribute to ALS. This led Rangaraju and colleagues to hypothesize that compounds that slow the aging process might be valuable as drugs against ALS. To that end, their lab screened more than 89,000 molecules for those that delay aging and extend life span in C. elegans, a small worm that is widely used to study aging.

That screen turned up more than 100 molecules that extend worm life span. Rangaraju is now testing those compounds in a worm model of ALS to see if they also contribute to longevity in the context of the disease.

The worm research model of ALS shares important characteristics with human ALS, including “protein aggregation, movement defects, reduction of neuron-to-muscle signals and a shorter life span,” Rangaraju says. She already has identified several compounds that extend life span in these worms, and now will test others, and determine how the most promising ones influence protein aggregation or other aspects of ALS. She then plans to test the most promising molecules in mouse models of ALS, the next step in drug development.

“In the field of ALS, great progress has been made in developing animal models of the disease and unraveling disease mechanisms,” says Rangaraju. “These findings allow us to test novel strategies to develop therapeutic molecules to ameliorate the disease.”

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

David Richman, professor of neurology at the University of California, Davis, was awarded an MDA research grant totaling $412,500 over a period of three years to study the anti-MuSK myasthenia (AMM) form of myasthenia gravis (MG).

In most people with MG, an autoimmune disease of muscle, individuals make antibodies that react against a part of the muscle called the acetylcholine receptor. But, Richman says, in the AMM form of the disease, antibodies are made against a second protein, muscle-specific kinase (MuSK), also located on the muscle surface. Many of the usual MG treatments are not effective against the AMM form of the disease.

Richman has developed a rat model of AMM, and will use magnetic resonance imaging (MRI) to measure muscle loss in the rats. He also will conduct microscopic and biochemical tests to characterize the affected muscles, and experiments on cells in culture to test various chemical treatments that could have therapeutic potential.

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

Eric Ross, associate professor of biochemistry and molecular biology at Colorado State University in Fort Collins, was awarded an MDA research grant totaling $363,000 over a period of three years to study proteins whose aggregation causes neurodegeneration.

Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), are characterized by the formation of protein clumps, or aggregates, in or around muscle-controlling nerve cells called motor neurons. Aggregates also are seen in the muscle disease inclusion-body myositis (IBM). These aggregates are believed to indicate an ongoing toxic process within the cell and may be toxic themselves.

“Interestingly, similar protein aggregation can be seen even in simple single-cell organisms such as yeast,” says Ross. Some aggregates can harm not only the cell in which they form, but also neighboring cells by spreading to them and inducing aggregation. Such proteins are called prion-like for their resemblance to proteins found in prion diseases like bovine spongiform encephalopathy (mad cow disease).

Yeast makes a powerful model system in which to study the spread of prion-like proteins, Ross says, because it grows rapidly and its genes can be easily manipulated. “Based on studies in yeast, our lab has developed methods to identify new disease-associated proteins in other organisms. Remarkably, in just the past few years, various labs have linked mutations in six of these proteins to certain inclusion-body myopathies and some forms of ALS.”

Ross will be examining how the sequence of amino acids in these proteins affects aggregation and toxicity, and how disease-associated mutations change the physical properties of the proteins.

“These studies will provide insight into the causes of these diseases, facilitate the identification of potential drug targets for therapeutic intervention, and improve our ability to identify other disease-associated prion-like proteins,” he says.

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

Jeffrey Rothstein, professor of neurology and neuroscience at Johns Hopkins University in Baltimore, Md., was awarded an MDA research grant totaling $392,706 over a period of three years to study the most common genetic cause of amyotrophic lateral sclerosis (ALS), using cells derived from patient skin samples.

“Understanding the pathophysiology of and developing new therapeutics for ALS and dementias such as Alzheimer’s disease and frontotemporal dementia has been an enormous challenge,” Rothstein says. Among the biggest roadblocks has been the difficulty of developing appropriate models of the disease — ones that closely parallel the human condition.

A new technique to overcome this barrier is the use of induced pluripotent stem cells (iPS cells). These cells can be taken from the skin of an individual with ALS and treated with growth factors to return them to a less differentiated state. From this stem-cell-like condition, they can then be induced to develop into any cell type, including muscle-controlling nerve cells called motor neurons or other cells of the central nervous system.

Rothstein plans to use iPS cells from people whose ALS is caused by a mutation in the C9ORF72 gene, the most common genetic cause of ALS. By comparing these cells to cells from unaffected individuals, Rothstein hopes to find a molecular signature for the disease-causing effects of the mutant gene. That signature, or biomarker, can then be used to quickly assess the effects of potential therapies on the cells. “The use of these human cells may allow us to efficiently and quickly develop a drug therapy for the C9ORF72 form of ALS,” he says.

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

Eric Schon, professor of neurology at the College of Physicians & Surgeons of Columbia University in New York, was awarded an MDA research grant totaling $405,000 over a period of three years to develop strategies for treatment of mitochondrial myopathies.

Mitochondrial myopathies are muscle diseases caused by defects in the mitochondria, subcellular structures that create energy from cellular fuel. Mitochondria contain their own DNA (mtDNA) and reproduce themselves within cells. In people with a mitochondrial myopathy, some mitochondria are mutated and function poorly, while others are healthy.

“There are no general therapeutic strategies to combat diseases involving mitochondrial DNA mutations,” Schon says. His group recently showed that in cells containing only mutated mtDNAs, it was possible to eliminate those mitochondria using rapamycin, a drug that stimulates the cell to degrade defective mitochondria. “We have now found that in cells containing a mixture of normal and mutated mitochondria, rapamycin dramatically increases the proportion of ‘good’ mitochondria and restores cellular bioenergetic function within only a few days.”

The implication of this finding is that inducing cells to selectively degrade their mutant mitochondria, paving the way for more reproduction by the good mitichondria, could be a promising method to treat mitochondrial myopathies.

Schon will explore this potential and study its mechanism, as well as search for other compounds with similar effects. “Using these approaches, we hope to gain insight, both practical and basic, into novel approaches to treat mitochondrial myopathies,” he says.

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

Rabi Tawil, professor of neurology at the University of Rochester Medical Center in Rochester, N.Y., was awarded a one-year MDA research grant totaling $92,222 to develop a biomarker for facioscapulohumeral muscular dystrophy (FSHD).

FSHD is caused by aberrant expression (activity) of a gene called DUX4, which is usually silenced in adult muscle tissue. DUX4 turns on other genes, and activity of these genes is believed to cause disease by multiple mechanisms, including direct toxicity, interference with normal cell function and provoking the immune system.

“Having identified potential therapeutic targets in FSHD,” says Tawil, “it becomes crucial to identify sensitive, disease-related biological markers [biomarkers] that can be easily measured in blood or muscle tissue to assess the effectiveness of future disease-modifying drugs.” FSHD researchers recently came to consensus that development of biomarkers was a top priority for progress in the disease.

Tawil will be investigating whether a small group of these abnormally expressed genes may serve as biomarkers. He will examine muscle biopsies and blood serum from individuals with FSHD and unaffected individuals, and compare the level of proteins made from these genes. Any differences will then be correlated with the overall disease severity and the severity of changes in the muscle.

“At the end of this study we hope to have promising biomarkers for future clinical trials,” he says. “Research is now focused on treatment of FSHD, and consequently having all the tools ready for future clinical trials is essential.”

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

Joan Taylor, associate professor of pathology at the University of North Carolina in Chapel Hill, was awarded an MDA research grant totaling $396,000 over a period of three years to study how muscle cells repair damaged membranes.

When a muscle contracts, it puts a great stress on the membrane that surrounds and encloses the muscle cell. That stress is reduced, and the membrane protected from rupture, by proteins that link the inside of the cell to the outside. Those proteins include dystrophin and the dystroglycan complex. Mutations in these proteins are the cause of Duchenne muscular dystrophy (DMD) and other forms of muscular dystrophy, which are characterized by repeated tears in the muscle cell membrane.

Membranes can repair themselves, says Taylor, “however, the specific mechanisms by which this occurs are incompletely understood.” Her team has identified a protein called GRAF1 that appears to be intimately involved in the repair process, and she has developed a mouse model to explore the function of GRAF1. She will now fully test the hypothesis that GRAF1 is necessary to promote membrane re-sealing, using a laser-based membrane injury model in skeletal muscle cells to identify the underlying mechanisms.

Taylor also will explore the capacity of GRAF1 (administered by a gene-therapy-based approach) to diminish muscle pathology in dystrophic mice. “These studies will undoubtedly lead to new and important directions for therapies to target a multitude of congenital dystrophies,” she says.

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

Muthusamy Thiruppathi, a postdoctoral research associate in microbiology and immunology in the College of Medicine at the University of Illinois at Chicago, was awarded an MDA development grant totaling $180,000 over a period of three years to pursue ways to restore normal immune system function in myasthenia gravis (MG).

MG occurs when certain cells in the body’s immune system mistakenly target specific proteins on skeletal muscle, causing weakness. The immune system is usually tightly regulated by immune cells called regulatory T cells. In other autoimmune disorders, it is now recognized that there is a defect in the number or function of these cells, and that this contributes to the development of autoimmunity (a condition in which the body's immune system mistakenly attacks its own tissues).

Thiruppathi and colleagues recently have shown that in MG, the number of regulatory T cells is normal, but they do not function properly to suppress unwanted immune responses. “We will now thoroughly examine the nature of this immune defect in MG,” he says, using blood cells collected from individuals with MG and unaffected individuals.

Thiruppathi also will be exploring a strategy to enhance the function of these cells using a natural immune system growth factor called granulocyte-macrophage colony-stimulating factor.

By developing a deeper understanding of exactly how the immune system goes awry, it may be possible to “change the approach to the treatment of myasthenia gravis from global, nonspecific immune modulation to focused, individualized, cellular therapy,” he says.

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

Socrates Tzartos, professor of biochemistry at the Hellenic Pasteur Institute in Athens, Greece, was awarded an MDA research grant totaling $345,033 over a period of three years to develop diagnostic tools for diagnosis of the low-density lipoprotein receptor-related protein 4 (LRP4) form of myasthenia gravis (MG).

MG is an autoimmune disease in which the body’s immune system targets proteins located at the neuromuscular junction, causing weakness. In most patients, the target is the acetylcholine receptor, and in others it is muscle-specific kinase. But 10 percent of MG patients do not have either of these forms, and are said to have seronegative MG (SN-MG). “SN-MG presents a serious gap in MG diagnosis and understanding,” says Tzartos.

Recently, antibodies against LRP4, another protein found at the neuromuscular junction, have been found in some SN-MG patients, and evidence suggests this may be another cause of disease. However, there is not yet a reliable, clinically practical test available for the routine diagnosis of LRP4-MG. Tzartos will be developing such a test by making the protein in animals, purifying it, and comparing a range of assays for their ability to detect the protein. He then plans to test a large number of SN-MG patients to determine the true prevalence of LRP4-MG among this group. Finally, he will explore the pathologic mechanisms at work in LRP4-MG in animal models.

“Since it is known that MG is heterogeneous [varied] in terms of pathophysiology [effects on the body], the outcome of this project is expected to have great impact for this group of MG patients, and provide new insights on the physiology of the neuromuscular junction,” Tzartos says.

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

Xin Wang, assistant professor of neurosurgery at Harvard Medical School in Boston, Mass., was awarded an MDA research grant totaling $405,000 over a period of three years to identify and test novel drug candidates for amyotrophic lateral sclerosis (ALS).

The need for new drugs in ALS is clear, Wang says, because the only drug approved for the disease is riluzole, which extends survival on average by only about three months.

Preliminary evidence suggests that increased cellular signaling of the melatonin system may be neuroprotective. Melatonin, a hormone secreted by the pineal gland, binds to the melatonin receptor 1A (MT1). Wang will test the hypothesis that increased stimulation of MT1 will slow disease development and progression. Her work will involve identifying compounds called MT1 agonists that bind to and stimulate the receptor. She will then test these agonists in cell culture and in a mouse model of ALS.

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

Noah Weisleder, associate professor of physiology and cell biology at Ohio State University in Columbus, was awarded an MDA research grant totaling $405,000 over a period of three years to study muscle repair for development of treatment for limb-girdle muscular dystrophies (LGMD).

In all muscular dystrophies, muscles are damaged during normal use. Part of that damage occurs when the outer membrane of the muscle cell tears under the force of normal muscle contraction. The cell has mechanisms to repair torn membranes, allowing the survival of these damaged cells, but these mechanisms are insufficient in LGMD and other muscular dystrophies.

“These findings suggest that a therapeutic approach that increases membrane repair capacity could have broad efficacy across a number of different muscular dystrophies in human patients,” Weisleder says.

His group has previously shown the importance of a protein called Mitsugumin 53 (MG53) in the repair process, and has demonstrated that it can be directly applied to cells and tissues to increase the repair capacity, including in a rodent model of Duchenne muscular dystrophy (DMD). He will now test this strategy in various rodent models of LGMD, to determine if this protein could be used as a therapeutic approach in humans.

“If MG53 can improve pathology in a number of different muscular dystrophies,” Weisleder says, “it is more likely that this protein therapy could be effectively moved towards clinical trials, as it would be able to treat a relatively large patient population spread across various types of muscular dystrophy.”

While such therapy would not be a definitive cure for any of the muscular dystrophies, it could provide meaningful therapy for patients until definitive treatments for the underlying causes of these diseases are available.

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

Sarah Youssof, at the University of New Mexico Health Sciences Center in Albuquerque, was awarded an MDA clinical research training grant totaling $180,000 over a period of two years to study outcome measures in oculopharyngeal muscular dystrophy (OPMD).

OPMD is a progressive, adult-onset disease that 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).

A critical barrier to the pursuit of clinical trials is the lack of established outcome measures that can capture disease progression and treatment effects.

Youssof’s goal is to explore the performance of a set of outcome measures for measurement of OPMD disease severity and to investigate patients’ perspectives on the disease.

The results of Youssef’s work could lead to clinical trials for OPMD incorporating validated outcome measures that reflect endpoints that are meaningful to people with the disease.

Funding for this MDA grant is effective July 1, 2013.

Daniela Zarnescu, associate professor of molecular and cellular biology at the University of Arizona in Tucson, was awarded an MDA research grant totaling $405,000 over a period of three years to investigate whether anti-diabetic drugs may reduce the death of muscle-controlling nerve cells called motor neurons in amyotrophic lateral sclerosis (ALS).

Zarnescu and colleagues have developed a model of ALS in fruit flies that carry a mutant form of the TDP43 gene, a known cause of ALS. “TDP43 has emerged as a common denominator for a significant number of ALS cases,” Zarnescu says, “because mutations in TDP43 can cause ALS and, in addition, normal TDP43 protein associates with cellular inclusions found in autopsy samples from ALS patients, regardless of the genetic cause of the disease.”

She has used this model to test candidate drugs that are already approved for other uses. Her work led to the identification of several types of drugs currently used to treat diabetes that also reduced death among the ALS research flies. The drugs work to affect signaling by the hormone insulin, suggesting that the insulin pathway may be a critical survival pathway in motor neurons.

“Given that our candidate drugs are already approved for use in humans, our work in the fly model will provide a rapid and cost-effective strategy to help determine whether these drugs could be adapted for the treatment of ALS,” Zarnescu says.

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