Grant - Summer 2011 - FA — Des Richardson, Ph.D., D.Sc.
MDA has awarded a research grant totaling $625,959 over a period of three years to Des Richardson, professor and senior principal research fellow at the University of Sydney (Australia) School of Medical Sciences. The funds will help support Richardson's continued research into iron metabolism in Friedreich's ataxia (FA).
The aim of Richardson's studies is to examine the role of altered iron metabolism in the cellular energy factories called mitochondria.
Using molecular and cellular models, as well as a research mouse model that closely mimics the neurodegeneration and heart problems observed in people with FA, Richardson and colleagues will test a variety of strategies designed to help elucidate the function of frataxin, the protein that’s deficient in this disease.
The team also will test a new experimental therapy designed to replace or bypass the function of frataxin by getting iron to the mitochondria in a form that can be easily utilized for the processes that are lacking when frataxin levels are inadequate.
"We gratefully acknowledge MDA funding," Richardson said. "The knowledge of these alterations is critical for developing new therapeutics that could replace the function of this molecule in patients."
Funding for this MDA grant began August 1, 2011.
Grantee: FA — Des Richardson, Ph.D., D.Sc.
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Grant - Summer 2010 - IBM — Virginia Kimonis
Virginia Kimonis, chief of the division of genetics and metabolism at the University of California, Irvine, received an MDA grant totaling $372,000 to conduct experiments designed to uncover the underlying molecular cause of inclusion-body myopathy associated with Paget's disease of Bone and/or frontotemporal dementia (IBMPFD).
In 2004, Kimonis and colleagues published study results describing the rare disease IBMPFD and identifying the gene responsible for it — valosin-containing protein, or VCP. The group also created a mouse model that carries a flawed human VCP gene and exhibits symptoms similar to those in humans with IBMPFD, including decreased muscle strength and coordination, fatigue, enlarged vacuoles (bubblelike spaces) in the quadriceps muscles, swelling of cellular "energy factories" called mitochondria and abnormal protein clumps.
The Kimonis lab's new project includes the creation of a new mouse model aimed at providing proof of principle that amelioration of IBMPFD symptoms is possible. The team will evaluate functional and biochemical indicators to assess disease progression and effects in these mice. The group also will study whether physical exercise accelerates or decelerates the progression of muscle weakness in the mice, as a means of assessing what effects physical exercise may have on people with IBMPFD.
"Funding from MDA is critical for our laboratory to be able to continue this important work in understanding the key mechanisms related to this progressive and fatal muscle disease," Kimonis said. "Because of its similarities to other muscle disorders such as limb-girdle muscular dystrophy (LGMD), facioscapulohumeral muscular dystrophy (FSHD) and ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease), it's hoped that this research will advance a deeper understanding of mechanisms and potential treatments across a broad spectrum of neuromuscular diseases."
Funding for this MDA grant began August 1, 2010.
Grantee: IBM — Virginia Kimonis
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Grant - Summer 2011 - FA — David Lynch, M.D., Ph.D.
MDA has awarded a research grant totaling $202,222 over two years to David Lynch, professor of neurology at Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine. The funds will help support Lynch's study of the relationship between diabetes and Friedreich's ataxia (FA).
Some individuals with FA develop severe cardiomyopathy (heart disease), while others also may develop diabetes and a resistance to the effects of the hormone insulin, Lynch said, noting "This phenomenon may have implications for the overall progression of FA and the mechanisms involved in causing the disease."
Lynch and colleagues plan to examine the relative likelihood of people with FA to develop diabetes. The team will use measurements of blood sugar and blood insulin levels to assess which features of FA make a particular individual more likely to have abnormal insulin resistance.
The team will work to identify specific genes that contribute to abnormal insulin resistance in FA and also determine whether frataxin, the protein that is deficient in FA, contributes to the development of insulin resistance and diabetes.
The MDA grant will “support development of the collaborative group of individuals who will contribute to this project, which leverages previous data also developed with MDA support," Lynch said.
Funding for this MDA grant began August 1, 2011.
Grantee: FA — David Lynch, M.D., Ph.D.
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Grant - Summer 2010 - EDMD — Ji-Yeon Shin
MDA awarded $180,000 to Ji-Yeon Shin, a research scientist at Columbia University Medical Center, New York, for continued study of the molecular mechanisms that underlie Emery-Dreifuss muscular dystrophy (EDMD).
"EDMD is an inherited disease of skeletal muscle and heart. Although diagnosis has been improved by the discovery of the most common genetic mutations that cause EDMD, we still have a poor understanding of how these mutations cause muscular dystrophy," Shin said.
Shin's lab previously has discovered that proteins produced from instructions carried by the mutated genes in most cases of EDMD interact with another protein, called LAP1 (lamina-associated polypeptide 1), whose function as yet remains unknown. Shin's team has engineered a new "muscle specific LAP1 knockout" mouse that exhibits symptoms that mimic those in EDMD and has potential therefore to be used as an EDMD research mouse model.
In addition to further characterizing the mouse, Shin's new work will include investigation into how the LAP1 protein affects muscle cell function in mouse and human cultured cells, and in living mice.
The team hopes to generate a better understanding of how specific genetic mutations cause EDMD, which should enable it to identify new processes, such as cell signaling pathways, that could be targets for the development of novel drugs to treat the disease.
"I am very happy to be selected as a Development Grant awardee, and I have great hopes for what I can achieve from the current project funded by MDA," Shin said. "The previous results that have been generated in the last two years built up exciting groundwork. Now the support of MDA will bring this project to the next level and allow us to study cellular mechanisms that underlie the development of Emery-Dreifuss muscular dystrophy."
Funding for this MDA grant began August 1, 2010.
Grantee: EDMD — Ji-Yeon Shin
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Grant - Summer 2010 - EDMD — Howard Worman
MDA awarded a grant totaling $310,893 to Howard Worman, professor of medicine and pathology, and cell biology at Columbia University Medical Center in New York, for research into treatments that target the underlying cellular disease process responsible for heart damage, or "cardiomyopathy," in people with Emery-Dreifuss muscular dystrophy (EDMD).
In previous research supported by MDA, Worman's group showed that inhibiting proteins in the MAP kinase signaling pathway improved heart function in a mouse model of EDMD.
"The 'first-generation' inhibitors that we used are not suitable for humans," Worman said. "In the current research, we will study drugs of the same classes that have already been given to humans to determine if they similarly improve heart function in these mice."
The group plans to administer the new inhibitors and then examine the mice using some of the same methods doctors use to examine the heart in humans, including echocardiography (a type of imaging study used to assess the heart's pumping ability). The investigators will extend their findings to other EDMD mouse models known to develop cardiomyopathy, and then ascertain whether administration of MAP kinase signaling inhibitors causes toxicity in these mice.
Positive results generated by Worman's research could pave the way for clinical trials of MAP kinase signaling inhibitors to treat humans with EDMD.
"MDA has supported our research on Emery-Dreifuss muscular dystrophy for more than 10 years," Worman said. "This most recent grant will allow us to translate these past 10 years of basic laboratory research into a treatment for human patients with muscular dystrophy."
Funding for this MDA grant began August 1, 2010.
Grantee: EDMD — Howard Worman
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Grant - Summer 2011 - DMD/BMD — Thomas Rando, M.D., Ph.D.
MDA has awarded a research grant totaling $602,087 over three years to Thomas Rando, a professor in the department of neurology and neurological sciences at Stanford (Calif.) University School of Medicine. The grant will help support Rando's studies to understand how scar-tissue formation (fibrosis) occurs in muscular dystrophies, especially Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). DMD is caused by an absence of the dystrophin protein, and BMD is caused by dystrophin protein that's only partially functional.
In skeletal muscles affected by muscular dystrophy, fibrosis develops as muscle fibers degenerate and are replaced by connective tissue.
"The goals of my experiments are to understand why fibrosis occurs in the muscular dystrophies and to determine the biochemical mechanisms that lead to it," Rando said.
"We have preliminary data that suggest that a specific biochemical pathway known as the TGF-beta signaling pathway is activated in dystrophic muscle and affects muscle stem cells in a way that leads to the development of fibrosis."
Rando and colleagues will directly test whether blocking this pathway leads to a reduction of fibrosis in the muscles of dystrophin-deficient mice that develop a DMD-like disease.
"These studies have the potential to lead directly to new therapies that will reduce the amount of fibrosis in the muscles of boys with Duchenne muscular dystrophy," Rando said.
Funding for this MDA grant began August 1, 2011.
Grantee: DMD/BMD — Thomas Rando, M.D., Ph.D.
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Grant - Summer 2010 - DMD/BMD — Zolt Arany
MDA awarded $352,188 to Zolt Arany, assistant professor in medicine at Beth Israel Deaconess Medical Center, part of Harvard Medical School in Boston, for research into the role of skeletal muscle metabolism in Duchenne muscular dystrophy (DMD).
"It has become increasingly clear that skeletal muscle metabolism plays a critical role both in the onset of, and resistance to, neuromuscular diseases like DMD," Arany said. "Blood vessels are a critical component of metabolism, because they bring oxygen and nutrients to metabolically active tissues."
Arany's team recently uncovered a metabolic pathway that strongly induces the formation of new blood vessels in muscle. Previous work by others already has established that the pathway protects against muscle damage in a model of DMD, but it's not understood how it accomplishes this.
The new work is designed to test the hypothesis, in the mdx mouse model of DMD, that the metabolic pathway protects against muscle degeneration and atrophy by boosting the density and activity of blood vessels.
"Without support from the MDA, we would not be able to initiate these important studies," Arany said. "MDA has had an important impact on research in muscle dystrophy, and its role now, in times of federal budgetary constraints, is more critical and influential than ever."
A greater understanding of precisely how this particular metabolic pathway protects skeletal muscle may lead to novel therapeutic approaches for DMD and other devastating muscle diseases.
Funding for this MDA grant began August 1, 2010.
Grantee: DMD/BMD — Zolt Arany
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Grant - Summer 2011 - DMD/BMD — Terence Partridge, Ph.D.
MDA has awarded a research grant totaling $474,278 over three years to Terence Partridge, a professor of pediatrics at George Washington University Medical School and Children's National Medical Center in Washington, D.C. The award will help support Partridge's work to improve the usefulness of the standard mouse model of Duchenne muscular dystrophy (DMD), the so-called "mdx" mouse.
The mdx mouse lacks dystrophin, the protein that's missing in people with DMD and only partially functional in people with the related disease Becker muscular dystrophy (BMD).
The muscular dystrophy developed by the mdx mouse "closely resembles DMD in some respects," Partridge said, "but differs in others. In order to make the best use of this valuable animal model, we need to fully understand the extent of the similarities and differences, so that we can take them into account when applying information gathered from the mouse to the situation in man."
Partridge and colleagues will develop reliable methods for making accurate and reproducible measurements of the rates of growth, death and regeneration of muscle taking place at different times in the mdx mouse.
"Nowadays, funding from MDA is especially important to those of us working on the interface between science and translational research," Partridge said. "MDA provides for the conduct of research that is fundamental in nature but is aimed at providing information that is directly relevant to the understanding of the disease processes or to the development of therapeutic agents to moderate those disease processes."
Funding for this MDA grant began August 1, 2011.
Grantee: DMD/BMD — Terence Partridge, Ph.D.
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Grant - Summer 2010 - DMD/BMD — Vihang Narkar
Vihang Narkar, assistant professor at the University of Texas Health Science Center at Houston, was awarded $302,326 to study the potential therapeutic value of increasing the overall amount of a specific type of muscle called "aerobic muscle" in Duchenne muscular dystrophy (DMD).
Loss of the structural protein dystrophin, the underlying cause of DMD, causes muscle instability, damage and progressive weakness, accompanied by a decrease in the ability to produce energy, along with severe fatigue.
Because aerobic muscles have enhanced capacity for energy production (which takes place inside cell compartments called mitochondria) and are resistant to fatigue, it's thought that biological regulators that could stimulate production of this type of muscle in individuals with DMD might ameliorate some of the symptoms in the disease.
Narkar's group has discovered one such "bio-regulator," a protein called ERRgamma. When activated in the skeletal muscles of mice with a DMD-like disease, ERRgamma prompts production of a highly aerobic and fatigue-resistant muscle.
In their new work, Narkar and colleagues plan to genetically activate ERRgamma in the skeletal muscles of mdx mice, a rodent model of DMD, as a means of increasing the overall amount of aerobic, fatigue-resistant muscles. A sophisticated battery of tests will help the investigators evaluate the effects of ERRgamma on muscle health and determine whether targeting the protein to dystrophic muscles may have therapeutic benefit in DMD.
"This is our first research grant from the Muscular Dystrophy Association," Narkar said. "It will play a very critical role in initiating and advancing this new and therapeutically promising area of research."
Funding for this MDA grant began August 1, 2010.
Grantee: DMD/BMD — Vihang Narkar
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Grant - Summer 2010 - DMD/BMD — Steve Wilton
MDA awarded a research grant totaling $368,100 to professor Steve Wilton at the University of Western Australia in Perth, for continued research into a strategy called "exon skipping," which bypasses mutations in the dystrophin gene responsible for Duchenne muscular dystrophy (DMD).
Wilton and his team were one of the first groups to use exon skipping to bypass DMD-causing mutations and partially restore production of the dystrophin protein missing in the disease. Since then, the exon-skipping field has rapidly progressed from an idea first demonstrated in studies of isolated cells to application in animal models of the disease and, more recently, to human clinical trials.
Two types of exon-skipping drugs that have reached the clinical trial stage are called 2Omethyl and morpholino. A third drug, 2 methoxyethyl, or "MOE," appears to be well-suited for exon skipping but was not made available for study until recently.
In their new work, Wilton and his team will conduct detailed preclinical studies in the mdx research mouse model of DMD to assess MOE's suitability for exon skipping.
In addition, the group has developed a number of other drugs designed to bypass a variety of different dystrophin mutations that should be responsive to exon skipping. The investigators will study the effectiveness and side-effect profiles of the new drugs.
"Without MDA support, the exon-skipping field would not be anywhere near as advanced as it is," Wilton said. "MDA funded this research when many other research funding bodies were very skeptical."
Funding for this MDA grant began August 1, 2010.
Grantee: DMD/BMD — Steve Wilton
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Grant - Summer 2011 - DMD/BMD — Tejvir Khurana, M.D., Ph.D.
MDA has awarded a research grant totaling $379,500 over three years to Tejvir Khurana, a professor of physiology at the University of Pennsylvania. The grant will support Khurana's research to increase the production of utrophin, a protein that may improve muscle strength and function in Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD).
Studies suggest that utrophin can, at least in part, substitute for the dystrophin protein missing in DMD and only partially functional in BMD. A mutation in the dystrophin gene is the root cause of both diseases.
Since functional utrophin is produced in the muscles of people with DMD and BMD, therapies based on supplying more of it are unlikely to cause an unwanted immune response. In contrast, therapies based on supplying functional dystrophin, which many people with DMD/BMD do not produce, may cause an unwanted immune response to this protein.
Khurana's strategy for increasing utrophin production is based on removing a biological "brake" that represses it.
"We have found that utrophin is in a state of repression," Khurana said, "and that a class of molecules called microRNAs cause this repression. We will develop methods to 'repress the repressors' and hence achieve utrophin upregulation."
Khurana and colleagues will test their strategy in dystrophin-deficient mice that develop a DMD-like disease.
Funding for this MDA grant began August 1, 2011.
Grantee: DMD/BMD — Tejvir Khurana, M.D., Ph.D.
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Grant - Summer 2010 - DMD/BMD — Sean Forbes
MDA awarded $179,327 to scientific researcher Sean Forbes at the University of Florida in Gainesville for research into impaired blood flow to muscles lacking the dystrophin protein in Duchenne muscular dystrophy (DMD).
Forbes plans to study an enzyme called neuronal nitric oxide synthase (nNOS) that contributes to blood flow and delivery of oxygen to muscles in the mdx research mouse model of DMD and another mouse model lacking nNOS. He’ll test the hypothesis that impaired blood flow during and following muscle use leads to inadequate delivery of oxygen to the muscles in DMD, contributing to muscle damage and accelerating the loss of healthy muscle tissue.
Forbes and his team will attempt to improve muscle blood flow via administration of the drug sildenafil citrate (brand name Viagra) and observe whether it lessens damage in DMD muscles. The group will use magnetic resonance imaging (MRI) and another type of imaging called spectroscopy (MRS) to measure changes in muscle blood flow, energy production and damage in mice. These noninvasive techniques may prove to be sensitive tools to monitor and visualize disease progression and effectiveness of treatment in DMD.
"This MDA Development Grant provides a valuable opportunity to pursue this exciting and important area of research. The funding will enable us to perform studies to examine muscle metabolism and blood flow in dystrophy, and will examine the effects of a prospective treatment for DMD," Forbes said. "These studies have the potential to set the foundation for future studies in children with DMD."
Funding for this MDA grant began August 1, 2010.
Grantee: DMD/BMD — Sean Forbes
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Grant - Summer 2011 - DMD/BMD — Peter Currie, Ph.D.
Peter Currie, a professor of medicine at Monash University in Clayton, Victoria, Australia, was awarded an MDA research grant totaling $375,000 over three years. The funds will help support Currie's research, which involves screening for possible therapeutic molecules using the zebrafish model of Duchenne muscular dystrophy (DMD).
The underlying cause of DMD is an absence of the muscle protein dystrophin due to any of a large number of mutations in the dystrophin gene. Becker muscular dystrophy (BMD), a less severe form of MD, is caused by dystrophin gene mutations that result in production of a partially functional dystrophin protein.
"While the current animal models of DMD have generated valuable insights into the pathological basis of the disease, each has their limitations," Currie notes. "We have isolated mutations in the zebrafish dystrophin gene and have determined that dystrophin-deficient zebrafish accurately model the human condition."
In this new project, Currie and his colleagues will undertake a drug screen for small molecules that can inhibit the onset of signs of muscular dystrophy in the dystrophin-deficient zebrafish.
"MDA funding has been critical in allowing me to pursue modeling muscular dystrophy in zebrafish," Currie said. "There is simply no way that the research that has happened around muscle disease modeling in my laboratory would have occurred at the pace that it has without the generous support of MDA."
Funding for this MDA grant began August 1, 2011.
Grantee: DMD/BMD — Peter Currie, Ph.D.
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Grant - Summer 2010 - DMD/BMD — Michele Calos
Michele Calos, professor in the department of genetics at Stanford University School of Medicine in Stanford, Calif., received a $200,000 MDA research grant to develop a new stem cell-based therapy for Duchenne muscular dystrophy (DMD).
"Funding from MDA is critical for us to develop these new ideas that could lead to novel strategies to combat DMD," Calos said. "A prior MDA grant has allowed us to make progress in the studies, and we are now poised to perform the critical experiments."
The new work involves extraction of stem cells from DMD mice. A good copy of the dystrophin gene, necessary but missing in DMD, will be added to the cells, which will then be returned to the mouse where they are expected to home in on damaged muscle and help create new muscle fibers to replace those damaged by the disease. The investigative team will also conduct experiments using a type of adult human stem cell called "adipose-derived mesenchymal stem cells," which are purified from fat tissue and have been shown to develop into muscle.
Successful results in these experiments eventually may lead to clinical trials and may indicate potential for use of a similar approach in other muscle diseases.
"Progress in the development of stem cell therapies offers major hope for regeneration of muscle mass and strength," Calos said, even for those in whom the disease has progressed.
Funding for this MDA grant began August 1, 2010.
Grantee: DMD/BMD — Michele Calos
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Grant - Summer 2011 - DMD/BMD — Paul Martin, Ph.D.
Paul Martin, a professor of pediatrics and of physiology and cell biology at Ohio State University College of Medicine, has been awarded an MDA grant totaling $396,000 over three years. The award will help support Martin's study of the possible therapeutic effects of an enzyme called GALGT2 in Duchenne muscular dystrophy (DMD).
GALGT2 is involved in adding sugar molecules to a protein called alpha-dystroglycan, part of a cluster of proteins located at the muscle-fiber membrane. This cluster is abnormal in a number of forms of muscular dystrophy.
Among the other proteins normally located in this cluster are dystrophin, which is deficient in DMD and abnormal in the related Becker muscular dystrophy (BMD); alpha-sarcoglycan, which is deficient in the type 2D form of limb-girdle muscular dystrophy (LGMD); and merosin, which is deficient in the type 1A form of congenital muscular dystrophy (CMD).
Previous work in Martin's lab has shown that raising GALGT2 levels can help compensate for the loss of dystrophin in a mouse model of DMD, inhibiting the development of muscle abnormalities in DMD model mice.
The Martin lab also has shown that increasing GALGT2 levels can have therapeutic effects on skeletal muscles in animal models of LGMD2D and CMD1A.
"Because GALGT2 is normally expressed in skeletal muscles," Martin said, "its overexpression may have fewer immunologic issues than gene replacement or exon skipping approaches." (The latter approaches increase levels of proteins that are abnormal or deficient in patients, potentially triggering an unwanted immune response.)
"MDA has played a seminal role in the development of my work," Martin said. "MDA funded two years of my postdoctoral training, provided me with my first research grant as an independent faculty member, and now will provide research funding to translate proof-of-concept studies into potential therapies."
Funding for this MDA grant began August 1, 2011.
Grantee: DMD/BMD — Paul Martin, Ph.D.
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Grant - Summer 2010 - DMD/BMD — Louis Kunkel
MDA awarded a grant totaling $375,000 to Louis Kunkel, director of the program in genomics at Children's Hospital in Boston, for research into compounds already approved for human use that may alter disease progression in Duchenne muscular dystrophy (DMD).
"There are thousands of compounds developed for use in humans for a variety purposes such as pain, diabetes and heart disease," Kunkel said. "The vast majority of these compounds have never been tested for their possible use in other diseases such as muscular dystrophy, something that can be easily accomplished in zebra fish."
In previous studies, Kunkel's lab has identified several compounds that increase the survival rate in zebra fish with a DMD-like disease and that are approved by the U.S. Food and Drug Administration for use in humans.
The team now plans to search for additional compounds, which it will test in the zebra fish model. The investigators will analyze indicators including survival rates, muscle function and toxicity, to determine the best candidate to go forward into mouse models.
"The beauty of the zebra fish is that they are permeable," Kunkel said. "They present an opportunity to directly test compounds in a live organism with the disease due to their large numbers, small size, transparency and their ability to absorb chemicals from their water environment."
Funding for this MDA grant began August 1, 2010.
Grantee: DMD/BMD — Louis Kunkel
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Grant - Summer 2011 - DMD/BMD — Michael Rudnicki, Ph.D.
MDA has awarded a grant totaling $375,000 over three years to Michael Rudnicki, director of the Regenerative Medicine Program at Ottawa Hospital Research Institute and a professor in the department of medicine at the University of Ottawa, Canada. This funding will support Rudnicki's continuing studies on the function of muscle satellite cells in mice with a disease resembling human Duchenne muscular dystrophy (DMD).
DMD is caused by any of a number of mutations in the gene for the muscle protein dystrophin that result in a complete absence of the dystrophin protein in the skeletal muscles and heart. The closely related disease Becker muscular dystrophy (BMD) is due to mutations in the dystrophin gene that result in dystrophin protein that's only partially functional.
Muscle satellite cells are required for the growth and repair of skeletal muscles. In previous studies, Rudnicki and his colleagues have found that there is a subset of muscle satellite cells that function as "satellite stem cells," giving rise to the satellite cells that then become muscle.
They've also found that satellite stem cells do not function properly in dystrophin-deficient mice; and that a protein called WNT7a stimulates proliferation of satellite stem cells and benefits normal and dystrophic muscle.
In this new set of experiments, Rudnicki's team will investigate the nature of the defect in satellite stem cells in dystrophin-deficient mice and the mechanism through which WNT7a treatment increases the numbers of these cells.
The researchers also will investigate the possibility of using WNT7a as a treatment for DMD or BMD, through experiments in dystrophin-deficient mice.
Rudnicki, who has received MDA support for several years, says, "MDA funding has been critical in allowing my lab to investigate the fundamental mechanisms that regulate the function of muscle stem cells."
Funding for this MDA grant began August 1, 2011.
Grantee: DMD/BMD — Michael Rudnicki, Ph.D.
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Grant - Summer 2010 - DMD/BMD — Josephine Nalbantoglu
Josephine Nalbantoglu, associate professor in the department of neurology and neurosurgery at McGill University in Montreal, Canada, received an MDA grant totaling $313,170 for research into increasing levels of the muscle protein utrophin as a therapeutic strategy in Duchenne muscular dystrophy (DMD).
Utrophin is structurally similar to the crucial muscle protein dystrophin, missing in DMD. Nalbantoglu and colleagues aim to validate, in muscle cells and in an animal model of DMD, the potential for utrophin to fulfill some of the functions normally carried out by dystrophin and compensate for the missing protein.
In completed studies, Nalbantoglu's group has shown in an animal model of DMD that utrophin levels can be increased by targeting specific sites in the gene that carries the instructions for utrophin with proteins called transcription factors. Muscle injected with these proteins exhibited fewer hallmarks of disease and increased function despite the absence of dystrophin.
Using the same approach, the team will now refine transcription factors designed to result in increased levels of the human utrophin protein. In parallel, the investigators will explore various methods for delivering the factors throughout the body.
"Funding from MDA is crucial for this work," Nalbantoglu said. The approach of using artificial transcription factors to increase levels of specific genes would have wide application to other muscle diseases. Artificial transcription factors are already in clinical trials for some non-muscle diseases."
Funding for this MDA grant began August 1, 2010.
Grantee: DMD/BMD — Josephine Nalbantoglu
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Grant - Summer 2011 - DMD/BMD — Melissa Spencer, Ph.D.
Melissa Spencer, professor of neurology and co-director of the Center for Duchenne Muscular Dystrophy at the University of California, Los Angeles, has been awarded an MDA grant totaling $501,493 over three years. The funds will help support Spencer's continuing studies of the role of a protein called osteopontin and of inflammatory processes in a mouse model of Duchenne muscular dystrophy (DMD).
DMD results from a nearly complete absence of the dystrophin protein in the skeletal muscles and heart. Becker muscular dystrophy (BMD), a closely related disease, results from a partially functional dystrophin protein. A large variety of mutations in the dystrophin gene give rise to DMD or BMD.
The osteopontin protein has been shown to play a role in promoting the entry of immune system cells into damaged, dystrophin-deficient muscle, which in turn results in scar-tissue formation (fibrosis).
The Spencer lab has received funding from MDA over the past decade. Spencer and her colleagues, particularly Irina Kramerova and Carrie Miceli, will now study how osteopontin regulates the muscle-invading immune system cells and the manner in which these cells cause fibrosis in mice with a DMD-like disease.
The investigators will use mouse models and cellular and immunological techniques to understand the processes involved. They also will use a specialized mouse that has been genetically engineered to allow for noninvasive imaging of muscles.
These studies will lay the foundation for development of drugs that target osteopontin in DMD or BMD, Spencer said.
"I credit MDA for enabling many of the successes my lab has achieved," she noted.
Funding for this MDA grant began August 1, 2011.
Grantee: DMD/BMD — Melissa Spencer, Ph.D.
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Grant - Summer 2010 - DMD/BMD — Gordon Lynch
MDA awarded $375,000 to Gordon Lynch, professor of physiology at the University of Melbourne, Australia, for research into strategies aimed at improving muscle function in Duchenne muscular dystrophy (DMD).
Lynch's research builds on previous studies conducted by his group and others that have demonstrated the potential of proteins called "growth factors" to preserve muscle fibers. These growth factors are regulated by a family of proteins called insulin-like growth factor binding proteins (IGFBPs).
Lynch's team has uncovered evidence that a particular IGF binding protein called IGFBP-2 may play a key role in the cycles of muscle fiber damage and repair that occur in DMD.
Using a mouse model genetically altered to exhibit either increased or decreased IGFBP-2 activity, the team will seek to determine whether the protein aggravates or improves the DMD disease process. The researchers also will study the effects of IGFBP-2 and other IGF binding proteins on muscle development and muscle repair.
"The MDA has generously supported my laboratory’s research for over a decade, allowing my team to make consistent and significant contributions to the field, including demonstrating the exciting potential of growth factors for improving muscle function in muscular dystrophy," Lynch said. "Support from the MDA has been critical in facilitating my mentorship of some very talented young doctoral students and postdoctoral scientists who have each made important contributions to muscular dystrophy research and become successful independent investigators in their own right."
Lynch's new research will generate important new information about the functional roles of IGF binding proteins in muscular dystrophy, and contribute to the development of therapies designed to improve the quality of life for those with muscle disease.
Funding for this MDA grant began August 1, 2010.
Grantee: DMD/BMD — Gordon Lynch
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Grant - Summer 2011 - DMD/BMD — Martin Childers, Ph.D.
Martin Childers, a professor at the Institute for Regenerative Medicine in Winston-Salem, N.C., has been awarded an MDA grant totaling $480,000 over three years. The Institute is part of Wake Forest University Baptist Medical Center.
The new funds will help support Childers' research on heart disease associated with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). DMD results from a complete lack of dystrophin protein in skeletal and cardiac muscles, and BMD results from the presence of partially functional dystrophin protein. Both diseases are caused by mutations in the dystrophin gene.
"Many patients with DMD die as young adults from heart failure," Childers said. "The reason for this is that the heart muscle carries a genetic mutation that damages the normal operation of this all-important muscle. Our project will allow for the discovery of new drugs that might reverse or prevent the effects of the disease on the heart muscle."
Childers and colleagues will use two types of new technology to find potential new drugs for heart disease related to dystrophin deficiency. First, they'll use a method called cellular "reprogramming" to create heart cells from the skin cells of DMD patients. "This remarkable new technology will allow us to study how a genetic mutation affects the heart cells of a specific patient," Childers said.
The second method the investigators will employ is a drug-discovery "platform" that can screen thousands of compounds in individual cells.
"By marrying these two incredible technologies, this project will allow, for the first time, the testing of new drugs directly on the heart cells of an individual patient without any risk to the patient," Childers noted.
Funding for this MDA grant began August 1, 2011.
Grantee: DMD/BMD — Martin Childers, Ph.D.
Grant type: Research Grant
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Grant - Summer 2010 - DMD/BMD — Dawn Cornelison
MDA awarded a grant totaling $160,000 to Dawn Cornelison, assistant professor in the division of biology at the University of Missouri-Columbia, for research into the role of a protein called syndecan-4 in muscle tissue repair after damage.
After muscle injury, Cornelison said, satellite cells (immature muscle cells) move in to make repairs. In order to do their job, the satellite cells need to perform a series of activities: They must first be 'activated' by signals resulting from injury; then divide several times to make more potential muscle cells; then stop dividing; and finally mature, or differentiate, into functional muscle.
In previous MDA-supported work, Cornelison and her research team analyzed a mouse engineered to lack the syndecan-4 protein and found that its satellite cells were unable to perform all of their normal muscle-repair functions. The group found that different parts of the syndecan-4 protein are responsible for regulating different satellite-cell functions in the muscle-repair process.
In its new work the group aims to identify proteins that interact with syndecan-4 and gain a better understanding of how the satellite cells carry out the four activities necessary for muscle repair.
"Funding from MDA has been critical to the progress and development of both this project and my scientific career," Cornelison said. "Particularly in the current environment, with the odds of obtaining funding for general research falling below 10 percent, knowing that MDA is there to sponsor research into muscle disease and regeneration is critical to retaining scientists in the field and encouraging others to undertake research into muscle diseases."
Funding for this MDA grant began August 1, 2010.
Grantee: DMD/BMD — Dawn Cornelison
Grant type: Research Grant
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Grant - Summer 2011 - DMD/BMD — Emanuela Gussoni, Ph.D.
MDA has awarded a grant totaling $384,066 over three years to Emanuela Gussoni, an assistant professor in the division of genetics and program in genomics at Children's Hospital Boston and Harvard University. The grant will support Gussoni's studies to improve the efficacy of stem cell transplantation as a strategy to treat Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) and possibly other forms of muscular dystrophy.
The direct injection of normal muscle stem cells into mice and people with muscular dystrophy has been attempted as a way to provide missing proteins to muscle tissue. (In DMD, the dystrophin protein is missing; in BMD, it's present but only partially functional.)
However, Gussoni said, studies have shown that, while the technique is safe in patients, their muscles have not shown significant improvement. One of the causes for the lack of improvement is the rapid death of the normal cells following transplantation.
To overcome this problem, different cell types more capable of surviving the transplant and producing the desired proteins must be identified. Gussoni's research team has found that human cells that produce a surface protein called MCAM can form muscle in tissue culture and following injection into animals.
If they live up to the preliminary expectations of Gussoni and her colleagues, MCAM-expressing cells could become candidates for cell transplantation to treat MD.
"MDA funding has been instrumental throughout my career," said Gussoni, who has received several MDA grants. "MDA develops and fosters both new and established investigators who are highly committed to improving the lives of people with muscle disorders."
Funding for this MDA grant began August 1, 2011.
Grantee: DMD/BMD — Emanuela Gussoni, Ph.D.
Grant type: Research Grant
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Grant - Summer 2010 - DMD/BMD — Carmen Bertoni
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.
Grantee: DMD/BMD — Carmen Bertoni
Grant type: Research Grant
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Grant - Summer 2010 - DMD/BMD — Bernard Jasmin
MDA awarded Professor Bernard Jasmin, vice-dean of research at the University of Ottawa in Canada, a grant totaling $360,000 to study the impact of small molecules called "exercise mimetics" in Duchenne muscular dystrophy (DMD).
One approach to counteract the effects of the loss of the muscle protein dystrophin in DMD involves increasing levels of a similar structural protein called utrophin. Studies performed in a widely used mouse model of DMD, the mdx mouse, have shown that increased utrophin expression can compensate for the lack of dystrophin and ameliorate symptoms of the disease.
Because utrophin activity normally is low and focused only in certain regions of the muscle, Jasmin's laboratory looks for ways to increase levels of the protein in DMD muscles.
"Our first preclinical study showed that treatment of mdx mice with an exercise mimetic known as GW501516 resulted in an increase in utrophin expression, improved muscle function and improved pathological symptoms of the disease," Jasmin said.
His current work builds on the previous study results, with plans for continued testing of GW501516 in the mdx mouse model of DMD, and expansion of the research to include testing of other molecules including AICAR, beta-GPA and resveratrol.
Because of the possible effects of exercise mimetics on utrophin in DMD-affected muscles, the small molecules hold potential for dramatic improvement in quality of life for individuals with the disease. GW501516 currently is under development to treat obesity by the pharmaceutical company GlaxoSmithKline, which could help speed its development for therapeutic use in people with DMD.
"MDA funding has allowed us to take a relatively basic molecular observation and perform research that eventually could result in development of novel therapeutic approaches for treatment of people with DMD," Jasmin said.
Funding for this MDA grant began August 1, 2010.
Grantee: DMD/BMD — Bernard Jasmin
Grant type: Research Grant
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