Grant - Winter 2012 - DMD/BMD - Julie Saba, M.D.
Senior scientist Julie Saba, at Children’s Hospital Oakland Research Institute in Oakland, Calif., was awarded an MDA research grant totaling $392,467 over a period of three years. The funds will help support Saba’s research into enhancing muscle regeneration and muscle stem cell functions as a new strategy for treating Duchenne (DMD) and Becker (BMD) muscular dystrophies.
In previous work, Saba and colleagues determined that metabolism of alipid (fat-like substance) called sphingosine-1-phosphate, or S1P, is important in maintaining normal muscle development. S1P stimulates cell signals that promote muscle cell survival and activate muscle stem cells.
The team has found that when S1P levels in mice are decreased using drugs or genetic approaches, a corresponding decrease in muscle stem cell activation and muscle regeneration after injury occurs. The investigators also have determined that S1P signaling and metabolism are activated during muscle injury but may be deficient in muscles affected by MD, thereby contributing to poor muscle regeneration.
“In contrast,” Saba said, “when we use a food-derived small molecule that causes accumulation of S1P, we observe improved muscle regeneration and stem cell functions in a mouse model of MD.”
Such findings suggest that stimulating S1P signaling may improve muscle regeneration and strength in people with MD.
In her new work, Saba will study the effects of modulating S1P as a therapeutic strategy designed to work by activating peoples’ own stem cells to improve muscle regeneration.
“We hope that in the future we may also be able to leverage similar strategies of S1P modulation to improve muscle regeneration in combination with cell therapy approaches that are currently showing limited success,” Saba said.
Funding for this MDA grant began February 1, 2012.
Grantee: DMD/BMD - Julie Saba, M.D.
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Grant – Winter 2013 – SMA - Christine DiDonato, Ph.D.
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.
Grantee: SMA - Christine DiDonato, Ph.D.
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Grant - Winter 2012 - DMD/BMD - James Ervasti, Ph.D.
James Ervasti, professor of biochemistry, molecular biology & biophysics at the University of Minnesota in Minneapolis, was awarded an MDA research grant totaling $390,000 over a period of three years to help support his research into improving two therapies currently in development for people with Duchenne (DMD) and Becker (BMD) muscular dystrophies.
Exon skipping is a strategy in which molecules called anstisense oligonucleotides (AONs) target error-containing parts of a gene and coax cells to retain the error-free parts for protein synthesis.
As with exon skipping, viral delivery of miniaturized dystrophin genes is designed to restore sufficient levels of the dystrophin protein, which is deficient in DMD and BMD.
Both strategies create non-natural versions of dystrophin, and Ervasti and colleagues have shown that the miniaturized dystrophin proteins are prone to misfolding, instability and clumping into aggregates — all of which likely limit their effectiveness.
In his new research, Ervasti will study ways to assess and optimize the stability of miniaturized dystrophin proteins in the laboratory before they are tested in animal models with dystrophin deficiency. Ervasti's team also will examine how exon-skipping strategies currently under investigation to treat DMD and gene deletions associated with BMD affect the stability of dystrophin.
A better understanding of how missing stretches of the dystrophin protein affect folding "may further allow us to identify drugs to treat patients with BMD and also enhance the effectiveness of exon skipping approaches," Ervasti said.
Funding for this MDA grant began February 1, 2012.
Grantee: DMD/BMD - James Ervasti, Ph.D.
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Grant - Summer 2012 - DMD/BMD — Veronica Hinton, Ph.D.
Veronica Hinton, associate professor of clinical neuropsychology at Columbia University in New York, was awarded an MDA research grant totaling $397,596 over three years to study cognitive problems in children with dystrophinopathies, which include Duchenne (DMD) and Becker (BMD) muscular dystrophies.
"Children with dystrophinopathies are at risk for having delayed language development, poor academic achievement and limited social skills in addition to muscle weakness,” Hinton notes. “This cognitive and behavioral profile puts them at increased risk for poor quality of life, but the profile can be modified and improved with early detection and proper intervention.”
Hinton is working to better understand the specific nature of the cognitive problems that children with dystrophinopathies may experience — information that is vital to minimizing and ameliorating the learning and behavior challenges that many children and families experience.
With colleagues, Hinton is using neuropsychological tests to examine cognitive and behavioral performance in a diverse group of children. The children participate in tests that involve answering questions, solving picture riddles and doing computer-administered puzzle tasks. Parents and teachers complete rating forms about each child’s daily life behavior.
Hinton’s study is designed to do an in-depth assessment of executive function (the higher thought processes that include making or following complicated plans, solving complex problems, following a series of directions and making sound judgments) and verbal working memory skills, and provide information about how these skills affect “real life” outcomes in school, socialization and quality of life.
"Research in this area has been limited, yet effective in raising awareness and understanding about the cognitive and behavioral risks associated with a diagnosis of dystrophinopathy,” Hinton says. “With that knowledge has come much improved care for the individuals affected.”
Funding for this MDA grant began Aug. 1, 2012.
Grantee: DMD/BMD — Veronica Hinton, Ph.D.
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Grant – Winter 2013 – OPMD - Sarah Youssof, M.D.
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.
Grantee: OPMD - Sarah Youssof, M.D.
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Grant - Winter 2012 - DMD/BMD - David Thomas, Ph.D.
MDA awarded a research grant totaling $390,000 over a period of three years to David Thomas, the William F. Dietrich Professor of Structural Biology and Biophysics at the Minnesota Muscle Laboratory, University of Minnesota in Minneapolis.
The funds will help support Thomas' research into the role of calcium trafficking in Duchenne (DMD) and Becker (BMD) muscular dystrophies.
Defects in the sarcolemma (the membrane that surrounds a muscle fiber) of people with muscular dystrophy lead to elevated concentrations of calcium in the muscle fiber — a condition that can cause cell death.
Recent reports have indicated that increasing activity in skeletal muscle of a protein called SERCA increases calcium transport out of the fiber, lessening disease severity in mouse models of muscular dystrophy. Such an approach relies on gene therapy.
Thomas and colleagues plan to develop a small-molecule approach to achieve the same end. The group intends to identify small-molecule compounds that directly activate SERCA from skeletal muscle and then evaluate each compound's ability to restore health and function to single skeletal muscle cells and intact skeletal muscles. Finally, the investigators plan to begin testing the most promising compounds in mice.
The results of this project are expected to provide proof-of-concept of for a small-molecule strategy to treat muscular dystrophy and identify a set of lead compounds for drug development.
Funding for this MDA grant began February 1, 2012.
Grantee: DMD/BMD - David Thomas, Ph.D.
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Grant – Winter 2013 – OPMD - Ayan Banerjee, Ph.D.
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.
Grantee: OPMD - Ayan Banerjee, Ph.D.
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Grant - Summer 2012 - DMD/BMD — Tom Thompson, Ph.D.
Tom Thompson, associate professor in the department of molecular genetics, biochemistry and microbiology at the University of Cincinnati in Ohio, was awarded an MDA research grant totaling $330,000 over three years. The funds will help support Thompson's study of potential therapies based on blocking a protein called myostatin for Duchenne (DMD) and Becker (BMD) muscular dystrophies.
"In our bodies, a protein called myostatin inhibits the size and mass of muscle, so therapies aimed at inhibition of myostatin are in high demand," Thompson explains. One potential concern, however, is that myostatin inhibitors need to be specific in order to limit potential side effects.
Humans have proteins that naturally inhibit myostatin. Thompson and colleagues are using a technique called X-ray crystallography to determine, at the atomic level, how these naturally occurring inhibitors bind to and neutralize myostatin. Their focus is on a protein called GASP1, which binds myostatin with high specificity.
The investigators plan to identify the mechanism by which GASP1 binds to myostatin.
In addition, the team will study another inhibitor called follistatin, which helps degrade myostatin by binding with cell surface molecules calledheparin.
This knowledge may make it possible to leverage the body's own system to inhibit myostatin, or develop other strategies to block it, Thompson says.
Funding for this MDA grant began Aug. 1, 2012.
Grantee: DMD/BMD — Tom Thompson, Ph.D.
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Grant - Spring 2014 - SMA - Stephen Kolb, M.D., Ph.D.
Stephen Kolb, an assistant professor in the Departments of Neurology and of Molecular & Cellular Biochemistry at Ohio State University, has been awarded an MDA human clinical trial grant totaling $183,354 over three years as supplemental funding for the SMA NeuroNEXT biomarkers study. This study is being conducted by the U.S. National Institutes of Health (NIH) to compare children with and without spinal muscular atrophy (SMA) during the first two years of life. Its purpose is to determine measurements of SMA progression during this period so that these measurements (“biomarkers”) can be used to assess the effects of experimental treatments in future trials. The MDA funding will allow additional training of evaluators of motor function.
Funding for this MDA human clinical trial grant began June 1, 2014.
Grantee: SMA - Stephen Kolb, M.D., Ph.D.
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Grant - Winter 2012 - DMD - Vladimir Ljubicic, Ph.D.
Vladimir Ljubicic, a postdoctoral fellow in the department of cellular and molecular medicine at the University of Ottawa in Ontario, Canada, was awarded an MDA development grant (DG) totaling $180,000 over a period of three years for his investigation into potential therapies for Duchenne muscular dystrophy (DMD). (MDA development grants are awarded to exceptional postdoctoral candidates who have the best chance of becoming independent researchers and future leaders of neuromuscular disease research.)
Scientists have shown that increasing levels of a structural protein calledutrophin and properly localizing it in the cell appears to partially compensate for the missing dystrophin protein — the underlying cause of DMD.
Utrophin has been observed at higher levels in "slow-twitch" muscle fibers (which are less affected in DMD), and at lower levels in "fast-twitch" fibers.
"A critical question," Ljubicic said, "is whether the benefits associated with slow-twitch fibers in DMD are strictly dependent on the increased levels of utrophin, or on some other factor associated with the slow-twitch fiber type."
In human skeletal muscle cell cultures, and also in mouse models of DMD, Ljubicic will test several compounds to determine whether they promote development of slow-twitch fibers.
Because the compounds he plans to test already are in clinical trials for other disorders, favorable results from Ljubicic's research could accelerate the development and implementation of new therapies for DMD centered either on increased utrophin activity in the cell and/or promotion of the slow-twitch muscle-fiber type.
Funding for this MDA grant began February 1, 2012.
Grantee: DMD - Vladimir Ljubicic, Ph.D.
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Grant – Winter 2013 – Muscle Physiology - Masahiro Iwamoto, Ph.D., D.D.S.
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.
Grantee: Muscle Physiology - Masahiro Iwamoto, Ph.D., D.D.S.
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Grant - Sping 2014 - SMA - Rashmi Kothary, Ph.D.
Rashmi Kothary, a senior scientist in the Regenerative Medicine Program at Ottawa Hospital Research Institute in Canada, has been awarded an MDA research grant totaling $253,800 over three years to further investigate a potential new treatment approach for spinal muscular atrophy (SMA) . Kothary and colleagues will continue to develop inhibitors of an enzyme called rho kinase to see if they are beneficial in this disease. Early experiments in mice have shown promise.
Funding for this MDA research grant began May 1, 2014.
Grantee: SMA - Rashmi Kothary, Ph.D.
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Grant - Winter 2012 - DMD - Robert Korneluk, Ph.D.
MDA awarded a research grant totaling $425,952 over a period of three years to Robert Korneluk, director of the Apoptosis Research Centre at the Children’s Hospital of Eastern Ontario Research Institute, and distinguished professor at the University of Ottawa in Ontario, Canada.
The funds will help support Korneluk’s study of the Nuclear Factor kappaB(NFkB) signaling pathway in muscle diseases such as Duchenne muscular dystrophy.
The NFkB signaling pathway is critical for normal skeletal muscle function, and is important for promoting recovery in response to muscle injury. There also is strong evidence that NFkB signaling is involved in the disease process of many muscle diseases.
Korneluk and colleagues recently found that two proteins called cIAP1 and cIAP2, initially identified by the group, are required for various aspects of NFkB signaling in skeletal muscle. The investigators also found that the loss of cIAP1 protein activity in muscle, in cultured cells and in mice, leads to changes in the NFkB signaling pathway, with subsequent improvement of muscle function and recovery.
Korneluk’s team plans to define the roles and mechanism of action of cIAP1 and cIAP2 in NFkB signaling in skeletal muscle, and evaluate their contribution to the DMD disease process. Additionally, the investigators will evaluate the therapeutic potential in muscular dystrophy of several drugs that specifically and strongly target cIAP1 and cIAP2 for destruction.
Funding for this MDA grant began February 1, 2012.
Grantee: DMD - Robert Korneluk, Ph.D.
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Grant - Summer 2012 - DMD/BMD — Ryan Wuebbles, Ph.D.
Ryan Wuebbles, a postdoctoral fellow in pharmacology at the University of Nevada School of Medicine in Reno, was awarded an MDA development grant (DG) totaling $180,000 over three years to study the potential use of a protein called laminin-111 as the basis of therapies for Duchenne (DMD) and Becker (BMD) muscular dystrophies.
MDA development grants are awarded to exceptional postdoctoral candidates who have the best chance of becoming independent researchers and future leaders of neuromuscular disease research.
In a research mouse model with a disease resembling DMD, treatment with laminin-111 has been shown to prevent muscle damage and improve resistance to exercise-induced muscle injury. The proteins' large size, however, makes it difficult to manufacture, so Wuebbles and colleagues are working to determine whether a small part of the protein is capable of producing the same effects.
Wuebbles plans to test different parts of laminin-111 in cells cultured from DMD research mice and from people with the disease. The most promising of these will be tested in a DMD research mouse model, where any effects can be compared to those generated by the full-length protein.
"Protein therapeutics are emerging as some of the strongest Duchenne muscular dystrophy therapeutic candidates," Wuebbles says. "Exciting new protein treatments such as laminin-111 offer a directed natural approach compared to traditional small chemical compounds."
Funding for this MDA grant began Aug. 1, 2012.
Grantee: DMD/BMD — Ryan Wuebbles, Ph.D.
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Grant - Winter 2012 - DMD - Lawrence Steinman, M.D.
MDA awarded a research grant totaling $308,061 over a period of three years to Lawrence Steinman, Zimmerman Chair and professor of neurology, neurosciences and pediatrics at Stanford University School of Medicine in Stanford, Calif. The funds will help support Steinman’s work to inhibit immune system response to replacement of the missing dystrophin protein in Duchenne muscular dystrophy.
Dystrophin-specific immunity has been reported in people with DMD both before and after treatment with gene therapy.
Steinman and colleagues plan to “map the exact nature” of the immune response to dystrophin in boys with Duchenne MD. In addition, the investigators have invented a strategy designed to shut down the immune response to dystrophin, and plan “to test this approach in experimental gene therapy in mice with a DMD-like disease.”
Steinman said that most attempts to suppress unwanted immunity in DMD use “big-hammer drugs” with strong immune system suppression properties. His new approach is more selective, he noted, designed to “turn off the immune response specifically when it is unwanted,” leaving the rest of the immune system intact.”
“Ultimately, this could increase the success of gene therapy in DMD,” Steinman said, “by inhibiting an unwanted immune system response when the normal dystrophin molecule is produced.”
Funding for this MDA grant began February 1, 2012.
Grantee: DMD - Lawrence Steinman, M.D.
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Grant – Winter 2013 – MM – Mitochondrial Myopathies - Eric Schon, Ph.D.
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.
Grantee: MM – Mitochondrial Myopathies - Eric Schon, Ph.D.
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Grant - Spring 2014 - SMA - Lyndsay Murray, Ph.D.
Lyndsay Murray, a lecturer in anatomy at the University of Edinburgh in Scotland, has been awarded an MDA development grant totaling $152,280 over three years to determine the earliest changes in gene activity that occur in spinal muscular atrophy (SMA). By conducting experiments in mice with and without an SMA-like disorder, Murray and colleagues will study the genetic changes that occur prior to the death of nerve cells in the SMA-like condition. The work is expected to lead to new ideas of how to protect nerve cells that carry SMA-causing abnormalities.
Funding for this MDA development grant began May 1, 2014.
Grantee: SMA - Lyndsay Murray, Ph.D.
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Grant - Summer 2012 - DMD/BMD — Rita Perlingeiro, Ph.D.
MDA awarded a research grant totaling $390,000 over three years to Rita Perlingeiro, associate professor in the Department of Medicine at the University of Minnesota in Minneapolis. The funds will help support Perlingeiro's study of genetic correction and muscle regeneration in Duchenne (DMD) and Becker (BMD) muscular dystrophies.
"The practical and ethical problems associated with the use of embryonic stem cells have been eliminated with the revolutionary discovery of reprogramming somatic cells, such as skin, to a pluripotent state (iPS cells)," Perlingeiro explains. "This enables the generation of patient-specific induced pluripotent stem cells that could be used for transplantation." (Pluripotent cells can mature, or differentiate, into any cell type and can be expanded indefinitely in the lab.)
Perlingeiro and colleagues have invented and continue to refine a method to efficiently generate immature skeletal muscle cells from iPS cells. In addition, they have shown that, once transplanted, the cells integrate with existing skeletal muscle cells in an iPS cell model of DMD, and in cells taken from healthy mice and healthy humans.
Now, Perlingeiro is working to determine the efficiency with which genetically corrected iPS cells can increase muscle regeneration in DMD mice.
Perlingeiro's work could lay the groundwork for clinical development of pluripotent stem cells for muscular dystrophy.
"Because disease progression for DMD takes over a decade, there is sufficient time to generate and test iPS cells," Perlingeiro says, "making DMD an ideal candidate for early-stage iPS cell therapy clinical trials."
Funding for this MDA grant began Aug. 1, 2012.
Grantee: DMD/BMD — Rita Perlingeiro, Ph.D.
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Grant - Spring 2014 - Nemaline Myopathy - Henk Granzier, Ph.D.
Henk Granzier, a professor of molecular and cellular biology, physiology and biomedical engineering at the University of Arizona in Tucson, has been awarded an MDA research grant totaling $253,800 over three years to study how lower than normal levels of a protein called nebulin affect muscle cells. Nebulin deficiency is the underlying cause of one type of nemaline myopathy. Granzier and colleagues have developed nebulin-deficient mice that develop a disorder resembling human nemaline myopathy. They will conduct experiments in these mice to better understand the basis of muscle weakness in this disorder and to test the effects of experimental treatments.
Funding for this MDA research grant began May 1, 2014.
Grantee: Nemaline Myopathy - Henk Granzier, Ph.D.
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Grant - Summer 2012 - DMD/BMD — Joseph Metzger, Ph.D.
MDA awarded a research grant totaling $237,868 over two years to Joseph Metzger, professor and chair of integrative biology and physiology at the University of Minnesota in Minneapolis. The funds will help support Metzger's work in development and testing of copolymer molecules, or "membrane sealants," for Duchenne (DMD), Becker (BMD) and other muscular dystrophies.
DMD and BMD are caused by an absence of dystrophin, a protein that helps keep muscle cells intact. Dystrophin deficiency causes muscle membranes to be fragile, with structural and functional abnormalities. These weakened cellular membranes make the muscle tissue highly susceptible to contraction-based injury and eventual destruction.
Metzger and colleagues are utilizing cutting-edge techniques in the fields of physiology (the study of chemical and physical processes involved in a living organism), chemistry, and chemical engineering to develop membrane-protective molecules as a therapeutic approach to treat muscular dystrophy.
"Molecular 'Band-Aids' for muscle membrane protection have the potential to spark a revolution in novel therapeutics for diseased striated muscles in muscle dystrophy," Metzger says.
Funding for this MDA grant began Aug. 1, 2012.
Grantee: DMD/BMD — Joseph Metzger, Ph.D.
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Grant - Spring 2014 - Muscle disease - Stephen Hauschka, Ph.D.
Stephen Hauschka, a professor of biochemistry at the University of Washington-Seattle, has been awarded an MDA research grant totaling $253,800 over three years to develop and test new “on-off” gene “switches,” also known as “regulatory cassettes,” to be used in gene transfer therapies to treat muscle disorders.
Funding for this MDA research grant began May 1, 2014.
Grantee: Muscle disease - Stephen Hauschka, Ph.D.
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Grant – Winter 2013 – MMD - Matthew Disney, Ph.D.
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.
Grantee: MMD - Matthew Disney, Ph.D.
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Grant - Spring 2014 - Muscle disease - Shihuan Kuang, Ph.D.
Shihuan Kuang, an associate professor of animal sciences at Purdue University in West Lafayette, Ind., has been awarded an MDA research grant totaling $253,800 over three years to investigate the use of low-oxygen conditioning of cells to improve stem cell-based therapies to treat muscular dystrophies.
Funding for this MDA research grant began May 1, 2014.
Grantee: Muscle disease - Shihuan Kuang, Ph.D.
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Grant - Summer 2012 - DMD/BMD — Dean Burkin, Ph.D.
Dean Burkin, associate professor of pharmacology at the University of Nevada School of Medicine in Reno, was awarded an MDA research grant totaling $308,028 over three years to study laminin-111 protein therapy for Duchenne (DMD) and Becker (BMD) muscular dystrophies.
Burkin and colleagues have shown in previous work that systemic delivery of the laminin-111 protein works as a potent therapeutic in a mouse model of DMD. Laminin-111 treatment in these mice results in stabilization of the muscle membrane and a reduction in levels of an enzyme called creatine kinase, or CK, which is a sign of muscle damage.
It remains unclear, however, whether laminin-111 protein therapy in people with DMD may be able to prevent muscle damage, or reverse it after it's already started.
Burkin is working to test the hypothesis that laminin-111 protein therapy can prevent muscle damage after DMD disease onset in mouse models of DMD and in dogs that have the disease.
To do this, Burkin and colleagues first plan to determine if laminin-111 prevents muscle damage after disease onset in the two animal models. Next, the team will test to see whether laminin-111 prevents heart muscle deterioration (cardiomyopathy) in mouse models of DMD, and finally the group will study whether laminin-111 prevents muscle disease in dogs with DMD.
Favorable results could pave the way for development of laminin-111 as a therapeutic for DMD and BMD.
Funding for this MDA grant began Aug. 1, 2012.
Grantee: DMD/BMD — Dean Burkin, Ph.D.
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Grant - Summer 2013 - DMD — Moon-Chang Choi, Ph.D.
Moon-Chang Choi, a postdoctoral researcher at Duke University in Durham, N.C., was awarded an MDA development grant totaling $120,000 over a period of two years to study one of the molecular controls regulating muscle repair.
When muscle becomes damaged, new muscle cells form by division ofsatellite cells, a type of stem cell found in muscles. “Understanding the mechanism that controls satellite cell activation could provide opportunities to increase muscle regeneration and provide therapeutic relief to patients with Duchenne muscular dystrophy (DMD),”Choi says.
His work will focus on a protein called HDAC4, which he has previously shown is required for satellite cell activation in damaged muscle. Now, Choi will further characterize the role of HDAC4 in satellite cell activation, using a mouse model in which HDAC4 is specifically inactivated in satellite cells. He also will examine the effect of a loss of HDAC4 in the most commonly used mouse model of DMD.
“The ability of muscle stem cells to transition from a quiescent state to a rapidly proliferative state is one of the most remarkable but mysterious aspects of stem cell biology,” Choi says. “Given that the satellite cell program is often impaired in muscle dystrophy, the study of these fundamental mechanisms could have important clinical implications.”
Funding for this MDA grant began August 1, 2013.
Grantee: DMD — Moon-Chang Choi, Ph.D.
Grant type: Development Grant
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