Grant - Summer 2013 - DMD — Rachelle Crosbie-Watson, Ph.D.
Rachelle Crosbie-Watson, professor of neurology at the University of California, Los Angeles, was awarded an MDA research grant totaling $300,000 over a period of three years to study whether increasing levels of the sarcospan protein can be therapeutic for Duchenne muscular dystrophy (DMD) and other muscle diseases.
In DMD, one of the major consequences of loss of dystrophin protein is that the muscle membrane, called the sarcolemma, becomes less stable and easier to damage. Replacing lost dystrophin is one therapeutic strategy; increasing sarcolemma stability through other means is an alternative.
“We have discovered a novel method that improves sarcolemma stability and adhesion [holding together],” Crosbie-Watson says, and the current study is aimed at testing the mechanisms and feasibility of this novel approach in animal models of DMD, limb-girdle muscular dystrophy (LGMD) and congenital muscular dystrophy (CMD).
The method involves delivering the gene that codes for the sarcospan protein. Raising the level of sarcospan leads to multiple effects at the sarcolemma, all contributing to increasing its stability. “We have shown that sarcospan ameliorates muscular dystrophy in the dystrophin-deficient mouse model for DMD, and we rationalize that sarcospan treatment will also benefit other forms of muscular dystrophy resulting from loss of muscle cell adhesion,” she says. The advantage of this approach is that, unlike dystrophin, the sarcospan gene is small and easily accommodated in the safest gene therapy vectors. Crosbie-Watson will continue fine-tuning this approach in the DMD mouse model, and extend it to models of LGMD and CMD.
“The outcome of these experiments will contribute to a better understanding of the molecular events contributing to the ability of sarcospan to alter expression of proteins at the cell surface,” she says, “and reveal the efficacy of sarcospan for the treatment of other muscular dystrophies.”
Funding for this MDA grant began August 1, 2013.
Grantee: DMD — Rachelle Crosbie-Watson, Ph.D.
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Grant - Winter 2012 - IBM - Sanford Bernstein, Ph.D.
Sanford Bernstein, a professor of biology at San Diego State University in California, was awarded an MDA research grant totaling $370,311 over a period of three years. The funds will help support Bernstein's research into the underlying molecular causes of, and potential treatments for, inclusion-body myopathy type 3 (IBM-3).
IBM-3 is caused by a mutation in a protein called myosin, the "molecular motor" that drives muscle contraction.
"Our biochemical and ultrastructural studies have shown that IBM-3 myosin is prone to unfolding and to forming clumps called aggregates," Bernstein said. "Further, muscle appears to respond to the mutant protein by producing autophagosomes, cellular bodies designed to encapsulate and degrade protein aggregates."
Bernstein's team will study the components that comprise the IBM-3 aggregates. Then, in an IBM-3 fruit fly research model that they developed, the investigators will test various approaches aimed at hastening the clearance of protein aggregates and ameliorating defective muscle structure and function in IBM-3.
"IBM-3 is a rare disease, and no model that produces the inclusion bodies we see in our drosophila model has been developed," Bernstein said. "Hence, use of this model presents the current best opportunity to develop a better understanding of the basis of the disease or its possible treatment."
Funding for this MDA grant began February 1, 2012.
Grantee: IBM - Sanford Bernstein, Ph.D.
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Grant - Summer 2012 - LGMD — Melissa Spencer, Ph.D.
Melissa Spencer, professor of neurology at the David Geffen School of Medicine at University of California, Los Angeles, was awarded an MDA research grant totaling $390,000 over three years to study the role of an enzyme called calpain 3 in type 2A limb-girdle muscular dystrophy (LGMD2A).
With colleagues, Spencer has demonstrated that characteristics and disease processes of LGMD2A are different from those seen in other dystrophies.
In Duchenne muscular dystrophy and other types of LGMD, the muscle cell membrane is weakened from the genetic mutation and the muscle cells die, Spencer explains. "In LGMD2A, muscle membranes remain intact, a finding which has left researchers without an explanation for the underlying mechanism of disease."
LGMD2A is caused by mutations in the CAPN3 gene, which carries genetic instructions for building a protein called calpain 3. Over the last decade, Spencer's team has generated numerous research mouse models that have provided insight about the biological function of calpain 3 in muscle development and muscle growth, but it's remained unclear how CAPN3 mutations lead to muscle dysfunction.
The team discovered that muscles lacking calpain 3 have severe deficits in the signaling pathways responsible for muscle growth — particularly thecalcium calmodulin kinases (CaMK) pathway.
Now Spencer is working on determining the relationship between calpain 3 and CaMK signaling.
Spencer's work could uncover the underlying defects for LGMD2A and lead to therapeutic targets for stimulating muscle growth in the setting of muscle degeneration. It also could shed light on other related muscular dystrophies, such as multiminicore disease.
Funding for this MDA grant began Aug. 1, 2012.
Grantee: LGMD — Melissa Spencer, Ph.D.
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Grant - Summer 2013 - DMD — Morayma Reyes, M.D., Ph.D.
Morayma Reyes, assistant professor of pathology at the University of Washington in Seattle, was awarded an MDA research grant totaling $300,000 over a period of three years to study a strategy for reducing heart muscle damage in Duchenne muscular dystrophy (DMD).
People with DMD develop cardiovascular problems in their early teen years, and cardiac complications are the major cause of death in the disease. A significant contributor to the damage done to heart muscle is fibrosis, or development of fibrous tissue within the muscle. Fibrosis is a response toinflammation, part of the body’s immune response. Reyes will be studying the effect of blocking a molecular pathway that contributes to that inflammation.
She has characterized cells surrounding blood vessels within the fibrotic tissue of heart muscle in the mdx mouse, a mouse model of DMD. “We hypothesize that these cells respond to inflammatory cues and deposit collagen, and thus form fibrotic tissue in the perivascular tissue of mdx hearts,” she says. “We will study the role of these cells in mdx cardiac fibrosis.”
In particular, she will study a potentially important signaling pathway, called the PDGF receptor alpha pathway. “We hypothesize that signaling through PDGF receptor alpha results in activation of a fibrotic program in these cells. We will test this by administration of PDGF-A, which should result in increased fibrosis.”
She will then block the pathway to reduce fibrosis, testing the potential benefits of a drug called Crenolanib. “These studies will lay the foundation for preclinical studies using Crenolanib to treat fibrosis in DMD patients,” Reyes says.
Funding for this MDA grant began August 1, 2013.
Grantee: Morayma Reyes, M.D., Ph.D.
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Grant - Winter 2012 - FSHD - Scott Harper, Ph.D.
MDA awarded a research grant totaling $317,464 over a period of three years to Scott Harper, an assistant professor of pediatrics at the Ohio State University College of Medicine in Columbus. The funds will help support Harper's work to develop a new mouse model of facioscapulohumeral muscular dystrophy (FSH, or FSHD).
"The root causes of FSHD have puzzled scientists and clinicians for decades, but some recent breakthroughs support the hypothesis that a gene called DUX4 is involved in the disease," Harper said. "Now that we have a gene target in DUX4, we can begin developing treatments that counteract that gene's toxic effects to muscle."
Harper noted that animal models of human diseases including FSHD are "important tools for testing therapeutics," but that "unfortunately, no such model exists for FSHD."
With colleagues, Harper plans to develop an FSHD research mouse model that contains DUX4 for use in the study of the disease, and the development and testing of potential therapies.
"I am hopeful that the FSHD field has turned a corner and that we have now entered a new era in which rational therapeutic strategies for FSHD are now possible," Harper said. "We believe this animal model will help in this effort."
Funding for this MDA grant began February 1, 2012.
Grantee: FSHD - Scott Harper, Ph.D.
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Grant - Summer 2012 - FSHD — Rossella Tupler, M.D., Ph.D.
MDA awarded a research grant totaling $260,000 over two years to Rossella Tupler, research assistant professor in the program of molecular medicine at the University of Massachusetts Medical School in Worcester. The funds will help support Tupler’s search for the molecular cause of facioscapulohumeral muscular dystrophy (FSHD).
FSHD has been associated with a reduction (eight or fewer) in the number of D4Z4 elements (alleles) and the subsequent expression (gene activity) of DUX4, Tupler explains. “However, studies of families in Italy, Brazil and the United States suggest that D4Z4 reduction and DUX4 expression are not sufficient to cause disease.”
In Italian families, a study of 253 unrelated people with FSHD revealed that 204 (80.6 percent) carry D4Z4 alleles with 1-8 units, 19 (7.5 percent) have D4Z4 alleles with 9-10 repeats, and 30 (11.8 percent) carry D4Z4 alleles with 11 repeats or more.
In the United States, family members with identical D4Z4 repeat lengths included members who did not have the disease and members with classical FSHD; not all had DUX4 activity.
“Collectively, these results indicate that those DNA anomalies are not sufficient to cause FSHD and additional factors are necessary to disease development,” Tupler says.
With colleagues, Tupler is working to identify genetic elements that can cause FSHD disease onset. The team is using a technique called whole-genome sequencing to study the DNA of 12 families from Italy, Brazil and the United States in which D4Z4 reduction does not correlate with the presence of disease.
“A profound rethinking of the genetic disease mechanism and modes of inheritance of FSHD is now required,” Tupler says, “and entirely new models and approaches are needed.”
Funding for this MDA grant began Aug. 1, 2012.
Grantee: FSHD — Rossella Tupler, M.D., Ph.D.
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Grant - Winter 2012 - FSHD - Charles Emerson, Ph.D.
MDA awarded a research grant totaling $600,000 over a period of three years to Charles Emerson, director and senior scientist at Boston Biomedical Research Institute in Watertown, Mass. The funds will help support Emerson’s efforts to identify genetic modifiers of the DUX4 gene; such modifiers potentially could become therapeutic targets in facioscapulohumeral muscular dystrophy (FSH, or FSHD).
Evidence from recent studies suggests that the DUX4 gene (which carries instructions for the DUX4 protein) is the primary underlying molecular cause of FSHD. However, the mechanism by which DUX4 causes the disease remains unclear.
Preliminary studies conducted in Emerson’s lab, involving a large group of FSHD-affected families, have confirmed the importance of the DUX4 gene as a factor in the FSHD disease process. The studies also have identified an alternative disease mechanism in which family-specific genetic modifiers modulate DUX4 function and gene expression (production of the DUX4 protein), effectively enhancing or suppressing disease signs, symptoms and severity.
Emerson’s team plans to identify the underlying mechanisms that modulate DUX4 via studies in FSHD-affected families. Once identified, the DUX4 gene disease modifiers potentially may serve as therapeutic targets for treatment of FSHD.
Funding for this MDA grant began February 1, 2012.
Update (Feb. 12, 2014): Charles Emerson has relocated to the University of Massachusetts Medical Center in Worcester.
Grantee: FSHD - Charles Emerson, Ph.D.
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Grant - Summer 2012 - FSHD — Joel Chamberlain, Ph.D.
Joel Chamberlain, research assistant professor in the department of medicine at the University of Washington in Seattle, was awarded an MDA research grant totaling $330,780 over three years to study a therapeutic approach called RNA interference (RNAi) for the treatment of facioscapulohumeral muscular dystrophy (FSHD).
"Despite the surprising complexity of the FSHD disease pathway, several lines of research converge to identify DUX4 protein production as the final step in the disease pathway," Chamberlain says.
Now, Chamberlain and colleagues are working to develop a therapy that targets production of DUX4 through interaction with DUX4 messenger RNA, or mRNA. (RNA is a chemical cousin to DNA and is involved in a chain of steps between DNA and cellular protein production.)
"To carry out RNAi, we will use an RNA that specifically binds to the DUX4 mRNA and directs the cell to destroy the target DUX4 mRNA," Chamberlain explains. "Once inside the muscle, the RNA made to carry out RNAi is produced continuously to treat disease and is expected to remain active for many years."
The team also is working to create a mouse model of FSHD that mimics the human disease. The investigators will use the model — as well as new cell and mouse models from collaborating laboratories — to test their DUX4 RNAi approach. They plan to make the model available to other researchers for the testing of additional potential therapies.
"We have developed this targeted approach, referred to as RNA interferenceor RNAi, to reverse disease," Chamberlain says. "It works well in mouse models of muscular dystrophies, and we are the only laboratory to have succeeded in changing the course of the disease by delivering this therapy to all the muscles of the mouse with a single intravascular (into a blood vessel) injection."
Funding for this MDA grant began Aug. 1, 2012.
Grantee: FSHD — Joel Chamberlain, Ph.D.
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Grant - Winter 2012 - DMD/BMD - Pura Muñoz-Canoves, Ph.D.
MDA awarded a research grant totaling $390,000 over a period of three years to Pura Muñoz-Canoves, ICREA research professor and cell biology coordinator at Pompeu Fabra University in Barcelona. The funds will help support Muñoz-Cánoves' research into strategies aimed at reducing muscle scarring (fibrosis) in people with Duchenne (DMD) and Becker (BMD)muscular dystrophies.
Fibrosis is a hallmark of DMD and a major factor in gauging disease severity. Fibrosis also compromises the efficacy of ongoing preclinical gene- and cell-delivery therapies. No treatment exists for reversing fibrosis in DMD; nor is there a clear understanding of the mechanisms underlying fibrosis development in dystrophic muscle (muscle that is deficient in dystrophin protein).
Muñoz-Canoves and colleagues plan to test whether and how a protein called PAI-1 (plasminogen activator inhibitor-1) may regulate inflammation-driven muscle degeneration and fibrosis development in muscular dystrophy.
"The discovery of new causes of fibrosis development in dystrophic muscle will provide an opportunity for new strategies to halt disease progression," Muñoz-Canoves said. "Since muscle fibrosis also represents a major obstacle for successful engraftment of stem cells in dystrophic muscle, targeting molecules promoting fibrosis appears to be an easy-to-test alternative to improve future DMD stem cell therapies.
Funding for this MDA grant began February 1, 2012.
Grantee: DMD/BMD - Pura Muñoz-Canoves, Ph.D.
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Grant - Summer 2012 - EDMD/LGMD/CMT — Yosef Gruenbaum, Ph.D.
MDA awarded a research grant totaling $300,009 over three years to Yosef Gruenbaum, professor and elected chairman at the Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, in Israel. The funds will help support Gruenbaum’s study of proteins called lamins and their role in muscle diseases such as Emery-Dreifuss (EDMD) and limb-girdle (LGMD) muscular dystrophies, and Charcot-Marie-Tooth disease (CMT).
Relatively little is known about the biological pathways that are affected in muscle cells that have lamin defects, and why these changes lead to muscular dystrophy, Gruenbaum says. Now, using a nematode (worm) model of EDMD, Gruenbaum and colleagues are studying those pathways.
The investigators will use a variety of techniques in structural biology, genetics, cell biology and live imaging to investigate the effects of EDMD-linked lamin mutations and determine how those mutations affect the normal health and development of muscles.
Gruenbaum’s work is expected to uncover the underlying mechanisms at work in EDMD and potentially could lead to the identification of new drug targets and the development of new therapies to treat EDMD.
Funding for this MDA grant began Aug. 1, 2012.
Grantee: EDMD/LGMD/CMT — Yosef Gruenbaum, Ph.D.
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Grant - Winter 2012 - DMD/BMD - Nick Menhart, Ph.D.
Nick Menhart, associate professor of biology at the Illinois Institute of Technology, was awarded an MDA research grant totaling $265,251 over a period of three years to study the properties of modified dystrophin proteins in Duchenne (DMD) and Becker (BMD) muscular dystrophies.
"One of the leading near-term prospects for meaningful treatment of DMD is exon skipping," Menhart said, in which cellular machinery cuts out flawed genetic instructions during protein synthesis, allowing for the production of shortened but at least partially functional dystrophin protein. (Deficient levels of dystrophin protein are the underlying cause of DMD and BMD.)
There are alternative ways to skip portions of the dystrophin gene to effect the repair achieved with exon skipping. Each produces differently modified proteins, having different properties that, in turn, make them better or worse repairs.
Menhart and colleagues plan to characterize different "repaired" versions of dystrophin protein in an attempt to determine which are superior and which will be "maximally effective," in any given person, based on their specific genetic defect.
"This is clearly an exciting and even inspirational time in muscular dystrophy research, as exon skipping holds promise as perhaps a truly effective treatment for DMD," Menhart said. "A number of issues remain in translating this to a clinical setting, but so far … the outlook is good."
Funding for this MDA grant began February 1, 2012.
Grantee: DMD/BMD - Nick Menhart, Ph.D.
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Grant – Winter 2013 – SMA - John Manfredi, Ph.D.
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.
Grantee: SMA - John Manfredi, Ph.D.
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Grant - Summer 2013 - DMD — Zejing Wang, M.D., Ph.D.
Zejing Wang, associate in clinical research at the Fred Hutchinson Cancer Research Center in Seattle, was awarded an MDA research grant totaling $300,000 over a period of three years to develop gene therapy forDuchenne muscular dystrophy (DMD) — with a focus on treating the heart — in a canine (dog) model of the disease.
DMD is caused by a mutation in the dystrophin gene. Gene therapy in DMD has focused on delivering the gene via a viral vector, or carrier, derived from adeno-associated virus (AAV).
“Despite encouraging results using AAV-mediated delivery of dystrophin into skeletal muscles,” says Wang, “few attempts have been made to genetically treat cardiomyopathy.” Cardiomyopathy, or disease of the heart muscle, remains a major cause of death in DMD, with few treatments available.
Mutations in dystrophin also occur naturally in some dog breeds, making them an important model for studying treatment of the disease.
“Our project will develop AAV-mediated gene therapy for treating cardiomyopathy in a preclinical DMD dog model that can then be applied to treat human DMD patients suffering from cardiac failure. The preclinical DMD dog model represents the most relevant animal model that faithfully mimics human DMD, reproducing many of its features not seen in the mouse model, including cardiomyopathy.”
Wang’s work will focus on improving the ability of the AAV vector to enter heart muscle cells and carry on long-term dystrophin production there.
“Developing strategies for efficient gene delivery and sustained transgene expression in heart muscle will increase the likelihood of achieving the goal of effective gene therapy and the ultimate reduction of mortality in DMD patients,” he says.
Funding for this MDA grant began August 1, 2013.
Grantee: DMD — Zejing Wang, M.D., Ph.D.
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Grant - Winter 2012 - DMD/BMD - Nadine Wiper-Bergeron, Ph.D.
MDA awarded a research grant totaling $312,422 over a period of three years to Nadine Wiper-Bergeron, assistant professor in the department of cellular and molecular medicine at the University of Ottowa in Ontario, Canada.
The funds will help support Wiper-Bergeron's work on improving muscle stem cell transplantation in Duchenne (DMD) and Becker (BMD) muscular dystrophies.
One potential therapy for DMD and BMD is the use of stem cells to repair disease-damaged muscle. Stem cells can help the damaged muscle become healthy, reversing both muscle weakness and loss of muscle mass.
"So far this approach has not been very successful," Wiper-Bergeron said, "because in addition to repair we need some of the stem cells to live in the muscle all the time, to make more cells that can help with repair and muscle growth."
In previous work, Wiper-Bergeron discovered a new approach to improving muscle stem cell transplantation procedures that involves using a drug to reprogram immature muscle cells called myoblasts back into stem cells before transplantation. Using a research mouse model of DMD, Wiper-Bergeron and colleagues will now test their new approach and compare it to existing strategies.
"It is our aim to make myoblast transplantation more efficient and sustainable long-term by repairing injured muscle and creating a population of healthy stem cells within the muscle," Wiper-Bergeron said. "Successful completion of this project will provide the necessary preclinical data to translate our basic science into the clinic."
Funding for this MDA grant began February 1, 2012.
Grantee: DMD/BMD - Nadine Wiper-Bergeron, Ph.D.
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Grant - Summer 2012 - EDMD — Mary Baylies, Ph.D.
Mary Baylies, professor in the program of developmental biology at Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center in New York, was awarded an MDA research grant totaling $399,269 over three years to study LMNA gene mutations and the role of a protein called esconsin in Emery-Dreifuss muscular dystrophy (EDMD).
EDMD can result from mutations in the lamin A/C (LMNA) gene, which carries instructions for the lamin A and lamin C proteins. But how mutations in LMNA cause muscle disease is unclear, Baylies explains.
In previous work, Baylies and colleagues have shown that lamin C interacts with ensconsin, which plays a key role in muscle development.
Now, Baylies is working to determine the nature of the interaction of the two proteins and how they regulate muscle function, with the goal of providing new insight into the cellular processes required for optimal muscle function and for different muscle diseases.
Studies are being conducted in a drosophila (fruit fly) research model, which Baylies says is "particularly well-suited to rapidly finding processes critical for muscle function, due to similarities with mammalian systems at both the genetic and cellular levels." In the model, using time-lapse imaging, Baylies' team gets "an unparalleled view" of cellular processes required for both the development and maintenance of muscle.
“This is an exciting period in muscle biology,” Baylies says. “Imaging approaches continue to evolve and allow us to ‘see’ muscle structure like never before.”
Funding for this MDA grant began Aug. 1, 2012.
Grantee: EDMD — Mary Baylies, Ph.D.
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Grant – Winter 2013 – SMA - Gary Bassell, Ph.D.
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.
Grantee: SMA - Gary Bassell, Ph.D.
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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.
Grant type: Research Grant
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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.
Grant type: Research Grant
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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.
Grant type: Research Grant
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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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