Science That Changes Lives
From breakthroughs in the lab to real-world progress—accelerating research that delivers results for families today.
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.
Grant type: Research Grant
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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.
Grant type: Research Grant
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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 - 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 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 – 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.
Grant type: Research Grant
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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.
Grant type: Research Grant</