Innovations in Science
Grant – Winter 2013 – ALS - Jeffrey Rothstein, M.D., Ph.D.
Jeffrey Rothstein, professor of neurology and neuroscience at Johns Hopkins University in Baltimore, Md., was awarded an MDA research grant totaling $392,706 over a period of three years to study the most common genetic cause of amyotrophic lateral sclerosis (ALS), using cells derived from patient skin samples.
“Understanding the pathophysiology of and developing new therapeutics for ALS and dementias such as Alzheimer’s disease and frontotemporal dementia has been an enormous challenge,” Rothstein says. Among the biggest roadblocks has been the difficulty of developing appropriate models of the disease — ones that closely parallel the human condition.
A new technique to overcome this barrier is the use of induced pluripotent stem cells (iPS cells). These cells can be taken from the skin of an individual with ALS and treated with growth factors to return them to a less differentiated state. From this stem-cell-like condition, they can then be induced to develop into any cell type, including muscle-controlling nerve cells called motor neurons or other cells of the central nervous system.
Rothstein plans to use iPS cells from people whose ALS is caused by a mutation in the C9ORF72 gene, the most common genetic cause of ALS. By comparing these cells to cells from unaffected individuals, Rothstein hopes to find a molecular signature for the disease-causing effects of the mutant gene. That signature, or biomarker, can then be used to quickly assess the effects of potential therapies on the cells. “The use of these human cells may allow us to efficiently and quickly develop a drug therapy for the C9ORF72 form of ALS,” he says.
Funding for this MDA grant began Feb. 1, 2013.
Grantee: ALS - Jeffrey Rothstein, M.D., Ph.D.
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Grant - Summer 2015 - LGMD - Shinichi Takayama, M.D., Ph.D.
Shinichi Takayama, a research associate professor at Boston University School of Medicine, was awarded an MDA grant totaling $300,000 over three years to identify potential therapeutic targets in limb-girdle muscular dystrophy (LGMD). Takayama will study the scaffolding protein BAG3 and its interactions with proteins implicated in myofibrillar myopathies and LGMD. This innovative approach could reveal that a group of diseases have a common pathogenesis caused by aberrant protein assembly and could point the way to future therapeutic strategies.
Funding for this MDA research grant began Aug. 1, 2015.
Grantee: LGMD - Shinichi Takayama, M.D., Ph.D.
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Grant – Winter 2013 – ALS - Heather Durham, Ph.D.
Heather Durham, professor at the Montreal Neurological Institute of McGill University in Quebec, Canada, was awarded an MDA research grant totaling $355,936 over a period of three years to study the consequences of mutations in the FUS gene for muscle-controlling nerve cells called motor neurons.
Mutations in FUS are known to be a cause of amyotrophic lateral sclerosis (ALS), a disease that involves the death of motor neurons. The FUS protein binds to RNA, which cells use to bring protein-making instructions from the nucleus to other parts of the cell. FUS joins up with other proteins to do this. FUS mutations can disrupt the protein's ability to move through the cell and bind properly to other cell components to make these transport complexes.
“In neurons, the distribution of these RNA-containing complexes is particularly important for maintaining connections with other neurons, and for responding to the level of neuronal activity and stress,” Durham says. Her research will study the details of how mutations affect trafficking of FUS and its partners, including RNA, and how these abnormalities relate to or affect cellular adaptive responses. Understanding these important changes may shed light on how these and other ALS-causing gene mutations lead to the death of motor neurons.
“This is a very exciting time in ALS research,” she says. “The recent discoveries of new genes associated with ALS point us toward the commonalities and differences in the multiple disorders we call ALS. Those commonalities will not only help us to identify targets for therapy, but will establish the best preclinical models in which to evaluate their efficacy.”
Funding for this MDA grant began Feb. 1, 2013.
Grantee: ALS - Heather Durham, Ph.D.
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Grant - Summer 2015 - LGMD - Criss Hartzell, Ph.D.
Criss Hartzell, professor of cell biology at Emory University School of Medicine in Atlanta, Ga., was awarded an MDA research grant to elucidate the mechanisms underlying type 2L limb-girdle muscular dystrophy (LGMD), caused by mutations in the ANO5 gene. Hartzell will examine the role the ANO5 protein plays in trafficking and fusion of cell membranes during muscle repair, and how mutations in this protein disrupt these functions. The work may uncover unique targets around which to base new therapeutic approaches.
Funding for this MDA research grant began Aug. 1, 2015.
Grantee: LGMD - Criss Hartzell, Ph.D.
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Grant - Summer 2015 - FSHD - Antoine de Morrée, Ph.D.
Antoine de Morrée, a postdoctoral scholar at Palo Alto Veterans Institute for Research and Stanford University in Palo Alto, Calif., was awarded an MDA development grant totaling $180,000 over three years to test a way to stop muscles from making toxic DUX4 protein as a possible treatment for facioscapulohumeral muscular dystrophy (FSHD). The goals of de Morrée’s work are to understand how cells make stabile RNA messages, and to develop a way to destabilize RNA messages that allow cellular machinery to produce the DUX4 protein. These studies have the potential to lead to new treatments that will reduce the toxicity in the muscles of patients with FSHD.
Funding for this MDA development grant began Aug. 1, 2015.
Grantee: FSHD - Antoine de Morrée, Ph.D.
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Grant – Winter 2013 – ALS - Giovanni Manfredi, M.D., Ph.D.
Giovanni Manfredi, professor of neurology and neuroscience at Weill Medical College of Cornell University in New York, N.Y., was awarded an MDA research grant totaling $355,317 over a period of three years to study whether calcium imbalance in nervous system support cells called astrocytes contributes to amyotrophic lateral sclerosis (ALS).
The death of muscle-controlling nerve cells called motor neurons cause the symptoms of ALS, but in recent years it has become clear that astrocytes contribute to the death of motor neurons. Astrocytes normally help motor neurons; and how and why they harm them in ALS is unknown.
“We have developed a novel hypothesis to explain the mechanisms of astrocyte toxicity in familial ALS, which involves intracellular calcium signaling,” Manfredi says. Calcium serves as an internal sensor for regulating many cellular functions. “All cells, including astrocytes, have to keep calcium levels in check at all times.”
His work has suggested that changes within the astrocyte lead to impaired calcium regulation and secretion of toxic molecules, which in turn cause motor neuron death. He plans to further test this hypothesis by manipulating the amount of oxidative stress to which astrocytes are exposed, both in cell culture and in animal models, and studying how they handle calcium in response. His preliminary work has identified a protein that may be centrally involved in regulating calcium in astrocytes, and he will further study this protein to determine if it is a potential target for therapy.
“Numerous exciting reports have emerged in ALS research in the past few years, strongly suggesting that ALS is the product of the combined action of multiple cell types in the nervous systems, including neurons and glial cells,” Manfredi says. (Astrocytes are a type of glial cell.) “These new developments in ALS research will accelerate the understanding of the disease and the development of effective therapies.”
Funding for this MDA grant began Feb. 1, 2013.
Grantee: ALS - Giovanni Manfredi, M.D., Ph.D.
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Grant - Summer 2015 - FA - Sanjay Bidichandani, M.B.B.S., Ph.D.
CMRI Claire Gordon Duncan Chair in Genetics and Professor of Pediatrics Sanjay Bidichandani, at University of Oklahoma Health Sciences Center in Oklahoma City, was awarded an MDA research grant totaling $300,000 over three years to address clinically and scientifically important questions regarding the use of existing and novel HDAC inhibitors to increase levels of the frataxin protein in Friedreich’s ataxia (FA). Bidichandani and colleagues recently found that the mechanism of gene silencing in FA involves shutting off the FXN gene promoter, a region of the gene that typically controls when and how much a gene should be turned on. They are now working to identify therapeutic molecules that will effectively reverse FXN promoter silencing in FA, and to determine the precise mechanism by which promoter inactivation and reactivation occurs.
Funding for this MDA research grant began Aug. 1, 2015.
Grantee: FA - Sanjay Bidichandani, M.B.B.S., Ph.D.
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Grant - Summer 2015 - DMD - Yetrib Hathout, Ph.D.
Yetrib Hathout, associate professor in the department of integrative systems biology at Children’s National Medical Center in Washington, D.C., was awarded an MDA research grant totaling $300,000 over three years to develop a panel of molecular biomarkers, detectable in blood, for Duchenne muscular dystrophy (DMD). If successful, these biomarkers could help clinicians monitor progression of the disease and determine whether a drug or treatment is working. In addition, they may shed light on the molecular mechanisms of muscle degeneration and point the way toward new therapeutic strategies.
Funding for this MDA research grant began Aug. 1, 2015.
Grantee: DMD - Yetrib Hathout, Ph.D.
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Grant – Winter 2013 – ALS - Fenghua Hu, Ph.D.
Fenghua Hu, research scientist at Cornell University in Ithaca, N.Y., was awarded an MDA research grant totaling $360,000 over a period of three years to study the effects of TDP43 gene mutations in a model of amyotrophic lateral sclerosis (ALS).
Mutations in the TDP43 gene have been shown to cause ALS in some instances. Even in individuals with ALS who do not have TDP43 mutations, the TDP43 protein usually clumps together abnormally, forming aggregates within muscle-controlling nerve cells called motor neurons. “This suggests that the misbehavior of TDP43 protein could cause neurodegeneration,” Hu says.
The TDP43 protein found in the aggregates is often just a piece of the whole protein, indicating it has been cleaved. It is also often “tagged” with a smaller protein, called ubiquitin, used by the cell to mark a protein for destruction and recycling. “However, the role of TDP43 fragments and ubiquitination in disease progression is still not clear,” Hu says.
She plans to develop a model of ALS using zebrafish, a small and fast-growing fish used as a lab model for the study of many diseases. In the fish, she will study how TDP43 protein fragments induce toxicity and cause neurodegeneration, which should help researchers develop better targets for therapy in ALS.
Funding for this MDA grant began Feb. 1, 2013.
Grantee: ALS - Fenghua Hu, Ph.D.
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Grant - Summer 2015 - DMD - Thomas Rando, M.D., Ph.D.
Thomas Rando, at Palo Alto Veterans Institute for Research and Stanford University in California, was awarded an MDA research grant totaling $300,000 over three years to develop a mouse model — a so-called “reporter mouse” — that will reflect and quantify degeneration of skeletal muscles. Importantly, scientists will be able to use the mouse to test the ability of cell and gene therapies to alter the progression of Duchenne muscular dystrophy (DMD) and other muscular dystrophies.
Funding for this MDA research grant began Aug. 1, 2015.
Grantee: DMD - Thomas Rando, M.D., Ph.D.
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Grant - Summer 2015 - DMD - Rebecca Willcocks, Ph.D.
Rebecca Willcocks, an adjunct research assistant scientist in the department of physical therapy at the University of Florida in Gainesville, has been awarded an MDA development grant totaling $171,422 over three years to study magnetic resonance biomarkers in Duchenne muscular dystrophy (DMD). Willcocks will use magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to describe how DMD affects the shoulder, upper arm and forearm muscles of boys, ages 9 to 18 years, with DMD. She also will examine the relationship between MRI and MRS measurements in the arm muscles and arm function (reaching, grasping and moving objects). If the MRI and MRS measures are sensitive to the state of the disease and predictive of functional performance, they may be useful in evaluating the impact and effectiveness of potential therapies in nonambulatory boys and men in clinical trials.
Funding for this MDA development grant began Aug. 1, 2015.
Grantee: DMD - Rebecca Willcocks, Ph.D.
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Grant - Summer 2015 - DMD - Natassia Vieira, Ph.D.
Natassia Vieira, an investigator at Biosciences Institute, University of São Paulo - São Paulo, Brazil, was awarded an MDA development grant totaling $180,000 to study a genetic mechanism that appears to compensate for mutations in the gene that causes Duchenne muscular dystrophy (DMD). Vieira will study the mechanism by which overexpression of a protein called Jagged1 protects dogs and fish carrying a DMD-causing mutation from exhibiting the typical symptoms and progression of the disease. She aims to validate the mechanism as a new and potentially very exciting new drug target for DMD.
Funding for this MDA development grant began Aug. 1, 2015.
Grantee: DMD - Natassia Vieira, Ph.D.
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Grant – Winter 2013 – ALS - Daniela Zarnescu, Ph.D.
Daniela Zarnescu, associate professor of molecular and cellular biology at the University of Arizona in Tucson, was awarded an MDA research grant totaling $405,000 over a period of three years to investigate whether anti-diabetic drugs may reduce the death of muscle-controlling nerve cells called motor neurons in amyotrophic lateral sclerosis (ALS).
Zarnescu and colleagues have developed a model of ALS in fruit flies that carry a mutant form of the TDP43 gene, a known cause of ALS. “TDP43 has emerged as a common denominator for a significant number of ALS cases,” Zarnescu says, “because mutations in TDP43 can cause ALS and, in addition, normal TDP43 protein associates with cellular inclusions found in autopsy samples from ALS patients, regardless of the genetic cause of the disease.”
She has used this model to test candidate drugs that are already approved for other uses. Her work led to the identification of several types of drugs currently used to treat diabetes that also reduced death among the ALS research flies. The drugs work to affect signaling by the hormone insulin, suggesting that the insulin pathway may be a critical survival pathway in motor neurons.
“Given that our candidate drugs are already approved for use in humans, our work in the fly model will provide a rapid and cost-effective strategy to help determine whether these drugs could be adapted for the treatment of ALS,” Zarnescu says.
Funding for this MDA grant began Feb. 1, 2013.
Grantee: ALS - Daniela Zarnescu, Ph.D.
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Grant - Summer 2015 - DMD - James Ervasti, Ph.D.
James Ervasti, professor in the department of biochemistry, molecular biology & biophysics at the University of Minnesota in Minneapolis, was awarded an MDA research grant totaling $300,000 over three years to develop methods of identifying non-invasive biomarkers that can be measured in all patients across the entire spectrum of Duchenne muscular dystrophy (DMD) disease severity. With colleagues, Ervasti will measure metabolites in a large group of DMD patients and in several different mouse models of DMD to compare the metabolite levels with disease severity. The studies could provide new insight into the skeletal muscle dysfunction in DMD patients and identify new biomarkers that significantly improve clinical trial design and assessment while opening clinical trials to non-ambulatory DMD patients.
Funding for this MDA research grant began Aug. 1, 2015.
Grantee: DMD - James Ervasti, Ph.D.
Grant type: Research Grant
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Grant - Summer 2015 - DMD - Donghoon Lee, Ph.D.
Donghoon Lee, a research associate professor in the department of radiology at the University of Washington in Seattle, was awarded an MDA research grant totaling $300,000 over three years to develop imaging biomarkers for Duchenne muscular dystrophy (DMD). Lee will develop noninvasive magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) methodologies that reflect specific underlying tissue and cellular events associated with degeneration and regeneration in muscular dystrophy. Since the equipment used for MRI and MRS is widely available and used in clinical practice, advances in the application of these techniques could quickly lead to improvements in outcome measures for clinical trials in DMD.
Funding for this MDA research grant began Aug. 1, 2015.
Grantee: DMD - Donghoon Lee, Ph.D.
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Grant - Summer 2015 - DMD - DeWayne Townsend, D.V.M., Ph.D.
DeWayne Townsend, assistant professor at the University of Minnesota in Minneapolis, was awarded an MDA research grant totaling $300,000 over three years to study the role of oxygen in the Duchenne muscular dystrophy (DMD)-affected heart. With this work, Townsend aims to determine whether decreases in oxygen (called hypoxia) are especially injurious to the heart in DMD, as cells affected by the mutation that causes DMD may use oxygen less efficiently, have difficulty generating energy at low oxygen levels, and be more susceptible to damage following even normally tolerated stresses. The presence of a significant role for hypoxia in the progression of DMD-associated cardiomyopathy (a leading cause of death in DMD) would have a direct impact on decisions about when to initiate ventilator support.
Funding for this MDA research grant began Aug. 1, 2015.
Grantee: DMD - DeWayne Townsend, D.V.M., Ph.D.
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Grant - Summer 2015 - DMD - Dada Pisconti, Ph.D.
Dada Pisconti, at the University of Liverpool, United Kingdom, was awarded an MDA research grant totaling $300,000 over three years to study how the environment established by fibrosis and inflammation affects the maintenance and regenerative properties of muscle stem cells in Duchenne muscular dystrophy (DMD). Pisconti will work to determine whether serine protease inhibitor proteins are involved in the DMD disease process. If successful, these studies could lead to a fast development opportunity for therapy, because drugs targeting serine protease activity exist and might be rapidly repurposed.
Funding for this MDA research grant began Aug. 1, 2015.
Grantee: DMD - Dada Pisconti, Ph.D.
Grant type: Research Grant
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Grant - Summer 2015 - DD - Aikaterini Kontrogianni-Konstantopoulos, Ph.D.
Aikaterini Kontrogianni-Konstantopoulos, an associate professor in the department of biochemistry and molecular biology at the University of Maryland School of Medicine in Baltimore, was awarded an MDA research grant totaling $300,000 over three years to study how the Myosin Binding Protein-C family of proteins may regulate contractile function of skeletal muscle in distal muscular dystrophy (DD). Kontrogianni-Konstantopoulos’ work will shed light on how mutations in this protein lead to disease and may have clinical relevance not only for distal arthrogryposis, but also for other muscular dystrophies as well.
Funding for this MDA research grant began Aug. 1, 2015.
Grantee: DD - Aikaterini Kontrogianni-Konstantopoulos, Ph.D.
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Grant - Summer 2015 - CMT - Robert Burgess, Ph.D.
Robert Burgess, a professor at The Jackson Laboratory in Bar Harbor, Maine, has been awarded an MDA research grant totaling $300,000 over three years. Burgess and co-investigator Scott Harper, associate professor at Nationwide Children’s Hospital Center for Gene Therapy in Columbus, Ohio, will test an AAV gene therapy approach to specifically block the altered form of the GARS gene in a newly developed mouse model for type 2D Charcot-Marie-Tooth disease (CMT). Successful completion of these studies could lead to a new therapy for type 2D CMT and provide a proof of principle for this approach that may be applicable to other types of CMT.
Funding for this MDA research grant began Aug. 1, 2015.
Grantee: CMT - Robert Burgess, Ph.D.
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Grant - Summer 2015 - CMT - Robert Baloh, M.D., Ph.D.
Robert Baloh, associate professor-in-residence in the department of neurology at the University of California, Los Angeles, has been awarded an MDA research grant totaling $300,000 over three years to study the molecular mechanism of type 2A Charcot-Marie-Tooth disease (CMT) due to mutations in the Mitofusin 2 (MFN2) gene. Baloh has developed a new mouse model that he will use in his research to test whether gene therapy with a gene called MFN1 could serve as a therapeutic approach.
Funding for this MDA research grant began Aug. 1, 2015.
Grantee: CMT - Robert Baloh, M.D., Ph.D.
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Grant - Summer 2015 - CMT - Daniel Summers, Ph.D.
Daniel Summers, a postdoctoral research scholar in the department of genetics at Washington University School of Medicine in St. Louis, was awarded an MDA development grant totaling $180,000 over three years to investigate how activation of a protein called SARM leads to the loss of metabolites that are essential for the health of peripheral nerves in Charcot-Marie-Tooth disease (CMT). Further knowledge of this pathway may highlight whether blocking SARM may be a novel therapeutic approach for CMT and other peripheral neuropathies.
Funding for this MDA development grant began Aug. 1, 2015.
Grantee: CMT - Daniel Summers, Ph.D.
Grant type: Development Grant
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Grant - Summer 2015 - CMT - Aaron DiAntonio, M.D., Ph.D.
Alan A. and Edith L. Wolff Professor of Developmental Biology Aaron DiAntonio at Washington University school of Medicine in St. Louis was awarded an MDA research grant totaling $300,000 over three years to identify novel targets to block nerve degeneration in Charcot-Marie-Tooth disease (CMT). DiAntonio will perform a genetic screen in fruit flies to identify genetic suppressors of nerve degeneration and then test these targets in human nerve cells in a dish. The resulting targets will be potential candidates for the treatment of peripheral neuropathy and other disorders in which motor axons are lost.
Funding for this MDA research grant began Aug. 1, 2015.
Grantee: CMT - Aaron DiAntonio, M.D., Ph.D.
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Grant - Summer 2015 - CMS - Ricardo Maselli, M.D.
Ricardo Maselli, a professor in the neurology department at the University of California Davis was awarded an MDA research grant totaling $300,000 over three years to test whether transplantation of stem cells engineered to secrete a needed protein could be a beneficial treatment strategy in congenital myasthenic syndromes (CMS). If studies in a mouse model are successful, testing could advance to patients. Promising results could steer the field to a new therapeutic strategy for CMS.
Funding for this MDA research grant began Aug. 1, 2015.
Grantee: CMS - Ricardo Maselli, M.D.
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Grant - Summer 2015 - CMD - Peter Currie, Ph.D.
Peter Currie, professor of medicine at Monash University in Australia, was awarded an MDA research grant totaling $300,000 over three years to test two therapeutic strategies for laminin alpha-2 deficiency in a zebrafish model of congenital muscular dystrophy (CMD). The work will support or refute the hypothesis that muscle fiber detachment is the primary defect in laminin 2-deficient muscular dystrophies, and could prompt a paradigm shift for therapeutic strategies in these diseases.
Funding for this MDA research grant began Aug. 1, 2015.
Grantee: CMD - Peter Currie, Ph.D.
Grant type: Research Grant
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Grant - Summer 2015 - CMD - Liza Pon, Ph.D.
Liza Pon, professor of pathology and cell biology at Columbia University in New York was awarded an MDA research grant totaling $300,000 over three years to study the underlying mechanisms at work in CHKB congenital muscular dystrophy (CMD). Pon also will test whether therapies that promote function of a protein known as the ryanodine receptor (RyR), which plays a critical role in contraction of skeletal and heart muscle, can promote muscle function or prevent muscle degeneration in a mouse model for CHKB CMD and in muscle cells taken from CHKB CMD patients.
Funding for this MDA research grant began Aug. 1, 2015.
Grantee: CMD - Liza Pon, Ph.D.
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