Science That Changes Lives
From breakthroughs in the lab to real-world progress—accelerating research that delivers results for families today.
Grant - Additional Grants 2012 - DMD — ReveraGen BioPharma
The Muscular Dystrophy Association has awarded $1,549,725 to ReveraGen BioPharma, a Rockville, Md., biotechnology company, for development of a dissociative glucocorticoid to treat Duchenne muscular dystrophy (DMD).
The goal is to develop a drug that provides the benefits of currently available glucocorticoids (such as prednisone and deflazacort), but that doesn't cause the negative side effects associated with these medications.
The award was made through MDA Venture Philanthropy (MVP), the drug development arm of MDA's translational research program, in partnership with the U.S. National Institutes of Health Therapeutics for Rare and Neglected Diseases (TRND) program.
ReveraGen BioPharma (formerly known as Validus BioPharma) has developed an experimental compound called VBP15, which may offer people with DMD the beneficial effects of prednisone and related drugs without the side effects.
The unwanted side effects, ReveraGen scientists have found, are largely due to the genomic mechanism of action in glucocorticoids. VBP15 does not appear to have this genomic mechanism of action, the scientists say, but it appears to retain the beneficial effects of glucocorticoids' nongenomic mechanisms, which are those that combat inflammation and stabilize cell membranes.
ReveraGen says mice with a DMD-like muscle disease benefited from treatment with this drug, showing improved muscle function, increased activity and reduced muscle inflammation.
Grantee: DMD — ReveraGen BioPharma
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Grant - Summer 2013 - CMT — Kleopas Kleopa, M.D.
Kleopas Kleopa, professor at the Cyprus Institute of Neurology and Genetics in Nicosia, Cyprus, was awarded an MDA research grant totaling $280,945 over a period of three years to develop gene therapy in a mouse model of X-linked Charcot-Marie-Tooth disease (CMT).
CMTX is due to mutations in the gene for connexin 32. This protein forms connections between layers of the insulating material around nerve cells, called myelin. Loss of connexin prevents the nerve cell from functioning properly, leading to muscle atrophy, weakness and sensory loss in the limbs. Kleopa has generated a mouse model of the disease, and has developed virus-like particles that can carry a functional copy of the gene, increasing connexin 32 protein production when delivered directly to the nerve.
Now, Kleopa will study a combination of gene delivery methods, including direct injection into the nerves, muscles and spinal cord. He also will examine treated mice for signs that the gene improves neuropathy (nerve abnormalities).
“Transgenic mice are particularly well suited for this study because treatment of peripheral neuropathy can only be validated in a vertebrate animal model, where the pathology can be studied in peripheral nerves,” Kleopa says. “Furthermore, this particular mouse model reproduces all major pathological aspects of the human disease, and therefore it is relevant to test potential treatments.
“In the last two decades research in the field of inherited neuropathies, especially the common forms, has provided many insights into the causes and mechanisms of disease. Developing genetic treatments, using the recently generated disease models, is an important and timely approach to also provide potential therapies for these disorders in the near future.”
Funding for this MDA grant began August 1, 2013.
Grantee: CMT — Kleopas Kleopa, M.D.
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Grant - Additional Grants 2013 - DMD — Christopher Penton, Ph.D.
Christopher Penton, who recently earned his doctorate in integrated biomedical sciences at Ohio State University in Columbus, was awarded an MDA research grant totaling $180,000 over three years to study ways to improve muscle regeneration and decrease muscle scar tissue formation in Duchenne muscular dystrophy (DMD).
Penton's grant was given through MDA's Bridge-to-Industry program, which connects promising new researchers to mentors in academia and industry. He'll work with one mentor at the University of Arizona in Tucson, Ariz., and another at the Oro Valley, Ariz., site of Sanofi, a multinational pharmaceutical company.
Grantee: DMD — Christopher Penton, Ph.D.
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Grant – Winter 2013 – DMD - Eric Hoffman, Ph.D.
Eric Hoffman, director of the Research Center for Genetic Medicine at Children's National Medical Center in Washington, D.C., was awarded an MDA research grant totaling $321,659 over a period of three years to study whether a process called asynchronous repair contributes to muscle degeneration in Duchenne muscular dystrophy (DMD).
Normal muscle repairs itself following injury, Hoffman points out, and that repair is a coordinated process within the muscle, taking place over about two weeks. “Our model is that muscle repair in DMD is asynchronous: Different regions of DMD muscle start the repair process at different times, and neighboring regions of the muscle get disoriented as to which time point in the two-week time frame of repair they are in. This results in inappropriate signals and failed regeneration.”
The implication of that model is that resynchronizing the repair process should provide therapeutic benefit. Hoffman has data suggesting that corticosteroid drugs, such as prednisone, which are effective in DMD, are “re-synchronization” agents for muscle repair. In this way, he thinks, they act similarly to some of the body’s own hormones that synchronize sleep/wake cycles and other time-related events in the body.
His work will further study this phenomenon and explore its implications for development of drugs that offer the same benefits as corticosteroids with fewer side effects. He thinks there also may be a role for using the clock to schedule dosing of current drugs, timing their delivery to improve efficacy and reduce side effects.
“It is an exciting time for development of therapeutic approaches in Duchenne muscular dystrophy and other neuromuscular diseases,” Hoffman says, noting that the growing understanding of the biology of the dystrophin gene and the effects of the dystrophin protein’s loss in muscle is leading to novel therapeutic approaches, and the focus on moving those new approaches to clinical trials has sped up the development of promising therapies.
Funding for this MDA grant began Feb. 1, 2013.
Grantee: DMD - Eric Hoffman, Ph.D.
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Grant - Summer 2012 - AMD — Dwight Koeberl, M.D., Ph.D.
MDA awarded a research grant totaling $253,812 over two years to Dwight Koeberl, associate professor in the department of pediatrics at Duke University Medical Center in Durham, N.C. The funds will help support Koeberl’s research on the development of gene therapy for acid maltase deficiency (AMD, or Pompe disease).
Koeberl is investigating a new therapy for Pompe disease, using a drug that improves the response to gene therapy. The drug, called a beta2-agonist, increases the amount of acid maltase (the enzyme that’s deficient in Pompe disease) taken up by muscle cells during gene therapy.
Koeberl and colleagues also are studying ways to stop the immune system from mounting a response and interfering with gene therapy.
Experiments are being conducted in a research mouse model of Pompe disease. The mouse, which lacks the gene for acid maltase, responds to therapy in a similar way to people with Pompe disease.
Favorable results in Koeberl’s study could lead to a new design for gene therapy in Pompe disease.
Funding for this MDA grant began Aug. 1, 2012.
Grantee: AMD — Dwight Koeberl, M.D., Ph.D.
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Grant – Winter 2013 – DMD - Deok-Ho Kim, Ph.D.
Deok-Ho Kim, assistant professor of bioengineering at the University of Washington in Seattle, was awarded an MDA research grant totaling $390,000 over a period of three years to develop better techniques for growing muscle for use in transplantation into a mouse model of Duchenne muscular dystrophy (DMD).
Muscle is a highly ordered tissue, with cells oriented in specific directions. Blood vessels and other muscle components must also take up specific positions in muscle for it to perform properly. Kim’s work is focused on developing materials that serve as scaffolds for growing muscle from stem cells in the laboratory, which then can be transplanted into living organisms to replace damaged muscle. These scaffolds work at the cellular scale to promote optimal growth of muscle in the most tissuelike patterns.
“This work aims to generate a functional muscle patch capable of providing long-term muscle strength and regenerative capacity, and to improve morbidity [symptoms] in DMD patients,” Kim says. “The optimal conditions will be utilized to create a robust muscle replacement with adequate force generation capacity. Since DMD is essentially a disease of deficiency of mature muscle cells, stem cell therapy presents an attractive route to cure the disease.”
His group also is working to integrate a muscle signaling molecule, calledS1P, into the growing muscle, to promote muscle stem cell proliferation and differentiation, and to help blood vessels grow properly in the muscle.
Funding for this MDA grant began Feb. 1, 2013.
Grantee: DMD - Deok-Ho Kim, Ph.D.
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Grant - Summer 2013 - CMT — Charlotte Sumner, M.D.
Charlotte Sumner, associate professor of neurology and neuroscience at Johns Hopkins University School of Medicine in Baltimore, Md., was awarded an MDA research grant totaling $300,000 over a period of three years to study the effects of the gene that causes one form of Charcot-Marie-Tooth disease (CMT).
CMT is characterized by the degeneration of peripheral nerves, resulting in disabling muscle weakness and sensory loss. One form of the disease, called type 2C CMT (CMT2C), is caused by mutations in a gene calledTRPV4 that helps control the flow of calcium in and out of cells. “Our long-term goal is to determine how mutations in TRPV4 lead to CMT2C and to develop treatments for this disease,” Sumner says.
Some effects of these gene mutations are known, but how they cause nerve degeneration is still unclear. Sumner has generated fly and mouse models of CMT2C in order to pursue that question. “The advantage of using fruit flies is that they allow us to rapidly evaluate the effects of multiple mutations and potential disease modifiers, as well as to assess TRPV4 function by calcium imaging.” The mouse, in turn, better mimics aspects of human physiology affected in the disease and can be used to test drugs.
“Together, these studies will provide important insights into the cellular and molecular mechanisms underlying TRPV4-mediated nerve disease, and in the future, we plan to use these fly and mouse models synergistically to develop new therapeutic interventions,” she says. “Because it is an ion channel expressed at the cell surface membrane [and therefore potentially accessible by therapeutic compounds], TRPV4 inhibition represents an attractive therapeutic strategy for patients with CMT2C.”
Funding for this MDA grant began August 1, 2013.
Grantee: CMT — Charlotte Sumner, M.D.
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Grant - Additional Grants 2013 - DMD — Anne Connolly, M.D.
Anne Connolly, a pediatric neurologist at Washington University in St. Louis, was awarded an MDA human clinical trial grant totaling $343,787 over a period of nearly three years (through April 30, 2016) to conduct a trial of prednisone in boys with Duchenne muscular dystrophy (DMD) who are younger than 2½ years old.
Connolly will conduct this phase 2 trial through the five centers that make up the MDA Duchenne Clinical Research Network.
Grantee: DMD — Anne Connolly, M.D.
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Grant - Summer 2012 - ALS — Marc Weisskopf, Sc.D., Ph.D.
MDA awarded a research grant totaling $301,614 over three years to Marc Weisskopf, associate professor of environmental and occupational epidemiology in the departments of environmental health and epidemiology at Harvard School of Public Health in Boston. The funds will help support Weisskopf’s search for nongenetic risk factors for amyotrophic lateral sclerosis (ALS).
“The search for nongenetic risk factors for amyotrophic lateral sclerosis (ALS) has progressed slowly over the past decades,” Weisskopf explains. “Although numerous hypotheses have been proposed, outside of age and male gender, no risk factor has emerged as a consistent and accepted predictor of risk.”
Weisskopf says that the lack of rigorous population-based studies of ALS with exposure data collected prospectively (before the onset of ALS) probably is one reason why scientists still have a poor understanding of very basic, fundamental aspects of the distribution of ALS in the population — for example, the distribution by race, ethnicity or socioeconomic status.
With colleagues, Weisskopf is studying the relationship between race/ethnicity, education and specific occupations, and the risk of developing ALS. The team is using the National Longitudinal Mortality Study (NLMS), a cohort study of almost 2.4 million men and women who completed the Current Population Survey (CPS) of the U.S. Bureau of the Census between 1973 and 2002.
"Our analytical approach is to examine how the factors determined at baseline relate to subsequent risk of death from ALS,” Weisskopf says. For this the investigators are using the National Death Index, which provides data on the causes of nearly all deaths in the United States since 1979.
“We have already identified 713 deaths from ALS, which, even as a minimum of the eventual total we will have, makes this study not only one of the largest of the few cohort studies with prospectively collected data, but also the only one that is representative of the U.S. population,” Weisskopf notes.
Funding for this MDA grant began Aug. 1, 2012.
Grantee: ALS — Marc Weisskopf, Sc.D., Ph.D.
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Grant - Summer 2013 - CCD — Robert Dirksen, Ph.D.
Robert Dirksen, professor of pharmacology and physiology at the University of Rochester Medical Center in Rochester, N.Y., was awarded an MDA research grant totaling $300,000 over a period of three years to evaluate calcium transport as a target for central core disease (CCD).
CCD is an inherited muscle disease that causes poor muscle tone and weakness, susceptibility to heat-related illnesses, and a risk of malignant hyperthermia, a dangerous reaction to certain anesthetic drugs. One cause of CCD is a defect in a muscle protein called the type 1 ryanodine receptor, which regulates the releases of stored calcium in the muscle. This release of calcium is critical for normal muscle contraction. Dirksen is working with a mouse model of CCD that carries a defect in the receptor. He will be exploring whether altering the receptor’s function with drugs or other means can ameliorate the disease in this model. In the process, he hopes to better define the pathways that lead to muscle damage in the disease.
“This project will define specific pathways that mediate core myopathy and muscle heat generation, and couple these fundamental advancements toward the testing and development of new drug interventions,” Dirksen says. “The benefits include an evaluation of the efficacy of targeted therapeutic interventions for the prevention of core myopathy and heat-induced sudden death in an established mouse model, and the likelihood that the results will lead to the first drug therapy for CCD and heat-related illness in humans.”
Funding for this MDA grant began August 1, 2013.
Grantee: CCD — Robert Dirksen, Ph.D.
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Grant - Additional Grants 2013 - ALS — National Institutes of Health (NIH) Laboratory
MDA has awarded $400,000 to National Institutes of Health (NIH) Laboratory of Neurogenetics researchers to perform exome sequencing on samples taken from 1,000 people with sporadic amyotrophic lateral sclerosis (ALS). The project will be led by neurologist Bryan Traynor, head of the Neuromuscular Diseases Research Group at the NIH in Bethesda, Md.
Data generated by the first-of-its-kind project will be made publicly available online and are expected to accelerate the pace of ALS research by helping scientists identify genes associated with the disease.
The exome-sequencing project, which is expected to be completed within 12 months, will produce genetic information for:
- 360 deceased individuals who had the sporadic (without any family history of the disease) form of ALS, for whom postmortem tissue samples are available; and
- 640 samples stored at the Coriell ALS Repository from people (both living and deceased) with sporadic ALS.
Exome sequencing data from a large number of people unaffected by ALS will be used for comparison in analysis.
Grantee: ALS — National Institutes of Health (NIH) Laboratory
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Grant - Additional Grants 2012 - DMD — Catabasis Pharmaceuticals
The Muscular Dystrophy Association has awarded $120,000 to Cambridge, Mass.-based Catabasis Pharmaceuticals. The award is part of a strategic partnership under which the pharmaceutical company will test two compounds — CAT-1004 and CAT-1040 — in the mdx research mouse model of Duchenne muscular dystrophy (DMD).
The award was made through MDA Venture Philanthropy (MVP), the drug development arm of MDA's translational research program.
Catabasis plans to demonstrate in the new four-month study that CAT-1004 reduces inflammation in muscle tissue and improves muscle function. It will compare CAT-1004, CAT-1040 and prednisolone to identify the most effective compound. If favorable results are obtained, the company plans to begin clinical trials in people with DMD.
Catabasis has completed a safety, tolerability and pharmacokinetics (what the body does to a drug) study of CAT-1004 in healthy human volunteers over an eight-week trial period. It has an open Investigational New Drug application for the compound with the U.S. Food and Drug Administration, which allows it to conduct clinical trials of the investigational drug in the United States.
Grantee: DMD — Catabasis Pharmaceuticals
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Grant - Summer 2012 - ALS — Christine Vande Velde, Ph.D.
MDA awarded a research grant totaling $358,242 over three years to Christine Vande Velde, research assistant professor in the department of medicine at the University of Montreal Hospital Research Center in Montreal, Quebec (Canada). The funds will help support Vande Velde’s study of the role of TDP43 and the stress granule mechanism in amyotrophic lateral sclerosis (ALS).
Vande Velde and colleagues are looking at the interplay between genetic susceptibility and environmental exposures to toxins that are thought to be relevant in ALS. It’s known that cells exercise a variety of mechanisms to mediate recovery following exposure to environmental stress, one of which is the formation of proteins and RNA molecules into clumps called stress granules.
In previous work, Vande Velde’s team has indicated that TDP43 plays an important role in stress granule formation.
“In particular, this grant focuses on TDP43 and its regulation of an important cell survival mechanism: the formation of stress granules,” Vande Velde explains. Her team will use a combination of cellular and rodent models to dissect the stress granule mechanism in which TDP43 operates and determine the impact of ALS-causing mutations on this pathway.
“This is an exciting area for ALS research,” Vande Velde says, “as demonstrated by a recent convergence on this topic by many groups.”
Funding for this MDA grant began Aug. 1, 2012.
Grantee: ALS — Christine Vande Velde, Ph.D.
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Grant - Spring 2014 - ALS - Aaron Gitler, Ph.D.
Aaron Gitler, an associate professor of genetics at Stanford University in Stanford, Calif., was awarded an MDA research grant totaling $253,800 over three years to investigate how mutations in the gene for a protein called profilin 1 cause amyotrophic lateral sclerosis (ALS).
In experiments conducted in cells, Gitler and colleagues have found that the profilin 1 protein may be a regulator of "stress granules" — tiny cellular factories that stores and process RNA molecules — and that further understanding this function may provide insights that lead to ALS therapy development.
Funding for this MDA grant began May 1, 2014.
Grantee: ALS - Aaron Gitler, Ph.D.
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Grant - Summer 2013 - CCD — Kurt Beam, Ph.D.
Kurt Beam, professor of physiology and biophysics at the University of Colorado at Denver, was awarded an MDA research grant totaling $300,000 over a period of three years to study two proteins that, when they malfunction, cause central core disease (CCD).
Muscle contraction in response to a nerve signal involves the interaction of two proteins: the dihydropyridine receptor (DHPR), which “senses” the electrical signal, and the ryanodine receptor (RyR1), which controls the release of calcium ions. Mutations in either one lead to CCD, as well as other muscle disorders. Beam will introduce the genes for these proteins into mouse muscle and nonmuscle cells. For both cell types, he says, researchers will measure the tiny electrical currents (less than a billionth of an ampere) produced by the DHPR. Fluorescence microscopy and calcium indicator dyes will be used to monitor movements of calcium inside individual cells; and confocal microscopy used to determine whether DHPRs and RyR1s are close to one another in the cells. The structure of these proteins then will be analyzed at a higher resolution by means of electron microscopy.
“Using these techniques, we hope to identify exactly what parts of the two proteins touch one another,” and how these sites of interaction and the overall shapes of the two proteins are affected by disease-causing mutations, Beam says.
“Although we have known for upward of 20 years that the DHPR and RyR1 are crucial for muscle contraction, we still do not understand the mechanism of their interaction, or exactly how disease-causing mutations affect this interaction,” says Beam. His research will attempt to better understand those interactions in order to define possible therapeutic targets for CCD and related muscle diseases.
Funding for this MDA grant began August 1, 2013.
Grantee: CCD — Kurt Beam, Ph.D.
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Grant - Additional Grants 2012 - ALS — NeuRx Diaphragm Pacing System (DPS)
The Muscular Dystrophy Association has committed $750,000 to help support a phase 2 clinical trial assessing the ability of the NeuRx Diaphragm Pacing System (DPS) to improve respiratory function and quality of life in people with amyotrophic lateral sclerosis (ALS).
Developed by Synapse Biomedical in Oberlin, Ohio, the DPS received approval from the U.S. Food and Drug Administration (FDA) on Sept. 29, 2011, as a “humanitarian use device” (HUD) for the treatment of chronic hypoventilation (inadequate breathing) in ALS. The surgically implanted device stimulates the movement of the diaphragm, the main muscle used in breathing.
In people with ALS who have chronic breathing problems and whose diaphragms are still able to respond to electrical stimulation, the DPS may forestall or negate the need for invasive ventilation.
Investigators will compare respiratory function and quality of life in people with ALS who use the DPS and those who receive the current standard treatment.
Grantee: ALS — NeuRx Diaphragm Pacing System (DPS)
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Grant – Winter 2013 – CMT - Vera Fridman, M.D.
Vera Fridman, at Massachusetts General Hospital in Boston, was awarded an MDA clinical research training grant totaling $180,000 over a period of two years to the effects of Serine in people with a form of Charcot-Marie-Tooth (CMT) disease called hereditary sensory and autonomic neuropathy type 1 (HSAN1).
CMT is the most commonly inherited neurological disorder, affecting 1 in 2,500 people worldwide. It is a slowly progressive disorder, causing degeneration of the peripheral nerves that control sensory information coming from the limbs. HSAN is a rare genetic neuropathy that causes severe numbness, weakness and ulceration of the feet and hands.
Two abnormal lipids (fat-like substances) have been identified in the blood of both humans and mice with HSAN1. It has been shown that levels of these lipids can be reduced by administering the amino acid serine, and that mice treated with serine have better motor and sensory function.
Fridman’s goal is to determine the effect of serine on symptoms of people with HSAN1 in order to assess whether serine supplementation may be an effective therapy for the disease.
Funding for this MDA grant is effective July 1, 2013.
Grantee: CMT - Vera Fridman, M.D.
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Grant - Summer 2013 - CCD — Julio Vergara, Ph.D.
Julio Vergara, professor of physiology at the University of California, Los Angeles, was awarded an MDA research grant totaling $300,000 over a period of three years to study the basis of central core disease (CCD).
CCD is an inherited muscle disease that causes poor muscle tone and weakness, susceptibility to heat-related illnesses, and a risk of malignant hyperthermia, a dangerous reaction to certain anesthetic drugs. One cause of CCD is a defect in a muscle protein called the type 1 ryanodine receptor, which regulates the releases of stored calcium in the muscle. This release of calcium is critical for normal muscle contraction.
Much remains to be understood about the connections between CCD and alterations in the ryanodine receptor, Vergara says. His work will pursue these connections in mice carrying the mutant gene.
“Our research aims to answer the following questions,” Vergara explains. “Why do mutated receptors predispose muscle fibers to triggering agents that lead to fulminant [sudden, rapid, severe] malignant hyperthermia episodes? And, how does dantrolene, a commonly used drug, prevent fulminant MH episodes?”
He will investigate these issues using a combination of state-of-the art optical and electrophysiological approaches in adult muscle fibers from animal models, and comparing calcium release among mice with different mutations in the receptor gene.
“The mice have become a great tool to investigate the molecular and pathophysiological alterations underlying the mysteriously intertwined malignant hyperthermia/CCD human pathology,” Vergara says.
Funding for this MDA grant began August 1, 2013.
Grantee: CCD — Julio Vergara, Ph.D.
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Grant – Winter 2013 – CMT - Ronald K. Liem, Ph.D.
Ronald Liem, professor of pathology and cell biology at Columbia University Medical Center in New York, N.Y., was awarded an MDA research grant totaling $318,264 over a period of three years to study the progression of disease in a mouse model of type 2E Charcot-Marie-Tooth (CMT) disease.
CMT is the most commonly inherited neurological disorder, affecting 1 in 2,500 people worldwide. It is a slowly progressive disorder, causing degeneration of the peripheral nerves that control sensory information coming from the limbs. CMT2E is caused by mutations in the gene for a protein called neuronal intermediate filament light (NFL). NFL provides stability to axons, the long extensions of muscle-controlling motor nerve cells called motor neurons that allow them to control muscle contractions.
Liem’s lab has created a mouse model of CMT2E by introducing a mutated copy of the gene. Their preliminary results indicate the mouse develops many of the same features as people with the disease, including deficits of movement and hearing. “We believe that this new mouse model is likely the best model of CMT type 2E and will allow us to study the progression of the disease at a level that is not possible in human subjects. We expect that the mouse model will also be useful for testing therapeutic compounds when they become available,” Liem says.
Liem will be performing detailed developmental and anatomic studies to follow the progression of the disease in mice, and to learn more about exactly how the mutation causes problems. One focus will be on the effects of the mutation on mitochondria, the cell’s "powerhouses," which are believed to be involved in CMT.
“These studies will give us a better understanding of the mechanisms by which nerve damage occurs as a result of this mutation,” Liem says. “We expect that the mouse model also will be useful for testing therapeutic compounds when they become available.”
Funding for this MDA grant began Feb. 1, 2013.
Grantee: CMT - Ronald K. Liem, Ph.D.
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Grant - Additional Grants 2012 - ALS — Bridge-to-Industry Training Program
MDA launched its innovative Bridge-to-Industry (B2I) program with a $180,000 grant over three years to postdoctoral fellow Archi Joardar at the University of Arizona in Tucson, to develop two promising drug candidates for the treatment of amyotrophic lateral sclerosis (ALS).
MDA’s Bridge-to-Industry, or B2I, is a pilot project that trains promising researchers in translational research by providing experience both in academia and the biopharmaceutical industry.
Through the B2I program, MDA is able to fund investigators to conduct drug development research under the guidance of two mentors: one experienced in academic research and the other experienced in the industrial side of drug development.
Daniela Zarnescu, associate professor in neuroscience and molecular & cellular biology at the College of Science, University of Arizona (UA), will provide academic mentoring to Joardar. Zarnescu currently has an active MDA research grant for her work on gene and drug discovery research in a fruit fly model that carries a mutation in the ALS-associated TDP43 gene.
Joardar will receive mentoring on the industry side from Chris Hulme, co-director of the BIO5 Institute in Oro Valley, Ariz. Hulme is an expert in small-molecule drug design and the development of chemical-based methods to hasten the drug discovery process.
Mentorship under Zarnescu and Hulme will provide Joardar with a unique environment in which to train while furthering the development of two promising ALS drug candidates identified in Zarnescu's work. Joardar will evaluate the ability of each drug to reduce neurotoxicity caused by ALS-associated mutations in the TDP43 gene..
Grantee: ALS — Bridge-to-Industry Training Program
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Grant - Summer 2012 - ALS — Alex Parker, Ph.D.
MDA awarded a research grant totaling $231,300 over three years to Alex Parker, assistant professor in the department of pathology and cellular biology at the University of Montreal Hospital Research Center in Montreal, Quebec (Canada). The funds will help support Parker's study of cellular stress response in neurodegeneration associated with amyotrophic lateral sclerosis (ALS).
Mutations in the genes for TDP43 and FUS proteins have been linked to ALS, Parker notes, "and they cause persistent cellular stress that ultimately overwhelms the neuron’s [nerve cell's] coping mechanisms, leading to cell death."
With colleagues, Parker is working to better understand a critical cell survival mechanism known as the endoplasmic reticulum stress response, which is known to reduce the toxicity caused by mutant TDP43 and FUS proteins. (The endoplasmic reticulum is a cellular compartment involved in the transport of proteins and other biological substances within cells.)
Using a C. elegans (nematode, or roundworm) model of ALS, Parker aims to identify small molecules that modify the ER stress response to help neurons overcome protein toxicity and stave off cell death.
Parker's work potentially could led to the identification of therapeutic targets and development of therapies for people with ALS.
"There are very few drugs available to treat neurodegeneration, and they are not very effective," Parker says. "We hope our findings accelerate drug discovery and development for ALS patients."
Funding for this MDA grant began Aug. 1, 2012.
Grantee: ALS — Alex Parker, Ph.D.
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Grant – Winter 2013 – CMS - Michael Linhoff, Ph.D.
Michael Linhoff, a postdoctoral fellow at Oregon Health and Science University in Portland, Ore., was awarded an MDA development grant totaling $119,944 over a period of two years to study neuromuscular junction defects in congenital myasthenic syndrome (CMS).
A common cause of CMS is mutation of the RAPSN gene. This gene encodes a protein, rapsyn, that helps other proteins assemble properly on the surface of the muscle at the neuromuscular junction (NMJ). The NMJ is where the motor neuron from the nervous system contacts the muscle. The neuron releases chemicals that cause the muscle to contract.
Linhoff and colleagues have shown that a RAPSN mutation causes defects not only on the muscle, but also on the neuron where it contacts the muscle. Mutation reduces the effectiveness with which the neuron releases its chemicals, reducing muscle contraction and causing weakness.
He is studying this effect in zebrafish, a well-characterized lab model for the study of the interaction between nerve and muscle. “Our lab previously identified a mutant fish line [with a mutation in the RAPSN gene], called twitch once, that exhibits use-dependent fatigue similar to patients with CMS,” Linhoff says.
He will be using high-resolution imaging technologies to study the mechanisms underlying the dysfunctions seen in the twitch once fish. Using the images, he will develop three-dimensional models of the zebrafish neuromuscular junction to discover the details of the neuronal defect caused by the mutation.
“Determining the molecular mechanisms underlying this dysfunction may yield potential therapeutic targets to correct use-dependent fatigue in patients with congenital myasthenias,” Linhoff says.
Funding for this MDA grant began Feb. 1, 2013.
Grantee: CMS - Michael Linhoff, Ph.D.
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Grant – Winter 2013 – CMD, LGMD - Sebahattin Cirak, M.D.
Sebahattin Cirak, pending assistant professor at the Children’s National Medical Center in Washington, D.C., was awarded an MDA development grant totaling $180,000 over a period of three years to hunt for elusive genes that cause congenital muscular dystrophy (CMD) and limb-girdle muscular dystrophy (LGMD).
Though CMD and LGMD are different diseases, they are similar in one respect: Both can be caused by a variety of different mutations in the same gene, and about half the time, the causative mutations are unknown.
New mutation hunting techniques have become available in the past several years that allow researchers to find gene mutations by examining the gene’s “messenger,” called RNA. Genes carry the instructions for making a new protein. To do so, a gene creates a “working copy” of itself using RNA. By carefully analyzing that RNA with a variety of techniques, it is possible to discover new gene mutations.
Cirak will use RNA extracted from muscle biopsies of people with CMD or LGMD. “I hope to uncover these elusive mutations by studying RNA, using the latest available sequencing technology,” he says.
“This research will improve the methods for molecular diagnostics of the muscular dystrophies,” he adds, with the goal of providing more families with the knowledge of the cause of their disease. In addition, the discovery of new genes can reveal new information about the exact causes of the disease, potentially suggesting new avenues for developing treatments.
Funding for this MDA grant began Feb. 1, 2013.
Grantee: CMD, LGMD - Sebahattin Cirak, M.D.
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Grant – Winter 2013 – BMD, DMD - Linda Baum, M.D., Ph.D.
Linda Baum, professor and vice chair of pathology and laboratory medicine at the Geffen School of Medicine at the University of California, Los Angeles, was awarded an MDA research grant totaling $405,000 over a period of three years to study molecules on the muscle surface that regulate important aspects of cellular communication and survival.
All cells, including muscle cells, are coated with an elaborate set of molecules called glycoproteins. These perform multiple critical functions, including: attaching cells to one another, relaying messages between cells, and ultimately, helping the cell survive. While animal models replicate important aspects of muscle diseases such as Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), the glycoproteins on animal cells differ from those of human cells. These differences may mean that mouse models of DMD do not completely represent the disease that affects people, Baum says.
The precise functions of many of the different glycoproteins on human muscle cells are unknown. Baum’s research will include characterizing the entire set of human muscle glycoproteins, determining the function of a subset of them, and screening for compounds that improve muscle function through their effect on these glycoproteins.
Because she is interested in human-specific glycoproteins, Baum will be studying human cells derived from skin biopsies of boys with DMD and their parents. She will “reprogram” these cells in the lab to become muscle cells, which can then be used for drug screening.
“By using these human muscle cells to screen drug libraries to identify compounds that improve cell function, our aim is to rapidly target therapeutic agents that will be efficacious in patients with Duchenne and Becker muscular dystrophies,” Baum says.
Her results also may be applicable for individuals who have forms of congenital muscular dystrophy, such as Walker-Warburg syndrome, that result from defects in cellular glycosylation (the process of creating glycoproteins).
Funding for this MDA grant began Feb. 1, 2013.
Grantee: BMD, DMD - Linda Baum, M.D., Ph.D.
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Grant - Summer 2013 - ALS — James Shorter, Ph.D.
James Shorter, associate professor of biochemistry and biophysics at the University of Pennsylvania in Philadelphia, was awarded an MDA research grant totaling $300,000 over a period of three years to develop an experimental approach targeted at protein aggregates in amyotrophic lateral sclerosis (ALS).
In almost all cases of ALS, aggregates or “clumps” of protein accumulate in motor neurons, which may contribute to the death of these cells. Shorter is exploring the possibility that disaggregating [breaking apart] these proteins and returning them to their normal state may be therapeutic. “Unfortunately, mammalian cells have limited ability to disaggregate and renature [properly refold] proteins,” Shorter says, so he employs an enzyme from yeast, called Hsp104.
Shorter is planning to generate variants of the Hsp104 protein that are even more active at breaking up aggregates of the various proteins known to be involved in ALS, including TDP43, FUS and SOD1. After generating such variants, he will test their abilities in yeast and fruit flies, another standard lab model.
“Hsp104-based disaggregases [enzymes that break up aggregates] likely hold great potential as ALS therapeutics,” he says, “as well as for unraveling the role of protein aggregation in ALS pathogenesis.”
Funding for this MDA grant began August 1, 2013.
Grantee: ALS — James Shorter, Ph.D.
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