Innovations in Science

Grant - Additional Grants 2012 - DMD/BMD — Tivorsan Pharmaceuticals

MDA has awarded $1 million to Tivorsan Pharmaceuticals for development of TVN-102, an experimental treatment for Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD).

The award was made through MDA's Venture Philanthropy (MVP) arm, part of MDA's translational research program. Tivorsan is a biotechnology company located in Providence, R.I.

TVN-102 is an experimental drug based on biglycan, a naturally occurring protein found in the membrane surrounding each muscle fiber. Biglycan is part of a cluster of proteins located at intervals in the membrane. These shock-absorbing clusters appear to protect the membrane as muscle fibers contract and relax.

Tivorsan hopes to have completed animal testing and other FDA-required studies of TVN-102 and to request permission for human trials of the drug by late 2012. The company hopes to begin human testing of TVN-102, probably in healthy volunteers without DMD or BMD, in 2012 or 2013.

If the preliminary studies show the drug is safe and well-tolerated and that it has the potential to be effective in treating DMD or BMD, tests in people with one of these diseases will likely follow.

Grantee: DMD/BMD — Tivorsan Pharmaceuticals

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Grant – Winter 2013 – DMD - Joan Taylor, Ph.D.

Joan Taylor, associate professor of pathology at the University of North Carolina in Chapel Hill, was awarded an MDA research grant totaling $396,000 over a period of three years to study how muscle cells repair damaged membranes.

When a muscle contracts, it puts a great stress on the membrane that surrounds and encloses the muscle cell. That stress is reduced, and the membrane protected from rupture, by proteins that link the inside of the cell to the outside. Those proteins include dystrophin and the dystroglycan complex. Mutations in these proteins are the cause of Duchenne muscular dystrophy (DMD) and other forms of muscular dystrophy, which are characterized by repeated tears in the muscle cell membrane.

Membranes can repair themselves, says Taylor, “however, the specific mechanisms by which this occurs are incompletely understood.” Her team has identified a protein called GRAF1 that appears to be intimately involved in the repair process, and she has developed a mouse model to explore the function of GRAF1. She will now fully test the hypothesis that GRAF1 is necessary to promote membrane re-sealing, using a laser-based membrane injury model in skeletal muscle cells to identify the underlying mechanisms.

Taylor also will explore the capacity of GRAF1 (administered by a gene-therapy-based approach) to diminish muscle pathology in dystrophic mice. “These studies will undoubtedly lead to new and important directions for therapies to target a multitude of congenital dystrophies,” she says.

Funding for this MDA grant began Feb. 1, 2013.

Grantee: DMD - Joan Taylor, Ph.D.

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Grant - Additional Grants 2013 - DMD — Robert Griggs, M.D.

Robert Griggs, a professor of neurology at the University of Rochester in New York state, received an MDA grant of $237,316 over three years to cover travel costs for North American participants in a clinical trial of prednisone and deflazacort, two corticosteroid drugs used to treat Duchenne muscular dystrophy (DMD). The average participant and his parent or guardian will have to stay overnight near the trial site to complete all procedures at each visit — a considerable expense for many families.

In an attempt to balance the side effects and benefits of corticosteroids for DMD, multiple dosing regimens have been in use. This multinational trial, known as FOR-DMD, will compare the three most widely used regimens of two corticosteroids to determine the optimal dosing schedule.

Grantee: DMD — Robert Griggs, M.D.

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Grant - Summer 2013 - CMT — Peter Hiesinger, Ph.D.

Peter Hiesinger, associate professor at the University of Texas Southwestern Medical Center in Dallas, was awarded an MDA research grant totaling $300,000 over a period of three years to investigate the causes of type 2B Charcot-Marie-Tooth disease (CMT2B).

CMT2B is caused by mutations in a gene called rab7. The protein made from the gene performs a critical function in the degradation of debris in all cells. “Even though the gene is known, it is unclear how the mutations found in patients affect the gene’s function,” Hiesinger says. Without knowing how the mutation causes disease, it is difficult to design a therapy to treat it. He has developed models of the disease that suggest the mutation causes the protein to no longer be active, and that this loss of function affects nerve cells before other cells in the body.

“Our findings explain the genetic dominance [only one mutant copy of the gene, from either parent, is needed to develop the disease] and reveal a particular sensitivity of nerve cells for a defect in debris removal,” says Hiesinger. “This discovery opens the door for an understanding and a potential therapy of CMT2B based on the molecular manipulation of the underlying cause.

“Importantly,” he adds, “we suggest an increase of rab7 function as a therapeutic opportunity, in contrast to the currently suggested reduction of mutant gene function.”

In this project, Hiesinger will test this hypothesis of disease in a fly model of CMT2B and investigate rab7 function in detail.

Funding for this MDA grant began August 1, 2013.

Grantee: CMT — Peter Hiesinger, Ph.D.

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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 - 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 - 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 - 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 - 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 - 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 - 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 - 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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