Grant - Winter 2017 - DM – Maurice Swanson, Ph.D.
Maurice Swanson, professor in the department of molecular genetics and microbiology at the University of Florida College of Medicine in Gainesville, was awarded an MDA research grant totaling $300,000 over a period of three years to generate new research models for myotonic dystrophy (DM) and use them to test new therapeutic strategies.
One of the limiting factors for myotonic dystrophy therapy development has been a lack of animal models that recapitulate many of the aspects of the disease in humans.
With colleagues, Swanson will generate new mouse models for both type 1 and type 2 DM.
The team will use the models to investigate the molecular basis for the clinical differences and similarities between the two types of the disease. In addition, the team will test a new therapeutic strategy that involves blocking the production of disease-causing DMPK and CNBP expanded RNAs in all tissues of the body, including the central nervous system, by using small molecules that cross the blood-brain barrier.
If successful, the work could lead to the development of a new therapeutic strategy for DM.
Funding for this MDA research grant began Feb. 1, 2017.
Grantee: Maurice Swanson, Ph.D.
Grant type: Research Grant
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Grant - Winter 2017 - MG – Henry Kaminski, M.D.
Henry Kaminski, Meta A. Neumann Professor and Chair of the department of neurology at George Washington University in Washington, D.C., was awarded an MDA research grant totaling $367,187 over three years to test a therapeutic strategy in cell and rat models of myasthenia gravis (MG), with the intent to demonstrate the feasibility of the approach and then move to human clinical trials.
Most people with MG have antibodies against the acetylcholine receptor, located at the nerve-muscle communication point. These antibodies activate the complement system, which is a normal defense mechanism of the body to fight infections. But in MG the acetylcholine receptor antibodies, with the help of complement, destroy the muscle surface that transmits signals from the nerve.
Kaminski and colleagues have developed a technology that is designed to inhibit complement only at the nerve-muscle junction, thereby stopping the injury to the muscle and preserving normal complement function everywhere else in the body. The team will test their agent in cells and rat models of MG, with the intent to demonstrate the feasibility of the approach.
Kaminski’s work may lead to the development and testing of a complement inhibitor drug that has increased efficacy, limited side effects and lower cost of production than other similar drugs in development today.
Funding for this MDA research grant began Feb. 1, 2017.
Grantee: Henry Kaminski, M.D.
Grant type: Research Grant
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Grant - Winter 2017 - Mitochondrial myopathy – Eduardo Balsa Martinez, Ph.D.
Eduardo Balsa Martinez, a postdoctoral fellow in the division of cancer biology at the Dana-Farber Cancer Institute in Boston, was awarded an MDA development grant totaling $180,000 over three years to identify therapeutic targets in mitochondrial diseases such as mitochondrial myopathy.
Mitochondria are small organelles found in cells. They are considered the “powerhouse” of the cell and are necessary to sustain life and support growth. When mitochondrial function is disrupted, high energy-demanding tissues such as brain and muscles are severely affected.
Restoring the cell’s ability to produce energy represents one therapeutic approach to treating mitochondrial disease.
With colleagues, Balsa Hernandez has developed a platform using cells carrying mitochondrial mutations to screen for genes and compounds that could restore mitochondrial function. In addition, they have uncovered a compound that targets a specific class of protein called BRD4. In studies, the compound was shown to prevent cell death and alleviate some of the symptoms caused by mitochondrial mutations.
Now, using mouse models designed to mimic the features found in human mitochondrial diseases, the team will determine how the compound works at the molecular level and evaluate its safety and therapeutic potential.
If successful, Balsa Hernandez’ work could form the basis for the development of drugs designed to ameliorate the effects of mitochondrial myopathy and other mitochondrial diseases.
Funding for this MDA development grant began Feb. 1, 2017.
Grantee: Eduardo Balsa Martinez, Ph.D.
Grant type: Development Grant
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Grant - Winter 2017 - McArdle disease – Nigel Laing, Ph.D.
Nigel Laing, National Health and Medical Research Council principal research fellow and head of the Neurogenetic Disease Laboratory at the Harry Perkins Institute of Medical Research, The University of Western Australia in Perth, was awarded an MDA research grant totaling $149,412 over two years to test two potential gene therapy treatment approaches for McArdle disease.
McArdle disease occurs when an important enzyme that is required to break down energy stores in skeletal muscle is missing.
With colleagues, Laing will to test two potential gene therapy methods for treatment of McArdle disease in a mouse model. For the first method, the team will deliver a normal version of the missing enzyme — an approach Laing says is likely to cause an immune reaction as the body of a McArdle disease mouse (or a human patient) will not have seen the enzyme before.
In a parallel set of experiments, the team will deliver an alternative version of the enzyme. This alternative enzyme is normally found in adult brain tissue and in fetal skeletal muscle, where it has the same function as the missing enzyme in skeletal muscles. It is not missing in individuals with McArdle disease. Because the alternative version is so similar to the adult skeletal muscle enzyme, it may sufficiently restore enzyme function in McArdle disease muscle if it is increased to adequate quantities — without causing an immune reaction, as the body has already been exposed to it.
Laing’s work, if successful, could lead to therapies that could improve muscle function in McArdle disease.
Funding for this MDA research grant began Feb. 1, 2017.
Grantee: Nigel Laing, Ph.D.
Grant type: Research Grant
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Grant - Winter 2017 - LGMD and Miyoshi myopathy – Marshall Hogarth, Ph.D.
Marshall Hogarth, postdoctoral fellow at Children’s Research Institute, Children’s National Health System in Washington, D.C., was awarded an MDA development grant totaling $180,000 over three years, to improve understanding of the molecular and cellular basis of the fatty replacement of muscle in type 2B limb-girdle muscular dystrophy (LGMD) as well as in Miyoshi myopathy.
Gradual replacement of muscle with fat is a feature of the pathology in both LGMD2B patients and mice with insufficient levels of dysferlin protein. Loss of muscle function in LGMD2B patients and mice is correlated with the fatty conversion of muscle, which may suggest that the processes leading to fatty muscle conversion are significant to the disease process.
In a mouse model of dysferlin deficiency, Hogarth and colleagues have mimicked age- and injury-induced fatty conversion and degeneration of muscle similar to that observed in LGMD2B patients. In addition, they have developed a new mouse model where fatty conversion and muscle dysfunction associated with dysferlin deficiency has been attenuated.
Now, in studies conducted in these mouse models, the team will work to determine the cellular mechanism underlying the fatty replacement of LGMD2B muscle and identify approaches to prevent the process in order to inhibit loss of muscle function.
If successful, Hogarth’s work could enable therapeutic development to slow or block disease progression by preventing muscle loss. It could also compliment gene therapy approaches to restore dysferlin expression and improve muscle repair.
Funding for this MDA development grant began Feb. 1, 2017.
Grantee: LGMD and Miyoshi myopathy – Marshall Hogarth, Ph.D.
Grant type: Development Grant
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Grant - Winter 2017 - FSHD – Charles Emerson, Ph.D.
Charles Emerson, professor of neurology and director of the Wellstone Muscular Dystrophy Program at University of Massachusetts Medical School in Worcester, was awarded an MDA research grant totaling $300,000 over three years, to study the contribution of genes and epigenetic modifications to facioscapulohumeral muscular dystrophy (FSHD) disease processes.
With colleagues, Emerson will work to increase understanding about the underlying molecular processes that determine disease severity, which can vary greatly, in FSHD.
The team will investigate the molecular expression and functions of FSHD disease genes through a comparison of skeletal muscles produced from stem cells derived from FSHD patients with early-onset severe infantile disease, and muscle produced by stem cells derived from FSHD patients with adult-onset mild disease.
If successful, Emerson’s work may enable identification of new drug targets and development of stem cell and drug therapies designed specifically to reduce or eliminate the symptoms of FSHD.
Funding for this MDA research grant began Feb. 1, 2017.
Grantee: Charles Emerson, Ph.D.
Grant type: Research Grant
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Grant - Winter 2017 - FA – Vijayendran Chandran, Ph.D.
Vijayendran Chandran, assistant professor in the department of pediatrics, University of Florida School of Medicine in Gainesville, was awarded an MDA research grant totaling $300,000 over three years to identify biomarkers in Friedreich’s ataxia (FA).
FA is caused by deficiency of the frataxin protein. With colleagues, Chandran has developed a mouse model for FA, that exhibits symptoms similar to those seen in people with the disease and in which he can control the onset and progression of disease.
Now the team will use the new model to identify biomarkers at different stages of disease that could predict disease onset and progression in humans.
If successful, Chandran’s work could help clinicians and researchers measure and predict disease progression, and aid in preclinical development and testing of potential FA treatments.
Funding for this MDA research grant began Feb. 1, 2017.
Grantee: Vijayendran Chandran, Ph.D.
Grant type: Research Grant
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Grant - Winter 2017 - DMD – Emanuela Gussoni, Ph.D.
Emanuela Gussoni, associate professor at Boston Children’s Hospital and Harvard Medical School in Boston, was awarded an MDA research grant totaling $297,985 over three years to study the role of a protein called CD82 in Duchenne muscular dystrophy (DMD).
In DMD, muscle stem cells are thought to be continuously active as they attempt to repair muscle fibers that are damaged due to lack of dystrophin and/or its associated proteins.
Gussoni and colleagues recently identified a cell surface marker for muscle stem cells in human and mouse muscle, named CD82. CD82 is expressed in human muscle satellite cells. Importantly, CD82 protein expression is reduced in human DMD and in the muscles of a DMD mouse model called mdx5cv.
The team will now study the function of CD82 in muscle stem cells to determine how the decreased expression of this protein in dystrophic cells is linked to disease progression. The studies will provide the groundwork for developing future therapies aimed at boosting expression of CD82 as a way to stabilize the cell membrane, along with muscle stem cell function, in DMD-affected muscle.
Funding for this MDA research grant began Feb. 1, 2017.
Grantee: Emanuela Gussoni, Ph.D.
Grant type: Research Grant
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Grant - Winter 2017 - DMD – James Novak, Ph.D.
James Novak, postdoctoral associate at Children’s Research Institute, Children’s National Health System in Washington, D.C., was awarded an MDA development grant totaling $180,000 over three years to examine why exon skipping drugs are most effective at getting to muscles that are actively undergoing repair. The work, co-funded by the Hearst Foundation, is expected to help optimize the effectiveness of exon skipping therapies in Duchenne muscular dystrophy (DMD).
DMD is characterized by muscle degeneration, inflammation and fibrosis (scarring), resulting from mutations in the dystrophin gene that inhibit production of dystrophin protein.
Exon skipping, a promising therapeutic strategy for DMD, employs antisense oligonucleotides to permit the production of shortened but partially functional dystrophin protein. However, challenges including limited drug uptake and variable dystrophin restoration have been barriers in clinical testing.
Understanding the mechanisms that impinge on drug delivery is crucial to improving efficacy and advancing next-generation therapies.
Novak and colleagues have shown that exon skipping drugs are best able to get into muscle cells that are undergoing repair. Now the team will investigate muscle regeneration and inflammation as therapeutic targets to improve delivery of exon skipping drugs. Investigation of antisense delivery into different mouse models with differing pathologies is expected to delineate factors and define mechanisms that regulate exon skipping.
If successful, Novak’s work will clarify the disease processes that contribute to efficient delivery and efficacy of leading antisense agents and help to make this promising therapeutic strategy for Duchenne more effective.
Funding for this MDA development grant began Feb. 1, 2017.
Grantee: James Novak, Ph.D.
Grant type: Development Grant
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Grant - Winter 2017 - DMD – Mattia Quattrocelli, Ph.D.
Mattia Quattrocelli, at the Center for Genetic Medicine, Northwestern University – Chicago, was awarded an MDA development grant totaling $180,000 over three years to study the effects of glucocorticoids on muscle repair and regeneration in Duchenne muscular dystrophy (DMD). The work, co-funded by the American Association of Neuromuscular & Electrodiagnostic Medicine Foundation for Research and Education (AANEM), is expected to help improve glucocorticoid-based treatment strategies in DMD.
Currently, people with DMD often are treated with chronic administration of glucocorticoids, although the mechanism by which steroids exert their effect on DMD is not well understood. Furthermore, the use of steroids in other forms of muscular dystrophy is not recommended. And chronic steroid use is associated with significant side effects including obesity, loss of bone mass, growth suppression and — paradoxically — muscle degeneration, too.
With colleagues, Quattrocelli will examine the effects of steroids on dystrophic muscle repair and regeneration potential, and investigate the molecular circuitries linking these drugs to known pathways important in the pathology of muscular dystrophies.
Quattrocelli’s work could provide valuable insights for understanding the action of steroids with regard to the role of other genetic mutations influencing the course of muscular dystrophy. The work will address muscle repair mechanisms as potential drug targets for muscular dystrophies and could help design corticosteroid regimens to support muscle repair and boost muscle growth, while minimizing side effects.
Funding for this MDA development grant began Feb. 1, 2017.
Grantee: Mattia Quattrocelli, Ph.D.
Grant type: Development Grant
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Grant - Winter 2017 - DMD – Tejvir Khurana, M.D., Ph.D.
Tejvir Khurana, professor in the department of physiology & Pennsylvania Muscle Institute, Perleman School of Medicine at the University of Pennsylvania in Philadelphia, was awarded an MDA research grant totaling $240,000 over three years to test a therapeutic strategy for Duchenne muscular dystrophy (DMD).
DMD muscle is susceptible to damage because it is missing dystrophin, a protein that sits at the muscle cell membrane and is critical for maintaining the muscle’s structural integrity. One potential therapeutic strategy involves compensating for the lack of dystrophin with a similar protein. One such protein, utrophin, is a naturally occurring structural protein that closely resembles dystrophin and performs a very similar function in the muscle.
With colleagues, Khurana aims to develop utrophin upregulation as a therapeutic strategy to rescue dystrophic muscle in DMD. The team has found that utrophin expression is inhibited by the micro RNA let-7c, and will work to develop an inhibitor to this miRNA and test whether disinhibition of utrophin improves muscle function in a mouse model of DMD.
If successful, the work will demonstrate the potential of this therapeutic strategy and pave the way toward its development for use in humans.
Funding for this MDA development grant began Feb. 1, 2017
Grantee: Tejvir Khurana, M.D., Ph.D.
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Grant - Winter 2017 - CMT – Kleopas Kleopa, M.D.
Kleopas Kleopa, professor and senior consulting neurologist at the Cyprus Institute of Neurology and Genetics, Cyprus School of Molecular Medicine, in Nicosia, Cyprus, was awarded an MDA research grant totaling $119,999 over a period of two years to test whether gene therapy treatment after disease onset could lead to functional improvements in CMT1X, the second most common form of Charcot-Marie-Tooth disease (CMT).
With previous MDA support, Kleopa and colleagues pioneered a gene therapy approach to treat the X-linked form of CMT, showing that a single lumbar injection of the gene that is mutated in the disease was associated with production of normal protein in nerves and improvement of peripheral nerve health and motor performance.
Kleopa’s new work, co-funded by the CMT Association, will advance and expand on this approach as his team examines whether repeated injections can lead to increased protein levels, and tests whether treatment at later stages of the disease can lead to improvement similar to that seen for treatment in the early stages.
Funding for this MDA research grant began Feb. 1, 2017.
Grantee: Kleopas Kleopa, M.D.
Grant type: Research Grant
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Grant - Winter 2017 - CMT – Erik Storkebaum, Ph.D.
Erik Storkebaum, independent Max Planck Research group leader at the Max Planck Institute for Molecular Biomedicine in Münster, Germany, was awarded an MDA research grant totaling $291,000 over three years to study the underlying mechanisms that drive the disease process in Charcot-Marie-Tooth disease (CMT).
Familial forms of neurodegenerative diseases are caused by mutations in single genes. In an individual person, a single mutation in a neurodegeneration gene causes disease, but across a range of people, different mutations in the same disease gene typically occur. Furthermore, for a given neurodegenerative disease, distinct disease genes often encode proteins that function in the same molecular or cellular pathway.
It is unknown whether mutations in related genes, or even in a single gene, cause disease through a common molecular mechanism, or whether different mutations cause disease through disparate mechanisms. This is a key question from a therapeutic perspective, as common mechanisms may allow for unified therapeutic approaches.
Mutations in five distinct genes encoding proteins called tRNA synthetases, which play an essential role in the production of proteins in cells, all cause CMT. Storkebaum and colleagues will work with fruit fly models of CMT to determine whether different mutations across four distinct tRNA synthetase genes cause disease through the same or through disparate molecular mechanisms.
Should the results indicate that all mutations cause disease through a similar molecular mechanism, it could guide development of a common therapeutic approach to treat all forms of CMT caused by mutations in tRNA synthetases.
Funding for this MDA research grant began Feb. 1, 2017.
Grantee: Erik Storkebaum, Ph.D.
Grant type: Research Grant
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Grant - Winter 2017 - ALS – Mohamed Farah, Ph.D.
Mohamed Farah, assistant professor of neurology and neuroscience at Johns Hopkins School of Medicine in Baltimore, was awarded an MDA research grant totaling $300,000 over three years to investigate whether a drug currently in development for Alzheimer’s disease can improve function in ALS (amyotrophic lateral sclerosis).
It’s thought that repair and regrowth of motor nerve endings might result in restoration of function for motor neuron diseases such as ALS — particularly slowly progressing forms.
In previous work, Farah and colleagues discovered that manipulating the amount of BACE1, an enzyme whose job it is to cut other proteins into pieces, enhances peripheral nerve regeneration in mice. Those studies prompted the team to explore the possibility that using a drug to reduce BACE1 might be an effective means to encourage motor axon regrowth at an early stage of motor neuron disease in mice.
Because BACE1 inhibitors currently are being developed and tested as potential therapies for Alzheimer’s disease, Farah’s work could lead to rapid development and clinical evaluation of BACE1 inhibitors in motor neuron diseases. If successful, the approach could enhance the quality of life of people with ALS or other motor neuron diseases.
Funding for this MDA research grant began Feb. 1, 2017.
Grantee: Mohamed Farah, Ph.D.
Grant type: Research Grant
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Grant - Winter 2017 -ALS – Fen-Biao Gao, Ph.D.
Fen-Biao Gao, professor at the University of Massachusetts Medical School in Worcester, was awarded an MDA research grant totaling $300,000 over three years to identify new drug targets for ALS (amyotrophic lateral sclerosis).
C9ORF72 repeat expansion is the most common genetic mutation known to cause ALS. In this and several other forms of the disease, damage to DNA has been identified as a common, downstream pathway that can contribute to the death of nerve cells called motor neurons.
To understand how the C9 mutation drives the disease, Gao and colleagues have generated induced pluripotent stem cells (iPSCs) from C9 ALS patients and developed them into motor neurons and cortical neurons that recapitulate some key features observed in diseased cells, such as abnormal accumulation of RNA “clumps” and production of unusual toxic proteins. The team will use the iPSC-derived motor neurons as well as fruit fly models of ALS to investigate what causes DNA damage, and will perform a screen to identify new drug targets based on the findings.
Gao’s work will greatly enhance understanding of ALS disease mechanisms and may lead to the identification of key components in the DNA damage pathway that may serve as targets for therapy development.
Funding for this MDA research grant began Feb. 1, 2017.
Grantee: Fen-Biao Gao, Ph.D.
Grant type: Research Grant
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Grant - Winter 2017 - ALS – Jiou Wang, M.D., Ph.D.
Jiou Wang, associate professor at Johns Hopkins University in Baltimore, was awarded an MDA research grant totaling $300,000 over three years to work toward a better understanding of the underlying cause of ALS (amyotrophic lateral sclerosis).
Decades of research on SOD1 and other recently discovered ALS-associated genes have revealed that increased understanding of the mechanisms of protein misfolding and quality control in neurons is a critical step toward understanding ALS and related neurodegenerative diseases, including frontotemporal dementia. Perturbation of protein quality control is a common theme in most forms of ALS, so there could be broad impact from these studies.
With colleagues, Wang will work with fly, mouse, and human stem cell models of ALS to increase understanding of how protein quality control goes awry in ALS and whether better maintenance of protein homeostasis could be a viable therapeutic avenue to explore for the disease. The team has recently identified genes that modulate specific protein quality control pathways. Now they will explore whether these pathways could yield new drug targets for ALS.
Funding for this MDA research grant began Feb. 1, 2017.
Grantee: Jiou Wang, M.D., Ph.D.
Grant type: Research Grant
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Grant - Winter 2017 - ALS – Jie Jiang, Ph.D.
Jie Jiang, postdoctoral fellow at the Ludwig Institute for Cancer Research, University of California – San Diego, in La Jolla, Calif., was awarded an MDA development grant totaling $180,000 over three years to improve understanding of the disease mechanisms underlying the most common inherited form of ALS (amyotrophic lateral sclerosis).
Expanded repeated sections of DNA (GGGGCC hexanucleotide repeats) in a non-coding region of the C9ORF72 gene have been identified as the most common genetic cause of ALS and frontotemporal dementia (FTD), another neurological disease characterized by behavioral and language changes. It’s uncertain, however, if disease is caused by reduced levels of normal C9ORF72 protein and/or by toxic RNA and proteins manufactured using instructions encoded in the extra DNA.
Jiang and colleagues will work to determine whether the loss of normal C9ORF72 protein synergizes with toxic RNA and proteins to exacerbate disease in research mouse models.
Jiang’s work may guide direction of therapy development for C9ORF72 ALS/FTD.
Funding for this MDA development grant began Feb. 1, 2017.
Grantee: Jie Jiang, Ph.D.
Grant type: Development Grant
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Grant - Summer 2016 - SMA – Lyndsay Murray, Ph.D.
Lyndsay Murray, a lecturer in anatomy at the University of Edinburgh, in Scotland, United Kingdom, was awarded an MDA research grant totaling $292,174 over a period of three years to investigate how the mechanisms underlying spinal muscular atrophy (SMA) influence how therapies work at different stages of the disease.
In animal model studies, it has been shown that while treatment can nearly rescue an individual from the disease when given before symptoms begin, the benefits are drastically reduced when therapies are given after symptom onset. Most therapies currently in clinical trials for SMA are treating patients after symptoms have appeared, which is thought to limit their effectiveness.
With colleagues, Murray will conduct studies in a mouse model of SMA that are aimed at determining why the benefits of therapeutics are so limited after symptoms have started, and finding ways in which to maximize the benefits of these therapies during symptomatic stages of the disease. The work is expected to inform development of more effective therapies and increase understanding of when and why they have to be administered.
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: SMA – Lyndsay Murray, Ph.D.
Grant type: Research Grant
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Grant - Summer 2016 - SMA – Christine DiDonato, Ph.D.
Christine DiDonato, associate professor at the Ann & Robert H. Lurie Children’s Hospital of Chicago, was awarded an MDA research grant totaling $300,000 over a period of three years to decipher the mechanisms underlying muscle dysfunction in spinal muscular atrophy (SMA).
SMA is caused by insufficient levels of the survival motor neuron (SMN) protein. DiDonato and colleagues have developed SMA mice in which they have specifically increased SMN protein levels in motor neurons (nerve cells that lose function in SMA). The mice have normal functioning motor neurons, but they still have very clear functional deficits, thus unmasking muscle problems caused by low SMN levels in this tissue. This has important long-term implications for SMN-based therapies under current clinical investigation that target only the central nervous system.
DiDonato aims to characterize the muscle defects in SMA, identify altered molecular pathways in skeletal muscle that are responsible for muscle weakness and atrophy, and develop strategies to enhance muscle function.
The knowledge gained from this work is critical to understanding SMN’s role in skeletal muscle and devising ways in which skeletal muscle can be maintained and its function enhanced. It could point the way to the development of therapies that can be used independently or in conjunction with other therapies for SMA.
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: SMA – Christine DiDonato, Ph.D.
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Grant - Summer 2016 - OPMD – Anita Corbett, Ph.D.
Anita Corbett, professor of biochemistry at Emory University School of Medicine in Atlanta, was awarded an MDA research grant totaling $299,997 over a period of three years to increase understanding about what causes the muscle problems that occur in oculopharyngeal muscular dystrophy (OPMD).
The underlying genetic cause of OPMD is a very small change in a single gene called PABPN1. Corbett and colleagues are working to determine whether it will be sufficient to inhibit the disease-causing mutant PABPN1 protein, or if, in addition, normal PABPN1 protein will need to be replaced.
Corbett’s work may inform ongoing and future clinical trials to test treatments that can enhance quality of life for people with OPMD.
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: OPMD – Anita Corbett, Ph.D.
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Grant - Summer 2016 - Myotonic Dystrophy – Jack Puymirat, M.D., Ph.D.
Jack Puymirat, full professor of neurology at University of Laval, Quebec, Canada, was awarded an MDA research grant totaling $278,537 over a period of three years to establish proof-of-principle for brain delivery of an antisense therapy for brain deficits associated with myotonic dystrophy type 1 (DM1).
Central nervous system dysfunction and cognitive impairment in adults with DM1 are prominent disabling features that often have dramatic repercussions on the quality of life of patients. Although a great deal of progress has been made in recent years in the development of therapeutic antisense oligonucleotides (ASO) for DM1 and other diseases, the ASO currently in clinical trial for DM1 does not effectively cross the blood-brain barrier following systemic administration. Therefore, cognitive impairment and other central nervous system aspects of DM1 will need to be targeted in a different way.
With colleagues, Puymirat will conduct studies in mice to determine whether ASOs can effectively be targeted to treat brain deficits if they are given more directly into the central nervous system via intrathecal administration. (In intrathecal administration, a small needle is inserted into a space in the lower back below the end of the spinal cord in a medical procedure commonly referred to as a “lumbar puncture.”)
If successful, this work potentially could demonstrate proof-of-principle of ASO therapy to treat brain deficit in patients with DM1. In addition, it could lead the way to a clinical trial for DM1 based on intrathecal administration of ASOs and open the door to further research on the mechanisms underlying brain defects in DM1.
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: Myotonic Dystrophy – Jack Puymirat, M.D., Ph.D.
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Grant - Summer 2016 - Mitochondrial Myopathies – Marilena D’Aurelio, Ph.D.
Marilena D’Aurelio, assistant professor of research in neuroscience at Cornell University in New York, was awarded an MDA research grant totaling $300,000 over a period of three years to examine changes in metabolism that occur in mitochondrial myopathies (MM).
Mitochondrial diseases result from abnormalities in energy metabolism in cells. Although the genetic defects are known, many aspects of the disease are yet to be elucidated. In severe cases, proteins in the muscle cells are broken down in order to utilize key amino acids.
With colleagues, D’Aurelio will characterize the specific metabolic shifts seen in different disease cases, both in cell cultures as well as in blood from patients, in an effort to uncover the altered pathways of amino acid metabolism.
This work has the potential to identify biomarkers for specific mitochondrial myopathies, as well as different types of metabolic supplementation that may offset progression of disease.
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: Mitochondrial Myopathies – Marilena D’Aurelio, Ph.D.
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Grant - Summer 2016 - MG – Linda Kusner, Ph.D.
Linda Kusner, an associate professor in the department of pharmacology and physiology at George Washington University in Washington, D.C., was awarded an MDA research grant totaling $287,992 over a period of three years to validate a new therapeutic target for myasthenia gravis (MG).
Kusner aims to develop a therapy for MG that might eliminate or lessen the need for corticosteroids, the primary treatment used now. With colleagues, she has discovered the presence in MG-affected cells of a protein called survivin, which the group suspects supports the presence of autoreactive immune cells by allowing them to escape cell death. In studies that targeted the protein, conducted in animal models of the disease, Kusner and her team showed a reduction in levels of antibodies that attack acetylcholine receptors as part of the MG disease process.
In her new work, Kusner will assess thymus tissue from patients with MG and healthy individuals to determine whether survivin protein is present. Additionally, she will evaluate survivin-based therapeutics in an MG rodent model to assess the therapeutics’ ability to improve observable weakness, decrease the expression of autoreactive immune cells, decrease acetylcholine receptor specific antibodies, and decrease damage to the nerve-muscle junction.
The work is expected to provide a new fundamental understanding of basic mechanisms of autoimmunity and validate a survivin-targeted approach for therapeutic development in MG.
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: MG – Linda Kusner, Ph.D.
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Grant - Summer 2016 - LGMD and Miyoshi Myopathy – Miranda Grounds, Ph.D.
Miranda Grounds, emeritus professor and senior honorary research fellow at the University of Western Australia, was awarded an MDA research grant totaling $300,000 over a period of three years to study fat accumulation in muscle cells in limb-girdle muscular dystrophy (LGMD) type 2B.
Dysferlinopathies are a form of muscular dystrophy that is caused by problems in the gene that makes a protein called dysferlin, associated with cell membranes. In humans, dysferlinopathies result in weakness and loss of function of adult skeletal muscles, and manifest as LGMD2B or Miyoshi Myopathy. Dysferlin-deficient muscles in these diseases are characterized by remarkably high levels of lipid (fat) droplets within muscle tissue and fat accumulation that replaces muscle cells.
Grounds and colleagues will work to describe how the key aspects of lipid metabolism are altered in dysferlin-deficient muscles. The team will study the communication signals between muscle and fat cells and work to determine whether altered fat metabolism is responsible for adverse clinical effects of glucocorticoid treatment in dysferlinopathies.
Grounds’ work will provide insight into the disease mechanisms underlying dysferlinopathies and identify the best molecular targets for drug therapy, possibly using existing approved drugs.
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: LGMD and Miyoshi Myopathy – Miranda Grounds, Ph.D.
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Grant - Summer 2016 - LGMD – Madhuri Hegde, B.S., M.S., Ph.D.
Madhuri Hegde, associate professor in the department of human genetics at Emory University in Atlanta, was awarded an MDA research infrastructure grant totaling $300,000 over a period of three years to continue groundbreaking work to identify and characterize new gene defects that can cause limb-girdle muscular dystrophy (LGMD).
In the era of precision medicine, it is necessary that new therapies apply the right medication to the right patient at the right time, and it is an increasingly common requirement that a person’s clinical diagnosis be confirmed with a molecular diagnosis in order for him or her to participate in clinical trials.
MDA supports an LGMD testing program, in which more than 1,700 people have had their DNA sequenced, and a definitive molecular diagnosis of a particular LGMD subtype based on a known gene mutation has been found in 40 percent of cases. However, at least 30 to 40 percent of people diagnosed with LGMD still never get a molecular diagnosis, or get clinical reports noting “variants of unknown significance” in known genes.
Hegde aims to perform advanced genetic and functional assessments of these variants of unknown significance in an attempt to better understand how the variants might contribute to the cause of LGMD in these cases. This will not only benefit patients, who will receive more definitive diagnoses, but will also increase our understanding of genes involved in neuromuscular disorders and point to new therapeutic targets.
Funding for this MDA research infrastructure grant began Aug. 1, 2016.
Grantee: LGMD – Madhuri Hegde, B.S., M.S., Ph.D.
Grant type: Infrastructure Grant
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