Science That Changes Lives
From breakthroughs in the lab to real-world progress—accelerating research that delivers results for families today.
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.
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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.
Grant type: Research Grant
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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.
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Grant - Summer 2016 - LGMD – Michele Calos, Ph.D.
Michele Calos, professor of genetics at Stanford University School of Medicine in California, was awarded an MDA research grant totaling $300,000 over a period of three years to test gene therapy approaches in mouse models of limb-girdle muscular dystrophy (LGMD) types 2B and 2D.
With colleagues, Calos will study a gene therapy approach based on delivering the therapeutic gene — either dysferlin or alpha-sarcoglycan — through the bloodstream. The DNA will be injected rapidly into a vein near the ankle, where it will then be carried by the blood to all leg muscles.
The goal of this work is to demonstrate effective DNA delivery that results in improved condition of muscles and muscle function in the mice. A sequence-specific integration system will specifically target the therapeutic gene into a safe and permanent section of the genome. Because the gene will become a permanent part of the chromosomes in muscle cells, the therapy will act long-term.
These studies will pave the way for larger animal studies and human clinical trials. Success in LGMD types 2B and 2D may demonstrate that a similar approach will work for all 10 forms of recessive limb-girdle muscular dystrophy. Furthermore, this type of approach also may be helpful for other neuromuscular diseases.
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: LGMD – Michele Calos, Ph.D.
Grant type: Research Grant
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Grant - Summer 2016 - LGMD, IBM and myofibrillar myopathies – Chris Weihl, M.D., Ph.D.
Chris Weihl, associate professor of neurology at Washington University School of Medicine in St. Louis, Mo., was awarded an MDA research grant totaling $300,000 over a period of three years to explore the underlying mechanisms, and a potential treatment, for limb-girdle muscular dystrophy (LGMD) type 1D.
When cellular proteins misfold, aggregate (form clumps) and avoid being degraded by cellular garbage disposal and quality control systems, they can lead to a number of neuromuscular diseases, including LGMD1D. Protein “chaperones,” also known as heat shock proteins, protect against these damaging processes by helping proteins fold correctly.
Weihl and colleagues recently identified a protein known as DNAJB6 as essential for maintaining proper folding and assembly of muscle fiber proteins. Using animal and cell models of the disease, the group will now investigate whether small molecules known to improve protein folding can help ensure proper folding of DNAJB6.
If successful, this work could pinpoint an effective therapeutic strategy for LGMD1D and shed light on disease processes underlying inclusion-body myopathy (IBM) and myofibrillar myopathies.
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: LGMD, IBM and myofibrillar myopathies – Chris Weihl, M.D., Ph.D.
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Grant - Summer 2016 - IBM and other myopathies – Alfred Goldberg, Ph.D.
Alfred Goldberg, professor of cell biology at Harvard Medical School in Boston, was awarded an MDA research grant totaling $300,000 over a period of three years to study the mechanisms that may drive muscle atrophy in a number of diseases, including inclusion-body myopathy (IBM), forms of congenital myopathy, and various motor neuron diseases.
Goldberg and colleagues previously have shown that the debilitating loss of muscle mass in many neuromuscular disorders is primarily due to excessive degradation of muscle proteins. In recent years, much has been learned about the proteasome, the molecular machine that degrades most cell proteins, and Goldberg’s team has found that as muscle atrophies, the composition of these proteasomes changes in ways that seem to contribute to the accelerated protein destruction.
The team aims to explore the special features of proteasomes in atrophying muscle and how they relate to disease states. In addition, the group will test whether a newly discovered method to activate proteasomes might be useful in promoting the clearance of toxic proteins and thus slow progression of various diseases.
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: IBM and other myopathies – Alfred Goldberg, Ph.D.
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Grant - Summer 2016 - FA – Marek Napierala, Ph.D.
Marek Napierala, an assistant professor in biochemistry and molecular genetics at the University of Alabama at Birmingham, was awarded an MDA grant totaling $279,518 over a period of three years to investigate a therapeutic strategy for Friedreich’s ataxia (FA).
FA is caused by abnormally high numbers of specific DNA sequences, called GAA repeats, in the frataxin gene. The extra DNA blocks the flow of information from DNA to RNA (an intermediate step between the genetic instructions in DNA and the manufacturing of proteins) and ultimately leads to a deficiency of frataxin protein, which is insufficient to maintain healthy cells.
In collaboration with RaNA Therapeutics, Napierala and colleagues will study a new approach aimed at increasing the amount of frataxin in FA-affected cells. The team will use molecules called oligonucleotides (small specific DNA fragments that can enter diseased cells), to locate frataxin RNA and stabilize it in order to increase its “molecular lifespan” in patient cells. The strategy is not designed to increase production of frataxin RNA, which has proven to be difficult, but instead allows existing frataxin RNA to be available longer for the process of frataxin protein production.
Napierala’s team predicts that the result of oligonucleotide treatment will be an increased amount of frataxin protein in FA patient cells.
If the strategy is successful, Napierala’s work could lead to rapid development of treatments for FA.
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: FA – Marek Napierala, Ph.D.
Grant type: Research Grant
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Grant - Summer 2016 - FA – Michael Huang, Ph.D.
Michael Huang, the NHMRC Peter Doherty Postdoctoral Fellow in the department of pathology, Bosch Institute, at the University of Sydney, Australia, was awarded an MDA development grant totaling $177,100 over a period of three years to explore how deficiency of the frataxin protein in Friedreich’s ataxia (FA) may alter the function of cellular power supplies called mitochondria.
Because the heart and the nervous system rely heavily on mitochondria to fulfill their energy demands, they are most affected by mitochondrial dysfunction. Huang and colleagues will examine the extent to which frataxin protein deficiency disrupts mitochondrial function and the possibility of targeting this process as a therapy.
In cardiac- and neural-specific mouse models of FA, Huang’s team will explore alterations in the ability for mitochondria to fuse or divide in response to energy demands. They also will assess pathological changes in the synthesis and maintenance of mitochondria in FA, and will investigate whether vitamin B3 can boost mitochondrial health to prevent FA disease processes.
The work could lead to novel and accessible therapeutic strategies in FA.
Funding for this MDA development grant began Aug. 1, 2016.
Grantee: FA – Michael Huang, Ph.D.
Grant type: Development Grant
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Grant - Summer 2016 - FSHD - Joel Chamberlain, Ph.D.
Joel Chamberlain, research associate professor at the University of Washington School of Medicine in Seattle, was awarded an MDA research grant totaling $300,000 over a period of three years to increase understanding of the role of DUX4 protein in facioscapulohumeral muscular dystrophy (FSHD).
In the muscle cells of people with FSHD, too much of a protein called DUX4 is made, leading to cell death. To determine how excess DUX4 results in muscle damage in FSHD, Chamberlain and colleagues will examine DUX4 protein production in a range of human biopsy samples in an effort to determine the cellular location of DUX4 and the protein’s relationship to disease-related changes in the muscle.
In parallel, in studies conducted in a unique mouse model of FSHD developed in Chamberlain’s lab, the team also will examine the toxic effects of expressing very low levels of the DUX4 protein. These studies will help assess how DUX4 initiates a chain of events that cause the slow, progressive muscle damage seen in FSHD.
Chamberlain’s work may reveal drug targets and inform the development and testing of therapies for FSHD.
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: FSHD – Joel Chamberlain, Ph.D.
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Grant - Summer 2016 - DMD – Pier Lorenzo Puri, M.D., Ph.D.
Pier Lorenzo Puri, associate professor in the development, aging and regeneration program at Sanford Burnham Prebys Medical Discovery Institute in La Jolla, Calif., was awarded an MDA research grant totaling $298,965 over a period of three years to increase understanding about the complexity of cellular interactions that underlie Duchenne muscular dystrophy (DMD).
Puri and colleagues previously have shown that several populations of cells in DMD muscle play a key role in determining whether muscle successfully regenerates or develops fibrosis (scarring) instead. Using a compound called Givinostat, which currently is in clinical trials for DMD, he will delineate the role of each cell population in regeneration and clarify how the drug works on each of these types of cells.
Puri’s work may lead to the identification of new targets for therapeutic interventions.
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: DMD – Pier Lorenzo Puri, M.D., Ph.D.
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Grant - Summer 2016 - DMD – Pura Muñoz-Cánoves, Ph.D.
Pura Muñoz-Cánoves, a professor of research and cell biology at Pompeu Fabra University, ICREA and CIBERNED in Barcelona, Spain, was awarded an MDA research grant totaling $299,896 over a period of three years to study the role of autophagy in promoting muscle repair in Duchenne muscular dystrophy (DMD).
Muñoz-Cánoves and colleagues aim to answer fundamental questions on the biology of satellite cells (stem cells in skeletal muscle) in DMD, including why the capacity of satellite cells declines over the course of DMD disease progression. The team will examine the role of a cellular cleanup and garbage-disposal system called autophagy in a mouse model of DMD and determine whether increasing autophagy can promote muscle repair.
The work may point the way to new pathways that could be targeted with natural compounds to enhance or restore muscle regeneration in DMD patients, particularly at advanced age when muscle architecture is disrupted and loss of regenerative capacity is maximal.
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: DMD – Pura Muñoz-Cánoves, Ph.D.
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Grant - Summer 2016 - DMD – Diego Fraidenraich, Ph.D., FAHA
Diego Fraidenraich, assistant professor in cell biology and molecular medicine at Rutgers New Jersey Medical School in Newark, was awarded an MDA research grant totaling $300,000 over a period of three years to determine whether inhibiting production of a protein called connexin-43 (CX43) can reduce muscle damage in Duchenne muscular dystrophy (DMD).
It is not well understood why certain muscle fibers in people with muscular dystrophy are more susceptible to damage than others, or how this damage spreads to neighboring fibers. The Fraidenraich lab has demonstrated that a key protein for cell-to-cell communication, CX43, is abnormally expressed in DMD-affected skeletal muscle in mice and humans in areas where this damage occurs.
With colleagues, Fraidenraich will investigate the harmful role of CX43 and the mechanisms of cell-to-cell communication that lead to the spread of damage in DMD tissues and determine whether reduction of CX43 protein levels in mice lessens muscle damage and ameliorates disease. Their work may help to identify CX43 as a key player in DMD disease progression and lay the groundwork for development of a new therapeutic strategy aimed at targeting the dysfunctional protein.
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: DMD – Diego Fraidenraich, Ph.D., FAHA
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Grant - Summer 2016 - DMD, LGMD, CMD – Rachelle Crosbie-Watson, Ph.D.
Rachelle Crosbie-Watson, professor and vice-chair of graduate education at the University of California Los Angeles, was awarded an MDA research grant totaling $300,000 over a period of three years to test new therapies for cardiomyopathy (heart muscle weakness) associated with Duchenne muscular dystrophy (DMD).
Loss of functional dystrophin protein in DMD results in reduced muscle membrane stability, with muscle fiber fibrosis (scarring) and necrosis (death).
Continuing a successful line of MDA-supported research, Crosbie-Watson will confirm whether a protein called sarcospan can compensate for the loss of dystrophin protein in a mouse model of DMD, and whether a gene therapy approach based on sarcospan can ameliorate cardiac symptoms.
This work will lead to a better understanding of the molecular events that contribute to the ability of the sarcospan protein to alter expression of proteins at the cell surface and change the course of DMD, and determine the effectiveness of sarcospan for the treatment of other muscular dystrophies including some forms of limb-girdle muscular dystrophy (LGMD) and congenital muscular dystrophy (CMD).
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: DMD, LGMD, CMD – Rachelle Crosbie-Watson, Ph.D.
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Grant - Summer 2016 - ALS – Daniela Zarnescu, Ph.D.
Daniela Zarnescu, associate professor in molecular and cellular biology, neuroscience and neurology at the University of Arizona in Tucson, was awarded an MDA research grant totaling $299,818 over a period of three years to shed light on metabolic dysregulation in people with amyotrophic lateral sclerosis (ALS).
Metabolic dysregulation in ALS has long been recognized, but it isn’t understood why it occurs.
With the recent identification of cellular aggregates (clumps) containing TDP-43 protein, and the discovery of TDP-43 gene mutations in some ALS patients, the TDP-43 protein has emerged as a common denominator in a majority of ALS cases.
With colleagues, Zarnescu has developed a drosophila (fruit fly) model of ALS based on mutations in the gene for TDP-43 that exhibits alterations in motor function and lifespan that are remarkably similar to what is seen in the human disease. Using this model, the team has identified specific alterations in the cellular metabolic pathways that govern energy production in the nerve cells affected by ALS. These findings, they say, suggest defects in the way mitochondria, the cell’s power plants, are functioning.
The team will now test whether molecular and genetic tools together with dietary interventions can restore mitochondrial function and improve outcomes in fly and patient-derived cell models. The work may help establish the feasibility of developing therapeutic strategies aimed at restoring defects in energy production in ALS-affected cells.
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: ALS – Daniela Zarnescu, Ph.D.
Grant type: Research Grant
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Grant - Summer 2016 - ALS – Laura Ranum, Ph.D.
Laura Ranum, professor of molecular genetics and microbiology at the University of Florida in Gainesville, was awarded an MDA research grant totaling $146,712 over two years to develop an antibody therapy as a potential treatment for amyotrophic lateral sclerosis (ALS).
In 2011, Ranum and colleagues discovered that disease-causing “repeat expansion mutations,” in which short stretches of DNA are repeated extra times, can produce an unexpected type of mutant proteins that accumulate in patient brains. These proteins, called repeat associated non-ATG (RAN) proteins, have been shown to accumulate in a growing number of diseases including the most common genetic form of ALS and frontotemporal dementia (FTD) called C9ORF72 ALS/FTD.
Recently, the Ranum lab developed a new mouse model of this disease. These mice develop both ALS and dementia and are affected by devastating paralysis and neurodegeneration similar to what occurs in human patients.
In collaboration with Jan Grimm and colleagues at Neurimmune, the Ranum lab will test the therapeutic potential of human antibodies to target RAN proteins in the brains of the mice to see if treatments increase survival and decrease disease symptoms.
Ranum’s work will result in a greater understanding of the mechanisms behind ALS/FTD and may provide new treatment strategies urgently needed for ALS/FTD patients.
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: ALS – Laura Ranum, Ph.D.
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Grant - Summer 2016 - ALS – Leonard Petrucelli, Ph.D.
Leonard Petrucelli, professor and chair in the department of neuroscience at the Mayo Clinic in Jacksonville, Fla., was awarded an MDA research grant totaling $300,000 over a period of three years to shed light on critical disease mechanisms and drive more targeted therapeutics for amyotrophic lateral sclerosis (ALS).
Although a “repeat expansion mutation” (in which short stretches of DNA are repeated extra times) in the gene for C9ORF72 is the most common known cause of ALS to date, key questions remain unanswered: C9ORF72-associated ALS is characterized by the mislocalization and aggregation of the protein TDP-43, yet the connection between the repeat and this protein aggregation is unclear. Furthermore, the C9ORF72 repeat expansion is present throughout the central nervous system of patients, and yet only a specific subset of neurons (nerve cells) is susceptible to degeneration. This phenomenon of “selective neuronal vulnerability” is not well understood.
Recently, it was discovered that a very similar repeat expansion results in a disease known as Spinocerebellar Ataxia Type 36 (SCA36). Yet TDP-43 aggregation has thus far not been observed in SCA36 patients, and the disease is characterized by a different pattern of neurodegeneration than that found in ALS.
With colleagues, Petrucelli will focus on expressing the two repeats in the mouse nervous system and then using these models to determine which cellular and molecular processes are specifically disrupted by the presence of the C9ORF72 repeat. The work may reveal that any cellular functions that are affected by the expansion in C9ORF72, but not by the similar expansion associated with SCA36, are more likely to be responsible for TDP-43 aggregation and ALS-specific nerve cell death.
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: ALS – Leonard Petrucelli, Ph.D.
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Grant - Summer 2016 - ALS – Tania Gendron, Ph.D.
Tania Gendron, assistant professor of neuroscience at the Mayo Clinic in Jacksonville, Fla., was awarded an MDA research grant totaling $285,000 over a period of three years to investigate the c9RAN protein as a potential biomarker to measure the effectiveness of promising treatments for C9ORF72 amyotrophic lateral sclerosis (C9ALS) and serve as a prognostic biomarker to predict disease progression.
With therapies in development for C9ALS, the most common form of ALS known to date, it is crucial to have biomarkers in place that can inform clinical studies. It’s been found that in C9ALS, there is an expanded piece of RNA (an intermediate step between the genetic instructions in DNA and the manufacturing of proteins). RNA from this expansion codes for the production of potentially harmful c9RAN proteins. Evidence that these c9RAN proteins are toxic has spurred the field to investigate therapeutic approaches to counteract it.
Gendron and colleagues previously have reported that poly(GP), one of the c9RAN proteins produced in C9ORF72 ALS, is present in cerebrospinal fluid (CSF) and in white blood cells. The team will study CSF and blood collected from C9ALS patients and investigate whether measurements of the protein can be associated with clinical features of the disease. In addition, the team will work with C9ALS patient cell lines and CSF from mice engineered to model the disease to probe the effectiveness of poly(GP) in predicting treatment response.
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: ALS – Tania Gendron, Ph.D.
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Grant - Summer 2016 - ALS – Christi Kolarcik, Ph.D.
Christi Kolarcik, research associate at the University of Pittsburgh in Pennsylvania, was awarded an MDA development grant totaling $180,000 over a period of two years to investigate communication breakdown between nerve cells and muscles in amyotrophic lateral sclerosis (ALS). The work, co-funded by the American Association of Neuromuscular & Electrodiagnostic Medicine Foundation for Research and Education (AANEM), may help inform therapy development in ALS.
Communication between motor neurons (the nerve cells that lose function in ALS) and muscles occurs at the neuromuscular junction which is often compromised in neuromuscular disease. Motor neurons also connect with other nerve cells in the brain that aid the motor neurons in directing muscle movements. Multiple hypotheses exist on where these connections break down in ALS.
Kolarcik and colleagues will use a unique “systems level” approach to better understand the timeline of degeneration in the neural circuit as well as the contribution of other neuron types besides motor neurons. In studies conducted in a mouse model, the team will map the neural circuitry that controls motor neurons. This map will elucidate all the connections that exist from the muscle all the way up to other nerve cells connected to motor neurons in the brain. Kolarcik will study this nerve network during different disease stages, to determine how and when synaptic connections are affected as ALS progresses.
These studies will shed light on the time course of connectivity changes and transport deficits, and will provide insights into where within the neural network therapies should be targeted at various stages of disease.
Funding for this MDA development grant began Aug. 1, 2016.
Grantee: ALS – Christi Kolarcik, Ph.D.
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Grant - Summer 2016 - ALS – Heather Durham, Ph.D.
Heather Durham, professor in the department of neurology and neurosurgery at Montreal Neurological Institute, McGill University, Quebec, Canada, was awarded an MDA research grant totaling $299,017 over a period of three years to evaluate strategies that could prolong function of motor neurons, the nerve cells that lose function and die in amyotrophic lateral sclerosis (ALS).
ALS is a complex disease that involves widespread disruption of cellular functions. With colleagues, Durham has determined that the Neuronal Brg1/Brm Associated Factor (nBAF) protein complex is disrupted in the disease. nBAF regulates the expression of neuronal-specific genes that help neurons extend processes to connect to other neurons in the network. Key proteins in nBAF are lost in motor neurons in familial and sporadic ALS which could disrupt motor neuron connectivity and ultimately, result in motor neuron dysfunction.
Durham will examine the mechanisms involved in nBAF activity and function, and work to determine whether interventions in the pathway could have a protective effect on motor neurons.
An understanding of the key elements and processes associated with nBAF could pave the way toward new therapies for ALS that could help motor neurons function longer and stay connected in the network.
Funding for this MDA research grant began Aug. 1, 2016.
Grantee: ALS – Heather Durham, Ph.D.
Grant type: Research Grant
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