Summer 2020 - ALS - Michael Benatar, M.D., Ph.D.
"A holy-grail of physician-investigators engaged in both ALS patient care and research has been the efficient and effective use of clinically-derived data for research purposes. To address this critically unmet need, we have partnered with Epic (the maker of the most widely used electronic health record [EHR] system) to build the ALS Toolkit. This resource will permit broad sharing of de-identified clinical data in a regulatory-compliant manner."
Michael Benatar, Professor of Neurology at the Miller School of Medicine of the University of Miami, was awarded an MDA Clinical Research Network Grant totaling $916,261 over three years to support the multicenter deployment of the ALS toolkit, a module built into the Epic EHR that aims to facilitate structured data collection for research and improve quality of care.
Clinics are critical to ALS patient care, leading to improved quality of life and prolonged survival. Clinic visits can take several hours with substantial clinical data collected; however, these data have limited utility for research purposes because of the unstructured way in which the data are collected. The ALS toolkit will provide a platform for standardized data collection across clinical sites, which could obviate the need for separate research visits and reduce the burden on patients and physicians.
https://doi.org/10.55762/pc.gr.140912
Grantee: Clinical Procedures to Support Research (CAPTURE) - Michael Benatar, M.D., Ph.D.
Grant type: Neuromuscular Disease Clinical Research Network Grant
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Summer 2020 - ALS - Jonathan Glass, MD
"There is an enormous need for a better understanding of the clinical, demographic, and genetic features that underlie the clinical variability seen in patients suffering from ALS."
Jonathan Glass, M.D., Ph.D., Professor of Neurology at Emory University, has been awarded an MDA restricted research grant of $137,228 for one year to continue to provide the ALS research community with data, biofluids, and tissues from deeply phenotyped ALS patients and people without ALS who participate in Emory’s Clinical Research in ALS (CRiALS) project.
There is significant phenotypic and genetic heterogeneity observed among persons with ALS, which may partly explain some of the failures in clinical trials. The CRiALS database is considered one of the most valuable resources for ALS research with a large and extremely well characterized patient population. Dr. Glass’ work could pave the way for better defined disease features and ultimately clinical trials targeting specific patient populations.
Grantee: Clinical Research in ALS (CRiALS): A clinical database and specimen biobank - Jonathan Glass, MD
Grant type: Restricted Research Grant
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Summer 2020 - ALS - Jeffrey Rothstein, MD, PhD
"Recent studies in human disease support the notion that loss of such TDP43 function is compromised as an early event in neurons of cases of ALS-FTD. If so, a promising therapeutic strategy would be to complement the loss of TDP-43 splicing repression in neurons of ALS-FTD."
Jeffrey Rothstein, M.D., Ph.D., director of the Robert Packard Center for ALS Research at Johns Hopkins University School of Medicine, has been awarded an MDA restricted research grant of $54,785 for one year for investigator Philip C. Wong, PhD, professor of Pathology, to develop an adeno-associated virus (AAV) delivery method to validate a gene therapy strategy for ALS and frontotemporal degeneration (FTD).
TDP-43 pathology is a major pathological hallmark of nearly all cases of ALS yet the full picture of how TDP-43 pathogenesis affects neurons is not clear. The proposed strategy is hoped to compensate for the loss of normal RNA generation due to dysfunction related to TDP-43.
https://doi.org/10.55762/pc.gr.143537
Grantee: Validating an AAV gene therapeutic strategy for ALS-FTD - Jeffrey Rothstein, MD, PhD
Grant type: Restricted Research Grant
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Summer 2020 - Jeffrey Chamberlain, PhD
"Our new approach will continue development of a novel approach to delivering larger, possibly up to full-length, dystrophins."
Jeffrey Chamberlain, Ph.D., Professor and McCaw Endowed Chair of Muscular Dystrophy at the University of Washington School of Medicine, was awarded an MDA restricted research grant totaling $471,693 over two years to develop improved dystrophin vectors that can deliver larger and more functional dystrophins to muscles throughout the body in patients with Duchenne muscular dystrophy (DMD).
Current approaches for DMD gene therapy rely on AAV delivery of micro-dystrophin or gene editing tools, which each produce smaller than normal dystrophins. Dr. Chamberlain plans to develop improved dystrophin vectors than can produce larger and more functional dystrophin to muscles of DMD patients. If successful, this technology would be applicable to any DMD or Becker’s muscular dystrophy (BMD) patient.
Grantee: Generation of large dystrophins in muscle via AAV vector delivery - Jeffrey Chamberlain, PhD
Grant type: Restricted Research Grant
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Summer 2020 - ALS - Hiroshi Mitsumoto, MD, DSci
"We will conduct crucial statistical analyses to uncover ALS risk factors and the cause of ALS."
Hiroshi Mitsumoto, M.D., Wesley J. Howe Professor of Neurology at Columbia University Medical Center, has been awarded an MDA restricted research grant of $54,784 for one year to support continuation of three National Institutes for Health and Centers for Disease Control and Prevention-funded studies, for which MDA has already provided supplemental funding.
Studying the epidemiology associated with ALS is critical for developing a better understanding of the disease. Dr. Mitsumoto will continue to analyze large cohorts of ALS patients to identify potential environmental risk factors in ALS. This grant will also support a personalized clinical trial to determine if a Japanese herbal medication can target and improve muscle cramps in individuals with ALS.
Grantee: Statistical analyses of the ALS COSMOS, ARREST ALS, and ARREST Control studies - Hiroshi Mitsumoto, MD, DSci
Grant type: Restricted Research Grant
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Summer 2020 - Erik Henricson, PhD
"The overall goal of this project is to develop new and innovative mobile device-compatible methodologies based on low-cost easily obtained accelerometers and machine learning algorithm technologies with the objective of providing cost-efficient tools to allow consumers, clinicians and researchers to better evaluate the community mobility of people with neuromuscular diseases in clinical and research settings."
Erik Henricson, Assistant Professor of Physical Medicine and Rehabilitation at the University of California, Davis, was awarded an MDA Clinical Research Grant totaling $427, 822 to develop an automated sensor technology to evaluate ambulatory function in people with neuromuscular disease in the home, community, and clinical settings.
A number of potential therapies are in clinical development for neuromuscular diseases, with a growing recognition that treatment benefit will be greater the earlier it is initiated. Although many children are being diagnosed as toddlers or younger, they are rarely included in clinical trials because of the lack of reliable clinical endpoints for longitudinal follow-up.
Dr. Henricson has developed a machine learning algorithm that calibrates data from a single small sensor to determine gait characteristics, even in children, with a high degree of accuracy. In this project he will work with male and female patients with DMD, BMD, SMA, FSHD and CMT to further the development of this reliable, unobtrusive, easy-to-use, portable, and cost-effective technology that pairs with the patient’s own mobile device.
https://doi.org/10.55762/pc.gr.140910
Grantee: Machine Learning of Neuromuscular Disease Gait Parameters from Single Sensors - Erik Henricson, PhD
Grant type: Neuromuscular Disease Clinical Research Grant
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Summer 2020 - Myotonic Dystrophy DM - Charles Thornton, MD
"With drug development for myotonic dystrophy 1 (DM1) progressing rapidly, "access to genetic testing could become a significant bottleneck"."
Charles Thornton, M.D., Saunders Family Distinguished Professor in Neuromuscular Research at the University of Rochester Medical Center, has been awarded an MDA restricted research grant of $49,953 for one year to make improvements in technology for genetic testing of DM1, a relatively common form of muscular dystrophy.
Current genetic testing methods for individuals with DM1 are expensive, labor intensive, have limited throughput, and lack the precision needed to determine the size of the expanded CTG repeat. Dr. Thornton is developing a novel method of genetic analysis that is simple, amenable to high throughput, and able to determine repeat expansion sizes. This technology could be important for rapidly identifying the many thousands of people in the U.S. that will require genetic testing when treatments for DM1 are approved.
Grantee: Sequence Analysis of Myotonic Dystrophy - Charles Thornton, MD
Grant type: Restricted Research Grant
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Grant - Additional Grants 2019 - DM - Charles Thornton, MD
"The Myotonic Dystrophy Clinical Research Network is a natural extension of 30-plus years’ effort to understand the fundamental problems in myotonic dystrophy and then develop treatments to overcome the problems. MDA has supported a lot of the critical basic research that brought the field to this point where people can conceive and develop new treatments."
Charles Thornton, MD, professor of Neurology at the University of Rochester, was awarded an MDA clinical research network grant (CRNG) totaling $1,118,673 over three years to continue to lead the development of the Myotonic Dystrophy Clinical Research Network, which comprises six medical centers specializing in research and clinical care of myotonic dystrophy (DM) types 1 and 2. Dr. Thornton was previously awarded two other CRNGs totaling $918,000 each over the course of a combined six years.
Established in 2013 and supported by funding from MDA and other patient advocacy groups, the National Institutes of Health (NIH), and pharmaceutical company Biogen, the network’s aim is to gain a more detailed understanding of DM’s disease process and collect necessary clinical trial data to help determine the most appropriate outcome measures, biomarkers, and endpoints.
Since the network was formed, the six participating sites have developed standardized equipment and procedures for obtaining and analyzing needle muscle biopsies, quantifying measures of myotonia, and taking measurements of muscle strength and motor function. A group of coordinators and evaluators has been trained in all procedures, and strong relationships have been formed with patients and family members. The network completed initial studies of biomarkers and natural history, and it now aims to expand to larger cohorts, complete biomarker characterization, and gain a better understanding of the biological determinants of DM’s disease severity.
https://doi.org/10.55762/pc.gr.88907
Grantee: DM - Charles Thornton, MD
Grant type: Clinical Research Network Grant
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Grant - Additional Grants 2019 - DMD - Matthew Wood, PhD
"In this project we will investigate the use of exosomes as a method to encapsulate or “hide” AAVs from the immune system — so-called “stealth” AAVs — as a new method to help to dramatically improve the way that gene therapy might be delivered to DMD and other patients."
Matthew Wood, PhD, professor of Neuroscience at the University of Oxford and director of both the Oxford Rare Disease Center and the MDUK Oxford Neuromuscular Center, was awarded an MDA research grant totaling $210,000 over two years to optimize the delivery of genetic therapies such as oligonucleotides to tissues for treating Duchenne muscular dystrophy (DMD).
DMD is a genetic disease caused by a mutation in the dystrophin gene on the X chromosome that results in little or no production of dystrophin, an essential protein for keeping muscle cells intact. In September 2016, Sarepta Therapeutics’ Exondys 51 was the first gene therapy approved to treat DMD (it is an exon-skipping drug). The delivery of these types of therapies into the right tissues remains challenging, however, and Dr. Wood’s team has addressed this by developing a range of gene-delivery technologies, including peptides and nanotechnologies.
In gene-replacement therapy, adeno-associated virus (AAV) vectors are used to deliver a normal copy of a missing or mutated gene to a patient’s cells. However, AAVs can cause an immune response, making it impossible to deliver the therapy more than once. With this funding, Dr. Wood will develop a nanotechnology that uses exosomes, naturally occurring nanoparticles that transport proteins and genetic material between cells, to deliver gene therapies to cells potentially without provoking an immune response. The aim is to be able to treat people with pre-existing immunity to AAV as well as be able to administer more than one dose, if needed, to treat DMD over the course of the disease.
Grantee: DMD - Matthew Wood, PhD
Grant type: Research Grant
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Grant - Additional Grants 2019 - CMT – Michael Shy, PhD
"Rational clinical trials in CMT with outcome measures that can measure effectiveness are in place and will hopefully lead to effective treatments within the next three to five years for many subtypes."
Michael Shy, PhD, professor of Neurology and Pediatrics at the University of Iowa, was awarded an MDA Clinical Research Network Grant (CRNG) totaling $423,413 over three years to further develop the Inherited Neuropathies Consortium (INC), a network of clinical investigators dedicated to evaluating therapies for patients with inherited peripheral neuropathies, collectively known as Charcot-Marie-Tooth disease (CMT).
In CMT peripheral nerves degenerate, typically resulting in muscle weakness and sensory loss in the hands, arms, feet, and legs. The disease is progressive; however, the severity of symptoms and rate of progression depend on the type of CMT.
Dr. Shy has a long history of MDA funding, including receiving awards to create the North American CMT Network and to establish the North American CMT Consortium. His last grant was awarded for the Inherited Neuropathies Consortium (INC), an international collection of centers devoted to developing treatments for and treating patients with CMT.
With this most recent funding, Dr. Shy will expand the INC’s natural history data to become “clinical-trial-ready” for common and rare forms of CMT; identify, characterize, and facilitate treatments for novel forms of CMT; train future investigators in the field; and share INC data with scientists, physicians, and patients in an easily accessible manner.
Grantee: CMT – Michael Shy, PhD
Grant type: Clinical Research Network Grant
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Grant - Additional Grants 2019 - ALS - Stanley Appel, MD
Stanley Appel, MD, co-director of Houston Methodist Neurological Institute, chair of the Stanley H. Appel Department of Neurology and the Peggy and Gary Edwards Distinguished Chair in ALS at Houston Methodist Hospital, and professor of Neurology at Weill Cornell Medical College, was awarded an MDA human clinical trial grant totaling $558,800 over two-and-a-half years to expand the first-in-human study that demonstrated promising results leveraging patients’ own immune cells to treat amyotrophic lateral sclerosis (ALS). In ALS, muscle-controlling nerve cells called motor neurons are progressively lost, eventually causing muscles to become nonfunctional.
The award is part of a larger grant from The ALS Association, ALS Finding a Cure (ALSFAC), and MDA, which jointly awarded a clinical trial grant totaling more than $2.5 million over two-and-a-half years to leading investigators at the Houston Methodist Neurological Institute and Massachusetts General Hospital. The clinical trial grant is a collaborative study between the ALS team at Houston Methodist Hospital led by principal investigator Dr. Appel and the ALS team at Mass General Hospital led by Merit Cudkowicz, MD, chief of Neurology at Mass General Hospital and the Julieanne Dorn Professor of Neurology at Harvard Medical School.
Regulatory T-lymphocytes (Tregs) are a type of T-lymphocyte (a white blood cell that plays a central role in the immune response) that reduces immune system activation. Tregs are decreased in both numbers and function in the blood of people with ALS. Building on positive preclinical results showing that it was possible to restore Treg function outside the body, the first clinical trial in humans demonstrated that Tregs could be extracted from people living with ALS, expanded in vitro, and then safely infused back into the same patients, with three treated patients showing improved Treg suppressive function and slowed disease progression. The phase 2a clinical trial led by Dr. Appel will expand on the results of the first trial with participants receiving infusions of expanded regulatory (EPAR) T-cells followed by an ascending-dose, open-label extension trial.
https://doi.org/10.55762/pc.gr.81882
Grantee: ALS - Stanley Appel, MD
Grant type: Human Clinical Trial Grant
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Grant - Additional Grants 2019 - DMD – Rachelle H. Crosbie, PhD
"We hope to identify a pre-clinical candidate that will treat DMD by boosting sarcospan levels. We also want to learn more about how our lead compounds target sarcospan in muscle cells so we can design better, more effective drugs."
Rachelle H. Crosbie, PhD, professor and chair of Integrative Biology and Physiology at the University of California, Los Angeles, was awarded MDA Venture Philanthropy (MVP) funding totaling $389,463 over two years to develop a small molecule drug that increases expression of sarcospan, a protein that may help to prevent the muscle damage that occurs in Duchenne muscular dystrophy (DMD). MVP funding is awarded to researchers developing therapeutics for neuromuscular diseases to help lower the barriers and bridge the high-risk stages of drug development.
DMD is caused by mutations in the dystrophin gene on the X chromosome that result in little or no production of dystrophin, a protein essential to keeping muscle cells intact. While funded by an MDA postdoctoral fellowship starting in 1996, Dr. Crosbie identified a protein called sarcospan that may improve the structural integrity of dystrophic muscle in DMD.
After setting up her own lab, Dr. Crosbie continued to work on sarcospan. Her lab found that increasing the amount of sarcospan can convey a protective effect on skeletal and cardiac muscle in mice with muscular dystrophy. Her team has recently identified a set of small molecules that increase the levels of sarcospan, and with support from the MVP award, her team will chemically optimize these lead compounds and test them in DMD mice and DMD human cells. If successful, this work may lead to the development of a novel drug that could slow the loss of function in limb muscles, respiratory muscles, and heart.
Grantee: DMD – Rachelle H. Crosbie, PhD
Grant type: Venture Philanthropy Grant
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Grant - Summer 2019 - FSHD - Yi-Wen Chen, DVM, PhD
“We hope that we can demonstrate good bioavailability of the antisense oligonucleotide (ASO) therapy in muscle cells and high in vivo efficacy in the mouse model, which will allow us to move this forward for drug development.”
Yi-Wen Chen, DVM, PhD, associate professor at the Center for Genetic Medicine Research, Children’s Research Institute (CNMC) in Washington, DC, was awarded an MDA research grant totaling $200,000 over two years to develop an antisense oligonucleotide (ASO) therapy for facioscapulohumeral muscular dystrophy (FSHD).
FSHD leads to progressive degeneration of muscles, with the most pronounced effects appearing in muscles of the face, shoulder blades, and upper arms. FSHD is caused by abnormal expression of double homeobox 4 protein (DUX4), which causes toxicity and muscle cell death. Suppressing DUX4 expression is a primary therapeutic approach for halting disease progression, as it is thought that would prevent or slow down the many detrimental activities of this toxic protein on muscle cells.
As a new MDA grant awardee, Dr. Chen will develop an ASO-based therapy to knock down DUX4 expression using the same backbone chemistry as was successfully used for Spinraza (the first disease-modifying therapy to treat spinal muscular atrophy, approved by the US Food and Drug Administration in December 2016). Dr. Chen will start with previously identified FSHD ASO candidates that showed efficacy in cell culture and see how well they work in FSHD mice, aiming to take these ASOs closer to pre-clinical and clinical trials for treating FSHD.
https://doi.org/10.55762/pc.gr.87336
Grantee: FSHD - Yi-Wen Chen, DVM, PhD
Grant type: Research Grant
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Grant - Summer 2019 - CMT, MM, other NMDs - Wolfgang Pernice, PhD
“Our research aims to develop unbiased experimental strategies and tools to systematically address critical roadblocks in the identification and functional annotation of causative disease alleles in neuromuscular diseases.”
Wolfgang Pernice, PhD, a postdoctoral fellow in Neurology at Columbia University Medical Center in New York, was awarded an MDA development grant totaling $210,000 over three years to more accurately associate rare genetic variants to multiple neuromuscular diseases (NMDs).
For many major NMD categories, the causative gene can be identified in less than 50% of the cases. One of the complicating factors is that in many cases, rare gene variants are identified, but it’s unknown if a variant causes the disease or is harmless. Lacking are efficient, unbiased experimental strategies to systematically evaluate the relevance of these individual variants in disease. Likewise, it’s not known how many of these genes function in healthy individuals.
As a new MDA grantee, Dr. Pernice will use a novel imaging-based method and advanced machine learning to screen for disease-associated phenotypes in patient-derived cells with genetically confirmed NMDs, including Charcot-Marie-Tooth disease and mitochondrial myopathies. This method will allow him to establish a reference dataset by which to directly compare and evaluate new candidate mutations and conduct pharmacological screens for potentially therapeutic agents.
https://doi.org/10.55762/pc.gr.87332
Grantee: CMT, MM, other NMDs - Wolfgang Pernice, PhD
Grant type: Development Grant
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Grant - Summer 2019 - IBM - Thomas Lloyd, MD, PhD
“We expect that we will be able to use this model to better understand the role that inflammation plays in developing IBM pathology. We hope that we will be able to use this model to develop and test novel therapeutics for IBM patients.”
Thomas Lloyd, MD, PhD, associate professor of Neurology at Johns Hopkins University School of Medicine in Baltimore, was awarded an MDA research grant totaling $300,000 over three years to study muscle regeneration in a mouse model of inclusion body myositis (IBM).
Inclusion body myositis (IBM) is characterized by muscle inflammation, weakness, and atrophy (wasting). It is one of the idiopathic inflammatory myopathies, a group of disorders characterized by inflammation of the skeletal muscle.
Because one of the biggest barriers to therapy development in sporadic IBM (sIBM) has been the lack of animal models, Dr. Lloyd has created a model by transplanting sIBM muscle tissue from human biopsies into mice. As a new MDA grantee, Dr. Lloyd will study the interaction of the immune system and muscle regeneration in these mice and then screen for potential therapeutic strategies.
https://doi.org/10.55762/pc.gr.87338
Grantee: IBM - Thomas Lloyd, MD, PhD
Grant type: Research Grant
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Grant - Summer 2019 - ALS - Sandrine Da Cruz, PhD
“This work will provide critical insight for elucidating the mechanisms regulating protein aggregation and cell-to-cell spreading of protein aggregates, as well as [for] establishing safety and applicability of an antisense oligonucleotide (ASO) strategy as a therapy for fused in sarcoma (FUS) proteinopathies.”
Sandrine Da Cruz, PhD, assistant investigator of Neurobiology at the San Diego Branch of the Ludwig Institute for Cancer Research, was awarded an MDA research grant totaling $300,000 over three years to investigate the mechanisms underlying amyotrophic lateral sclerosis (ALS) caused by mutations in the fused in sarcoma (FUS) protein and potential therapies to treat the disease.
Despite having identified ALS-associated proteins, including FUS and TDP-43, the disease mechanism behind these proteins in ALS has yet to be discovered. Previously, Dr. Da Cruz used a mouse model to determine that if mutant FUS is delivered to the cytoplasm of a cell, then FUS aggregates there and spreads to adjacent cells in the central nervous system (CNS), worsening behavior in the mice associated with mutant FUS expression.
Dr. Da Cruz will use this funding to study both familial and sporadic ALS (and frontotemporal dementia, a related disease) in both an FUS mouse model and in cell culture. She will aim to determine the role of FUS aggregation and its cell-to-cell transmission in the CNS in the pathology of ALS. Dr. Da Cruz hopes to test the feasibility of lowering FUS levels using an antisense oligonucleotide as a first step in the development of a therapy, which may act to delay onset and slow progression of ALS.
https://doi.org/10.55762/pc.gr.87346
Grantee: ALS - Sandrine Da Cruz, PhD
Grant type: Research Grant
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Grant - Summer 2019 - DMD - Peter Currie, PhD
Peter Currie, PhD, professor of Medicine, Nursing, Health Sciences, and Developmental and Regenerative Biology at Monash University in Melbourne, Australia, was awarded an MDA research grant totaling $295,614 over three years to evaluate how correcting muscle stem cell dynamics in Duchenne muscular dystrophy (DMD) may help improve symptoms of the disease.
DMD is caused by a mutation in the dystrophin gene on the X chromosome that results in little or no production of dystrophin, a protein that is essential for keeping muscle cells intact. Recent studies, including those of Dr. Currie’s, have shown that dystrophin-deficient muscle has reduced ability to regenerate due to impaired function of satellite cells (a type of stem cell). Previous MDA-funded work allowed Dr. Currie to create zebrafish models of muscular dystrophy and screen for small molecules that can inhibit the onset of muscular dystrophy in these zebrafish.
Using this grant award, Dr. Currie will use his zebrafish system to examine the cellular and molecular processes that regulate muscle stem cell functions in vivo, which will hopefully enable new therapeutic approaches for the treatment of DMD. Dr. Currie will determine whether another membrane protein, laminin, can compensate for loss of dystrophin and restore satellite cell function and regeneration in DMD zebrafish.
https://doi.org/10.55762/pc.gr.87337
Grantee: DMD - Peter Currie, PhD
Grant type: Research Grant
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Grant - Summer 2019 - CMD, LGMD - Monkol Lek, PhD
“My focus in the genetics of neuromuscular diseases is to discover novel disease genes [and] mechanisms and build resources to better interpret rare variants discovered in known disease genes.”
Monkol Lek, PhD, assistant professor of Genetics at Yale University School of Medicine in New Haven, Conn., was awarded an MDA research grant totaling $300,000 over three years to improve the clinical interpretation of rare genetic variants identified in limb-girdle muscular dystrophy (LGMD) and congenital muscular dystrophy (CMD).
Despite advances in genetic technologies, only approximately 50% of individuals with rare neuromuscular diseases get a definitive genetic diagnosis. In Dr. Lek’s previously awarded MDA development grant, he was able to increase the diagnosis rate for LGMD through whole-genome sequencing and identify novel neuromuscular disease genes.
Still, even after more sophisticated genetic techniques, not all cases are solvable. Part of the problem is that not enough is known about the significance of rare variants that are difficult to interpret (so-called “variants of unknown significance,” or VUS). The research in this proposal aims to help decode some of those VUS.
Dr. Lek will use genome editing to introduce these VUS into cells and then develop a high-throughput assay in order to interpret the effect of those mutations. He will initially focus on two groups of neuromuscular diseases — collagenopathies and dystroglycanopathies — because the gene products related to these groups of diseases are typically expressed on the surface of muscle cells, making them easily accessible for high-throughput analysis and further functional studies.
https://doi.org/10.55762/pc.gr.87349
Grantee: CMD, LGMD - Monkol Lek, PhD
Grant type: Research Grant
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Grant - Summer 2019 - DMD - Michael Hicks, PhD
“Understanding how muscle stem cells interact with their niche is hugely important. It will help us understand how muscle stem cells become dysfunctional during muscular dystrophy. It will help us understand how stem cells form new niches, how these cells self-renew, and ultimately how skeletal muscles regenerate more efficiently.”
Michael Hicks, PhD, a postdoctoral fellow in Microbiology, Immunology, and Molecular Genetics at the University of California, Los Angeles, was awarded an MDA development grant totaling $210,000 over three years to study the potential of modulating the microenvironment and satellite cell niche in Duchenne muscular dystrophy (DMD) to support muscle stem cells.
DMD is caused by a mutation in the dystrophin gene on the X chromosome that results in little or no production of dystrophin, a protein that is essential for keeping muscle cells intact. Every skeletal muscle fiber has a specialized compartment called the satellite cell (SC) niche, which houses all the components to allow a transplanted donor cell to behave like an SC. An SC is a stem cell that can self-renew and repopulate new skeletal muscle after reoccurring injury. Stem cell therapy offers the potential to introduce into DMD muscle healthy, dystrophin-containing muscle with the capacity to regenerate.
Dr. Hicks will use this new funding to assess whether stem cells can engraft and self-renew in DMD mouse muscle. Using human induced pluripotent stem cells and transgenic mice, he will study the process of how muscle stem cells self-renew after transplantation, hopefully one day applying these tools to develop a long-term therapy for cell replacement in diseased muscle.
https://doi.org/10.55762/pc.gr.87330
Grantee: DMD - Michael Hicks, PhD
Grant type: Development Grant
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Grant - Summer 2019 - DM - Melissa Hinman, PhD
“Although digestive symptoms affect quality of life, few studies have focused on understanding their causes or developing therapies to treat them. Our work will be the first to use an animal model system to study the digestive symptoms of DM.”
Melissa Hinman, PhD, a postdoctoral fellow in Molecular Biology at the University of Oregon in Eugene, was awarded an MDA development grant totaling $210,000 over three years to conduct studies using zebrafish to understand and treat gastrointestinal symptoms of myotonic dystrophy (DM).
While weakness and myotonia (the inability to relax) of voluntary muscles are hallmark symptoms of the disease, DM can affect other parts of the body, too, including the digestive system. Common digestive symptoms include abdominal pain, altered gut movement, constipation, diarrhea, and changes in gut bacteria. Gastrointestinal symptoms in DM type 1 (DM1) are prevalent and are consistently reported as one of the most distressing aspects of the disease. However, very little research in this area exists.
Using this grant funding, Dr. Hinman will study defects in gut motility, intestinal barrier function, microbiota, and inflammation in DM1 zebrafish models that she has developed. Dr. Hinman will use her zebrafish model to test whether treatment with specific types of bacteria or drugs improves digestive symptoms. She hopes this will improve understanding of the mechanisms behind DM-related digestive symptoms and potentially identify candidate treatments.
https://doi.org/10.55762/pc.gr.87331
Grantee: DM - Melissa Hinman, PhD
Grant type: Development Grant
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Grant - Summer 2019 - LGMD - Martin Childers, PhD, DO
Martin Childers, PhD, DO, chief medical officer at Asklepios BioPharmaceutical Inc. in North Carolina, was awarded an MDA research grant totaling $192,500 over one year to perform pre-clinical studies using an adeno-associated virus (AAV) to deliver a gene therapy for limb-girdle muscular dystrophy type 2I (LGMD2I).
Limb-girdle muscular dystrophies are a diverse group of disorders with many subtypes categorized by disease gene and inheritance. LGMD2I is caused by mutations in the gene encoding fukutin-related protein (FKRP). In gene-replacement therapy for LGMD2I, an AAV vector is used to deliver a normal copy of the missing or mutated FKRP gene to a patient’s cells in order to make up for the inherited, non-functioning copy.
With this funding, Dr. Childers and Asklepios will build upon existing proof-of-concept work to collect the remaining pre-clinical data necessary for a first-in-human gene transfer clinical trial using AAV-FKRP in patients with LGMD2I. Upon successful completion of these studies, Asklepios will submit an Investigational New Drug (IND) application to the FDA, aiming to start a clinical trial in late 2020.
Grantee: LGMD - Martin Childers, PhD, DO
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Grant - Summer 2019 - FA - Jordi Magrane, PhD
Jordi Magrane, PhD, associate professor of Neuroscience at Weill Cornell Medical College in New York, was awarded an MDA research grant totaling $300,000 over three years to study the effect of frataxin protein deficiency in different cell types on the survival of sensory neurons in Friedreich’s ataxia (FA).
In FA, mutations in the frataxin gene (FXN) cause decreased production of frataxin protein, resulting in diminished energy production in cells, including those of the nervous system and heart. Dr. Magrane was previously awarded MDA early-in-career funding to study defects in mitochondrial axonal transport in amyotrophic lateral sclerosis (ALS) motor neurons. He will apply knowledge gained from that work to this new funding.
In this new work, Dr. Magrane will use animal models and cells from FA patients to investigate whether the preferential loss of large myelinated sensory neurons in FA is due to intrinsic properties of the neurons themselves or to interactions with the Schwann cells that provide their myelin. Successful completion of this project will help discover and possibly validate new targets for therapeutic intervention in FA.
https://doi.org/10.55762/pc.gr.87339
Grantee: FA - Jordi Magrane, PhD
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Grant - Summer 2019 - ALS - Jone Lopez Erauskin, PhD
“I expect to determine how stathmin-2 provides a crucial role in the maintenance and regeneration of the neuromuscular junctions that connect motor neurons and skeletal muscles. With this, I hope to uncover insights for the development of ALS treatments that will halt the progression of the disease from its early phases.”
Jone Lopez Erauskin, PhD, postdoctoral fellow in Cellular and Molecular Medicine at the San Diego Branch of the Ludwig Institute for Cancer Research, was awarded an MDA development grant totaling $210,000 over three years to study the mechanisms of maintenance and regeneration of the neuromuscular junction (NMJ) in amyotrophic lateral sclerosis (ALS).
Normally, nerve cells communicate with muscle cells by sending electrical signals across the NMJ. Frequently, disruption of this communication happens early in the course of ALS. Recently, Dr. Lopez Erauskin discovered that the loss of stathmin-2, a neuronal growth-associated protein, is universally found in sporadic and familial (inherited) ALS, and that stathmin-2 is essential for axonal (nerve fiber) regeneration.
In this project, Dr. Lopez Erauskin seeks to identify the mechanisms that underlie disruption of nerve-muscle connections in ALS through the loss of stathmin-2. These studies may enable the design of therapeutic strategies to maintain or restore nerve-muscle connections, thereby delaying or halting disease progression in ALS.
https://doi.org/10.55762/pc.gr.87329
Grantee: ALS - Jone Lopez Erauskin, PhD
Grant type: Development Grant
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Grant - Summer 2019 - ALS - Jeffrey D. Rothstein, MD, PhD
Jeffrey D. Rothstein, MD, PhD, director of the Brain Science Institute and director of the Robert Packard Center for ALS Research at Johns Hopkins University School of Medicine in Baltimore, was awarded an MDA research grant totaling $300,000 over three years to investigate the mechanism of cell-specific injury in C9ORF72-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
ALS is a progressive neuromuscular disease that destroys muscle-controlling nerve cells called motor neurons. In 2011, it was discovered that a defect in the C9ORF72 gene where one segment of the gene is repeated too many times — also known as a repeat expansion — is the most common cause of the familial form of ALS and is found in some sporadic cases as well. In some patients, the C9ORF72 mutation leads to both ALS and FTD, while in others it leads to FTD only for reasons still unknown.
In a series of previous grants, Dr. Rothstein compared induced pluripotent stem (iPS) cells from people with C9ORF72-ALS to cells from unaffected individuals to find a molecular signature, or biomarker, for the disease-causing effects of the mutant gene. In later MDA-funded work, he used ALS patient-derived stem cells to investigate the role of nuclear dysfunction in ALS caused by C9ORF72 mutations, with the aim of uncovering novel drug targets for ALS. His most recent grant was for Answer ALS, a nationwide consortium that is building a tool for data integration and characterization of disease networks in ALS.
In this newly awarded MDA grant, Dr. Rothstein will identify pathways behind cortical neuron degeneration in FTD versus spinal neuron degeneration in ALS by using human iPS cell-derived forebrain neurons and spinal motor neurons from patients diagnosed with C9ORF72-FTD and ALS/FTD. These studies will help to identify common cellular mechanisms of neurodegeneration in FTD and ALS as well as pathways unique to each cell type, which will better inform the design of therapeutic intervention in both diseases.
https://doi.org/10.55762/pc.gr.87342
Grantee: ALS - Jeffrey D. Rothstein, MD, PhD
Grant type: Research Grant
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Grant - Summer 2019 - DMD - James Ervasti, PhD
“While there has been tremendous progress in the advancement of therapies to treat DMD patients, we still have not cured anyone of the disease, and I believe that a better understanding of the problem will lead to better solutions.”
James Ervasti, PhD, professor of Biochemistry, Molecular Biology, and Biophysics at the University of Minnesota, Twin Cities, in Minneapolis, was awarded an MDA research grant totaling $300,000 over three years to study the mechanical characterization of dystrophin in Duchenne muscular dystrophy (DMD).
DMD is caused by a mutation in the dystrophin gene on the X chromosome that results in little or no production of dystrophin, a protein that is essential for keeping muscle cells intact. Dystrophin, and the related protein utrophin, have long been hypothesized to protect muscle during contraction by functioning as molecular shock absorbers, but direct evidence for this role is lacking.
Dr. Ervasti will test the hypothesis that dystrophin and utrophin act as shock absorbers by mechanically characterizing both proteins. His results will offer a new understanding into the functional similarities and differences between dystrophin and utrophin in normal muscle and inform development of dystrophin gene-targeted therapies and other drugs (including utrophin-promoting drugs) that might be used to replace the function of dystrophin in DMD.
https://doi.org/10.55762/pc.gr.87347
Grantee: DMD - James Ervasti, PhD
Grant type: Research Grant
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Grant - Summer 2019 - CMD, LGMD - Monkol Lek, PhD
“My focus in the genetics of neuromuscular diseases is to discover novel disease genes [and] mechanisms and build resources to better interpret rare variants discovered in known disease genes.”
Monkol Lek, PhD, assistant professor of Genetics at Yale University School of Medicine in New Haven, Conn., was awarded an MDA research grant totaling $300,000 over three years to improve the clinical interpretation of rare genetic variants identified in limb-girdle muscular dystrophy (LGMD) and congenital muscular dystrophy (CMD).
Despite advances in genetic technologies, only approximately 50% of individuals with rare neuromuscular diseases get a definitive genetic diagnosis. In Dr. Lek’s previously awarded MDA development grant, he was able to increase the diagnosis rate for LGMD through whole-genome sequencing and identify novel neuromuscular disease genes.
Still, even after more sophisticated genetic techniques, not all cases are solvable. Part of the problem is that not enough is known about the significance of rare variants that are difficult to interpret (so-called “variants of unknown significance,” or VUS). The research in this proposal aims to help decode some of those VUS.
Dr. Lek will use genome editing to introduce these VUS into cells and then develop a high-throughput assay in order to interpret the effect of those mutations. He will initially focus on two groups of neuromuscular diseases — collagenopathies and dystroglycanopathies — because the gene products related to these groups of diseases are typically expressed on the surface of muscle cells, making them easily accessible for high-throughput analysis and further functional studies.
https://doi.org/10.55762/pc.gr.87349
Grantee: CMD, LGMD - Monkol Lek, PhD
Grant type: Research Grant
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