Grant - Summer 2019 - DMD - Courtney Young, PhD
“This work will further advance pre-clinical development of our gene editing therapy for Duchenne. Assessing the immune response will allow for safety to be assessed and strategies to re-dose the therapy to be developed, which would greatly increase the efficacy and applicability of the therapy.”
Courtney Young, PhD, CEO of MyoGene Bio LLC in Los Angeles, was awarded an MDA research grant totaling $299,592 over three years to assess the immune response to repeated dosing of adeno-associated virus-dependent gene-replacement therapy 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 the protein dystrophin. Currently, gene-replacement and gene-editing (for example, the CRISPR gene-editing system) therapies rely on the adeno-associated virus (AAV) to deliver the replacement gene or gene-editing program to a patient’s cells. However, the virus can trigger an immune response in the body, so patients either have pre-existing immunity or will develop it after the first dose — ultimately preventing repeated dosing of the therapy.
At MyoGene Bio, Dr. Young and team have developed a gene-editing therapy using CRISPR/Cas9 aimed at allowing the production of dystrophin, and they have demonstrated the therapy can restore dystrophin in human cells and in mice. To safely enable repeated exposure to AAV, Dr. Young, who is an MDA early-in-career investigator, will develop an immunosuppressive protocol using humanized DMD mice to characterize the adaptive immune response to single and repeated exposures of AAV-CRISPR. Importantly, this work can inform practices not just in DMD but also across a wide array of diseases utilizing AAV-based gene therapy and gene editing.
Grantee: DMD - Courtney Young, PhD
Grant type: Research Grant
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Grant - Summer 2019 - CMT, SMA - Charlotte Sumner, MD
Charlotte Sumner, MD, professor of Neurology and Neuroscience at Johns Hopkins University School of Medicine in Baltimore, was awarded an MDA research grant totaling $300,000 over three years to study the role of mutations in the transient receptor potential vanilloid 4 gene (TRPV4) in causing one type of Charcot-Marie-Tooth disease (CMT) and distal spinal muscular atrophy (SMA).
CMT is characterized by the degeneration of peripheral nerves, resulting in disabling muscle weakness and sensory loss. One form of the disease, CMT type 2C (CMT2C), is caused by mutations in TRPV4, which codes for a cellular membrane channel protein that helps control the flow of calcium in and out of cells. Mutations in TRPV4 cause CMT2C and distal SMA, revealing an unexpected role for this Ca2+-permeable channel in neurodegeneration.
In previous MDA-funded research, Dr. Sumner generated fly and mouse models of CMT2C in order to better understand the mechanisms of disease. With this newest MDA grant, Dr. Sumner will focus on the role that TRPV4 may play in endothelial cells regulating the blood-nerve barrier. Defining the mechanisms by which TRPV4 mutations cause neuropathy is important because TRPV4 protein is a readily druggable therapeutic target — it is expressed at the plasma membrane and small molecules acting on it already exist.
Grantee: CMT, SMA - Charlotte Sumner, MD
Grant type: Research Grant
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Grant - Summer 2019 - DMD - Changwon Kho, PhD
“Given the high burden of cardiomyopathy in DMD patients, it is vital to identify the pathophysiological mechanisms in place in an effort to develop ways to effectively improve cardiac dysfunction and prevent muscular damage.”
Changwon Kho, PhD, assistant professor of Cardiology at the Icahn School of Medicine at Mount Sinai in New York, was awarded an MDA research grant totaling $300,000 over three years to study the SUMO1 protein as a therapeutic target for 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. Patients with DMD typically have cardiac complications, and heart failure is the major cause of death in DMD. It was recently discovered that the small ubiquitin-like modifier type 1 protein (SUMO1) pathway is defective in dystrophic hearts with established cardiomyopathy. In preliminary studies, Dr. Kho demonstrated that increasing activity of SUMO1, a naturally occurring protein, can restore calcium balance and cardiac function in DMD mice.
With this current funding, Dr. Kho will validate SUMO1 as a target and then begin to test candidate SUMO1 activators in a mouse model of DMD heart disease, aiming to provide a critical foundation for targeting the SUMO1 pathway as a treatment for DMD.
Grantee: DMD - Changwon Kho, PhD
Grant type: Research Grant
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Grant - Summer 2019 - IBM - Bradley Olwin, PhD
Bradley Olwin, PhD, professor of Molecular, Cellular, and Developmental Biology at the University of Colorado Boulder, was awarded an MDA research grant totaling $300,000 over three years to study the regulation of TDP-43 protein aggregates in normal and diseased skeletal muscle.
Over the past decade, the role of TDP-43 disregulation and aggregation in nerve cells in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) has become increasingly clear. In 1998, Dr. Olwin published work indicating TDP-43 had important roles in muscle cells as well.
This current grant funding will allow Dr. Olwin to build upon that novel work and study the dynamics of how TDP-43 myogranules (TDP-43-containing aggregates) form and dissolve in muscle cells normally, and in the context of diseases such as inclusion body myositis (IBM), an inflammatory myopathy. Understanding whether TDP-43 myogranules are functional or detrimental to muscle cells will be informative not just for IBM but also for other drug-development efforts focused on decreasing aggregation of TDP-43 (for example, in ALS and frontotemporal dementia).
https://doi.org/10.55762/pc.gr.87341
Grantee: IBM - Bradley Olwin, PhD
Grant type: Research Grant
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Grant - Summer 2019 - SMA - Ashlyn Spring, PhD
Ashlyn Spring, PhD, a postdoctoral fellow in Biological and Genome Sciences at the University of North Carolina at Chapel Hill, was awarded an MDA development grant totaling $210,000 over three years to study the relationship of immune system dysfunction in spinal muscular atrophy (SMA).
SMA is caused by a mutated or missing survival motor neuron 1 gene (SMN1) that prevents the body from making enough survival motor neuron protein (SMN), ultimately leading to the loss of motor neurons, muscle weakness, and paralysis seen in SMA. Previous findings suggest that the immune system is also dysfunctional in patients with SMA, making them more susceptible to infection. However, while major strides have been made in developing and approving therapies to treat the genetic mutations behind SMA, little is known about how the immune system dysfunction affects other tissues.
In this project, Dr. Spring, a first-time MDA grantee, will use fly, mouse, and human cell line models of SMA to investigate how the immune system’s response to infections is impacted in the disease. This work will lead to an understanding of why SMN1 mutations change immune system function as well as help identify targets for new therapeutics to improve treatment of SMA in the future.
https://doi.org/10.55762/pc.gr.87333
Grantee: SMA - Ashlyn Spring, PhD
Grant type: Development Grant
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Grant - Summer 2019 - SMA - Arthur Burghes, PhD
“In this proposal we aim to identify the genes that modify the severity of SMA and the changes in them that cause modification of severity. The identification of these changes will improve the ability to predict severity with a DNA test and initiate treatment at the appropriate time. In addition, these modifier genes can be novel therapeutic targets that can act independently of current therapies to increase SMN.”
Arthur Burghes, PhD, professor of Biological Chemistry and Pharmacology, Molecular Genetics, and Neurology at The Ohio State University Wexner Medical Center in Columbus, was awarded an MDA research grant totaling $200,000 over two years to study genes that might have the potential to modify the severity of spinal muscular atrophy (SMA).
In SMA, mutations in the survival motor neuron 1 gene (SMN1) prevent a person from making enough survival motor neuron protein (SMN). Lack of this protein is what causes the loss of motor neurons, muscle weakness, and paralysis that define SMA. In addition to the SMN1 gene, there is also a related SMN2 gene, which functions as a “backup” to producing some amount of SMN protein.
Dr. Burghes was previously awarded MDA funding to study how SMN2 copy number might predict severity of SMA. Currently SMN2 copy number is the best predictor of SMA severity and in general, having more SMN2 copies results in less severe SMA. However, both SMA type 2 and type 3 patients have three copies of SMN2. In this new work, Dr. Burghes will study the DNA of siblings who have three copies of SMN2, but one has SMA type 2 while the other has SMA type 3. He aims to identify new genes with the potential to modify the severity of the symptoms of SMA, which may potentially become novel therapeutic targets.
https://doi.org/10.55762/pc.gr.87335
Grantee: SMA - Arthur Burghes, PhD
Grant type: Research Grant
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Grant - Summer 2019 - MM - Antonio Barrientos, PhD
“Better understanding of the cellular and mitochondrial processes leading to COX assembly is expected to have a significant impact on health and neuromuscular disease. Our project will test therapeutic interventions involving copper delivery to mitochondria, which could be extremely useful to patients.”
Antonio Barrientos, PhD, professor of Neurology and Biochemistry and Molecular Biology at the University of Miami Miller School of Medicine, was awarded an MDA research grant totaling $300,000 over three years to study the relationship between genetic mutations and copper delivery to mitochondrial cells in the pathology of mitochondrial myopathies.
Mitochondria produce much of the energy that cells require to function, and an important component of that process is an enzyme called cytochrome c oxidase (COX). Without a properly assembled COX complex, cellular energy production is severely compromised; this affects the brain, muscles, and other organs with high energy demands. Previously, MDA awarded Dr. Barrientos funding to study the underlying molecular mechanisms of COX deficiency in some forms of mitochondrial myopathy as well as defects in mitochondrial protein complex assembly, which are a frequent cause of inherited mitochondrial myopathies.
The mitochondrial protein COX1, which is one of the proteins that make up the COX protein complex, requires copper in order to function and produce cellular energy. In this proposal, Dr. Barrientos will use patient-derived cells to study the proteins that help deliver copper to mitochondria, how their function is disrupted by mutations causing mitochondrial myopathies, and why this dysfunction is specific to certain tissues. Additionally, he will test various therapeutic strategies to enhance copper delivery.
https://doi.org/10.55762/pc.gr.87334
Grantee: MM - Antonio Barrientos, PhD
Grant type: Research Grant
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Grant - Summer 2019 - SBMA - Alireza Mashaghi Tabari, PhD
“To date, not many labs have probed the underlying nature of genetically inherited diseases using optical tweezer techniques. We are excited in setting a precedent to deliver such first time molecular biophysical studies.”
Alireza Mashaghi Tabari, PhD, assistant professor of Systems Biomedicine and Pharmacology at Leiden University in the Netherlands, was awarded an MDA research grant totaling $300,000 over three years to study how altered protein folding of the androgen receptor influences the pathology of spinal-bulbar muscular atrophy (SBMA).
SBMA is a genetic disorder in which loss of motor neurons — nerve cells in the spinal cord and brainstem — affects the part of the nervous system that controls voluntary muscle movement. SBMA is caused by repeat expansions in the androgen receptor gene. (A repeat expansion is a genetic defect where one segment of the gene is repeated too many times.) Mutations in the androgen receptor in SBMA alter protein folding, cell signaling, and protein aggregation for unknown reasons.
Chaperone proteins are key to protein folding and the removal of damaged, misfolded proteins. As a new MDA researcher, Dr. Mashaghi Tabari will use sensitive single-molecule approaches to understand how the structure of the androgen receptor is altered in SBMA, and specifically how chaperones are involved in the changes. These studies might inform therapy development for SBMA and other neuromuscular diseases where protein misfolding is involved.
https://doi.org/10.55762/pc.gr.87340
Grantee: SBMA - Alireza Mashaghi Tabari, PhD
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Grant - Additional Grants 2019 - DM – Locana
"DM is caused by expression of dysfunctional, repetitive RNA in diseased tissues, where application of Locana’s core RNA-targeting technology has been shown to have potential for single-dose therapeutic benefit and could provide a long-lasting approach for patients."
Locana, a leading RNA-targeting gene therapy company based on the work of one of its founders Gene Yeo, PhD, MBA, professor of Cellular and Molecular Medicine at the University of California, San Diego, was awarded MDA Venture Philanthropy (MVP) funding totaling $550,000 over two years to advance Locana’s development program for myotonic dystrophy (DM), the most common form of adult-onset muscular dystrophy. 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.
Myotonic dystrophy is a genetic neuromuscular disease that affects multiple muscles and systems, including skeletal muscle, cardiac muscle, the gastrointestinal tract, and the central nervous system. In both types of DM, DM1 and DM2, genetic mutations in the form of large repeat expansions of DNA lead to the development of clumps of RNA that become toxic to healthy cells. (RNA is the molecular step between DNA and protein.)
Locana’s RNA-targeting platform technology aims to address a wide spectrum of human genetic diseases, including DM. Locana has advanced a powerful modular RNA targeting-effector approach that is distinct from DNA-targeting approaches (such as CRISPR/Cas9) and nucleic acid-based RNA targeting approaches (such as antisense oligonucleotides). Locana intends to build a portfolio of therapies that address the root cause of genetic diseases driven by dysfunctional RNA behavior.
Grantee: DM – Locana
Grant type: Venture Philanthropy Grant
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Grant - Additional Grants 2019 - FSHD – Justin Cohen, PhD
"By emphasizing testing of FDA-approved compounds, the clinical trial pipeline can be sped up, reducing the wait time for any potential treatment."
Justin Cohen, PhD, a postdoctoral fellow at Yale University School of Medicine, was awarded an MDA development grant of $140,000 over two years to test FDA-approved drugs that target therapeutic pathways for facioscapulohumeral muscular dystrophy (FSHD). The award was made in conjunction with a grant from the Chris Carrino Foundation for FSHD. Since Dr. Cohen lives with FSHD himself, the award will provide for a lab technician who will work alongside Dr. Cohen to perform the benchwork for studies that he designs.
FSHD is caused by abnormal expression of double homeobox 4 protein (DUX4), which leads to the production of toxic proteins and muscle cell death. With this new funding, Dr. Cohen will identify biological pathways that contain therapeutic targets for FSHD and validate related genes among the pathways. He will then test drugs that target these pathways, with an emphasis on those that are already FDA-approved, for their ability to reduce both cell death caused by toxic DUX4 and biomarkers of FSHD — hopefully discovering one that could enter clinical trials for FSHD.
https://doi.org/10.55762/pc.gr.86380
Grantee: FSHD – Justin Cohen, PhD
Grant type: Development Grant
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Grant - Additional Grants 2019 - FSHD – Adam Bittel, PT, DPT, PhD
"We are interested in both understanding how exercise affects skeletal muscle in FSHD and identifying the key cellular events contributing to those responses."
Adam Bittel, PT, DPT, PhD, a postdoctoral fellow at Children’s National Medical Center in Washington, DC, was awarded the 2019 SSSI-MDA Fellowship Award. The award, co-sponsored by Strength, Science & Stories of Inspiration (SSSI) and MDA, will provide a total of $40,000 over two years to support Dr. Bittel’s work investigating the cellular mechanisms underlying the effects of exercise in facioscapulohumeral muscular dystrophy (FSHD).
During his doctoral studies, Dr. Bittel explored how exercise influences multi-organ metabolism in metabolic syndromes as well as in Barth syndrome, a genetic disease affecting skeletal and cardiac muscle. While exercise is known to improve muscle health and metabolism in other forms of muscular dystrophy, there are very few studies assessing the effects of exercise in individuals with FSHD. Dr. Bittel is interested in understanding how exercise affects skeletal muscle in a mouse model of FSHD (the FLExDUX4 mouse) and in identifying important cellular events contributing to those responses.
https://doi.org/10.55762/pc.gr.87251
Grantee: FSHD – Adam Bittel, PT, DPT, PhD
Grant type: Development Grant
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Grant - Winter 2019 - Pompe Disease – Ellen Roche, PhD
Ellen Roche, assistant professor of Medical Engineering at Massachusetts Institute of Technology, was awarded an MDA research grant totaling $300,000 over three years to develop a soft robotic “implantable ventilator” as an alternative ventilation therapy in patients whose diaphragm loses function due to neuromuscular disease, leading to chronic respiratory failure. She will target late-onset Pompe disease, but the therapy could be applied to a range of neuromuscular conditions with diaphragm problems. This device would provide a long-term alternative to current available therapies.
Grantee: Pompe Disease – Ellen Roche, PhD
Grant type: Research Grant
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Grant - Winter 2019 - ALS - Ze’ev Melamed, PhD
"I believe that my proposed study may open the door to a completely new and promising direction in ALS research. Implementation of cellular and genomics tools offers an innovative approach to uncover mechanisms through which stathmin-2 loss-of-function provokes ALS pathogenesis and if so, identify a feasible therapeutic approach."
Ze’ev Melamed, PhD, postdoctoral fellow at the Ludwig Institute for Cancer Research at the University of California, San Diego, was awarded an MDA development grant totaling $210,000 over three years to collaborate with Ionis Pharmaceuticals to determine how suppression of stathmin-2 protein, recently shown to be decreased in the motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients, drives motor neuron degeneration and whether reversal of stathmin-2 defects could have therapeutic potential for ALS.
One hallmark of most cases of ALS is the accumulation of the RNA-binding protein TDP-43 into aggregates (clumps) outside the nucleus of the cell, but it is still not understood how these defects contribute to disease. In previous work, Dr. Melamed used cell models to discover that TDP-43 regulates the maturation of the mRNA (DNA code creates RNA in the form of a messenger, or mRNA molecule) of stathmin-2, a microtubule-associated protein previously implicated in axonal growth and regeneration. In other words, he found that decreased levels of stathmin-2 mRNA is a consequence of TDP-43 pathology in ALS.
In this work, he will study how stathmin-2 affects the maintenance and repair of motor neurons, and how loss of stathmin-2 affects the ability of neurons to regenerate. He will also work with Ionis Pharmaceuticals to develop an antisense oligonucleotide designed to correct aberrant processing of stathmin-2 mRNA, possibly having the therapeutic effect of restoring levels of stathmin-2 in motor neurons of patients with ALS.
https://doi.org/10.55762/pc.gr.84539
Grantee: ALS - Ze’ev Melamed, PhD
Grant type: Development Grant
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Grant - Winter 2019 - EDMD - Tyler Kirby, PhD
"If we determine that DNA damage is a major cause of developing this form of muscular dystrophy, this will open up a new area of research for testing various therapeutic avenues. Many pharmacological treatments are currently being developed or in clinical trials to target DNA damage repair, mainly within the cancer field, which would facilitate the potential for rapid bench-to-bedside implementation."
Tyler Kirby, PhD, a postdoctoral fellow in Cell and Molecular Biology at Cornell University, was awarded an MDA development grant totaling $210,000 over three years to explore the novel hypothesis that activity of a DNA repair protein, DNA-dependent protein kinase (DNA-PK), is a primary driver of Emery-Dreifuss muscular dystrophy (EDMD).
Laminopathies are caused by mutations in the gene that codes for nuclear envelope proteins lamin A and C, which line the nucleus of the cell and give it structure. While lamin A/C is found in almost every cell type, most mutations affect only muscle tissue, causing a subset of muscular dystrophies, one of which is EDMD. In EDMD, mutations in the gene for lamin A/C make muscle cell nuclei and DNA vulnerable to damage, which starts activation of DNA repair. Previously, Dr. Kirby found that limiting the activity of a specific DNA repair protein, DNA-PK, using drugs already in clinical trials significantly improved the health of mutant muscle cells.
In this work, he will test the role of DNA damage on disease progression in both in vitro (in a petri dish) and in vivo (animal) models, as well as determine how DNA damage may lead to death of muscle fiber. Specifically, he will assess DNA damage across the spectrum of disease and measure the toxic effects of increased DNA-PK activity, including to metabolic and mitochondrial function.
https://doi.org/10.55762/pc.gr.84537
Grantee: EDMD - Tyler Kirby, PhD
Grant type: Development Grant
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Grant - Winter 2019 - DM - Tom Cooper, MD
"The overall goal of the work is to understand the molecular and physiological pathways leading from the disease-causing mutation to the molecular and cellular defects that cause cardiac conduction defects and arrhythmias."
Tom Cooper, MD, professor of Pathology and Immunology at Baylor College of Medicine, was awarded an MDA research grant totaling $325,571 over three years to study how the molecular defects that cause myotonic dystrophy type 1 (DM1) relate to the heart problems that are a prominent symptom of this disease (they affect at least half of individuals with DM1).
DM1 causes weakness of the voluntary muscles and an inability to relax muscles at will. As the disease progresses, many other organ systems are impacted, and the heart can weaken and develop an abnormal rhythm. The most lethal aspects of DM1 are the cardiac problems that develop with the disease.
DM1 occurs when a gene on chromosome 19 called DMPK contains an abnormally expanded section. The large repeat expansions form aggregates of toxic RNA that ultimately prevent proteins essential for healthy muscle function from being made properly. In previous MDA-funded work, Dr. Cooper created a mouse model on which he tested antisense oligonucleotides — short RNA-like molecules that bind to the excess RNA, blocking its interactions with other substances or causing it to be broken down — aimed at delivery to the heart muscle specifically.
In this work, Dr. Cooper hopes to better understand the pathogenic mechanisms compromising heart function in DM1 and to test the ability of different therapeutic approaches to reverse or rescue the cardiac complications in his DM1 mouse model.
https://doi.org/10.55762/pc.gr.84544
Grantee: DM - Tom Cooper, MD
Grant type: Research Grant
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Grant - Winter 2019 - ALS - Thomas Gaj, PhD
"We’re in the middle of a scientific revolution that’s seeing the development of increasingly precise and effective tools for correcting many different kinds of genetic defects. Our lab and many others are committed to using these and other emerging technologies to treat a range of neuromuscular diseases."
Thomas Gaj, PhD, assistant professor of Bioengineering at the University of Illinois at Urbana-Champaign, was awarded an MDA research grant totaling $300,000 over three years to evaluate whether gene editing could be applied as a potential treatment for amyotrophic lateral sclerosis (ALS) caused by mutations in the superoxide dismutase 1 (SOD1) gene. Mutations in SOD1 are estimated to cause about 2 percent of all ALS cases.
It is believed that mutations in the SOD1 gene cause the SOD1 protein to adopt abnormal toxic functions, leading to the loss of motor neurons that causes ALS. Gene editing allows researchers to change or correct DNA. A new kind of gene-editing technique called single base editing is modeled on the CRISPR-Cas9 system but with additional enzymes that modify DNA by converting one base in the DNA code to another.
Unlike traditional gene-editing tools, single base editors can alter a gene sequence without breaking the DNA. In this project, Dr. Gaj will use single base editing to reduce the amount of toxic SOD1 protein in the spinal cord of mice by either causing the mutated SOD1 gene to become inactive or by directly correcting a specific gene mutation. If successful, this work could pave the way for the development of a gene therapy for ALS based on single base editing technology as well as the discovery of how gene-editing technology can be used to treat other neuromuscular diseases.
https://doi.org/10.55762/pc.gr.84548
Grantee: ALS - Thomas Gaj, PhD
Grant type: Research Grant
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Grant - Winter 2019 - ALS - Tania Gendron, PhD
"We hope that the biomarkers of cognitive impairment identified through this work will prove useful in the clinical assessment and care of patients, and in the design of clinical trials. Moreover, because biomarkers for cognitive dysfunction are likely to reflect biochemical changes that precede its clinical manifestation, they may permit the earlier diagnosis of such dysfunction — information important for the effective timing of potential medical interventions."
Tania Gendron, PhD, assistant professor of Neuroscience at the Mayo Clinic in Jacksonville, Fla., was awarded an MDA research grant totaling $285,000 over three years to identify biomarkers to predict cognitive impairment in amyotrophic lateral sclerosis (ALS), which could be useful in patient care as well as for stratification of clinical trials.
As many as half of all ALS patients will show signs of impaired cognition during the course of the disease. Recognizing symptoms of cognitive impairment is important considering the effect they have on disease progression (patients with ALS who also have cognitive impairment have a shorter survival time), quality of life, and disease management and treatment of symptoms. To date, there are no validated biomarkers for cognitive impairment in patients with ALS.
The goal of this project is to deliver a panel of biomarkers that can detect emerging cognitive impairment in ALS patients. Dr. Gendron will use mass spectrometry-based proteomics to identify protein biomarkers of cognitive impairment in patients’ spinal fluid, and then determine whether these biomarkers correlate with the severity of cognitive impairment and if they can be used to determine the rate of disease progression and survival.
If successful, identifying biomarkers for cognitive impairment in ALS patients would help to improve patient stratification in clinical trials, as well as provide insight into the discovery of drug targets for treating cognitive impairment in not only ALS but also a variety of other neurological diseases.
https://doi.org/10.55762/pc.gr.84549
Grantee: ALS - Tania Gendron, PhD
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Grant - Winter 2019 - DM - Steven Zimmerman, PhD
"There is a lot known about the molecular origin of the disease and this has provided some very clear targets. What is needed is researchers to develop lead therapeutic agents that can be tested in cell-based assays and in animal models."
Steven Zimmerman, PhD, professor of Chemistry at the University of Illinois, Urbana-Champaign, was awarded an MDA research grant totaling $289,301 over three years to optimize synthetic compounds that can target the mutations in myotonic dystrophy type 1 (DM1) to improve their delivery and efficacy.
DM1 occurs when a gene on chromosome 19 called DMPK contains an abnormally expanded section. The large repeat expansions in the DMPK gene lead to the formation of clumps of toxic RNA that bind a key regulatory protein called muscleblind-like protein (MBNL). MBNL protein controls the alternative splicing of RNA, which is what allows the correct proteins essential for healthy muscle contraction and relaxation to be made.
Dr. Zimmerman’s team recently identified an oligomer that inhibits both the formation of the toxic RNA and its irregular binding to MBNL protein in cellular assays and in a DM1 mouse model. The goal of the newly funded research is to further develop this oligomer and structurally related compounds, thereby aiming to develop more effective lead therapeutic agents. Specifically, Dr. Zimmerman will optimize these compounds to improve their delivery and then test the pharmacokinetic (how the compound is absorbed, distributed, and metabolized in the body), toxicity, and efficacy properties in a DM1 mouse model.
Grantee: DM - Steven Zimmerman, PhD
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Grant - Winter 2019 - DMD - Steven Welc, PhD
"Identifying processes that regulate muscle fibrosis and inflammation are clinically important and could lead to novel strategies to treat DMD. Additionally, results from this research project could help to provide the foundation for the clinical use of Klotho to treat DMD."
Steven Welc, PhD, postdoctoral fellow in Physiology at the University of California, Los Angeles, was awarded an MDA development grant totaling $210,000 over three years to study the role of Klotho protein in reducing fibrosis in a mouse model of Duchenne muscular dystrophy (DMD).
Fibrosis occurs when excess fibrous connective tissue is created in an organ or tissue in an attempt to repair it. In DMD, lack of dystrophin causes muscles to deteriorate; this in turn causes the inflammatory response that promotes fibrosis, or the replacement of muscle fibers with connective tissue that leads to reduced function. In previous research, Dr. Welc discovered that the anti-inflammatory and anti-fibrotic Klotho protein was silenced in a mouse model of DMD, and there were decreased amounts of Klotho in the muscle cells of DMD patients. By restoring Klotho expression in a mouse model of DMD, he was able to modify inflammation and reduce fibrosis in muscle tissue.
In this work, Dr. Welc will test several possible mechanisms by which Klotho could reduce fibrosis in a mouse model of DMD. Specifically, he will examine the role of Klotho in regulating communication between macrophages and fibro-adipogenic progenitors (FAPs) by determining whether Klotho reduces proliferation and survival of FAPs, thereby reducing fibrosis in DMD mice.
https://doi.org/10.55762/pc.gr.84540
Grantee: DMD - Steven Welc, PhD
Grant type: Development Grant
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Grant - Winter 2019 - SMA - Stephen Meriney, PhD
"This project will directly test a novel treatment to address neuromuscular weakness in SMA patients. This treatment is not a cure but rather a symptomatic approach to increase acetylcholine release from neuromuscular synapses."
Stephen Meriney, PhD, professor of Neuroscience and Psychiatry at the University of Pittsburgh, was awarded an MDA research grant totaling $302,587 over three years to develop a combinatorial drug approach to discover possible therapeutics for spinal muscular atrophy (SMA). His work is focused on testing a novel calcium channel agonist (an agonist produces the same reaction as the molecule that usually binds the receptor) to boost motor neuron signal strength. He will also study combining this drug with the current antisense oligonucleotide therapy (ASO) for SMA.
In SMA, the leading genetic cause of death in infants, very little full-length survival motor neuron protein (SMN) is made due to a mutated or missing survival motor neuron 1 gene (SMN1). Without the protein, there is a loss of motor neurons in the spinal cord, resulting in weakness and atrophy of the voluntary muscles. In 2016, the U.S. Food and Drug Administration approved Biogen’s nusinersen (brand name Spinraza) to treat SMA. Spinraza is an ASO drug designed to increase production of the needed SMN protein. While transformative, the treatment does not completely cure the disease and most patients still experience deficits.
Starting his career with an MDA fellowship, Dr. Meriney went on to define the deficits at the neuromuscular junction (NMJ), followed by a focus on trying to strengthen the NMJ as a type of add-on therapy. The goal of this proposed work is to test whether a novel calcium channel agonist drug could boost the signal sent from the nerve to the muscle to achieve increased strength in SMA. Dr. Meriney will test this drug in a mouse model of SMA already receiving an ASO to determine whether the agonist can provide additional benefit in combination with a therapy such as Spinraza.
https://doi.org/10.55762/pc.gr.84557
Grantee: SMA - Stephen Meriney, PhD
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Grant - Winter 2019 - FA - Sanjay Bidichandani, PhD
"The mechanism of gene silencing in FA is known as epigenetic silencing. As we dig deeper, we realize that the silencing mechanism is more complex than was initially appreciated. A fuller understanding of the epigenetic silencing mechanism will help yield therapeutic targets and perhaps even biomarkers to track therapeutic response in people with FA."
Sanjay Bidichandani, PhD, professor of Pediatrics at the University of Oklahoma Health Sciences Center, was awarded an MDA research grant totaling $300,000 over three years to study the role of epigenetic silencing of the frataxin gene (FXN) in Friedreich’s ataxia (FA).
In FA, mutations in the FXN gene cause decreased production of frataxin protein, resulting in diminished energy production in cells, including those of the nervous system and heart. MDA funding helped Dr. Bidichandani participate in research that led to the discovery of the FXN gene and its role in causing FA. In past work, Dr. Bidichandani discovered a DNA hypermethylation in FXN of people with FA. However, to identify effective therapeutic targets and biomarkers, a complete understanding of exactly how the silencing mechanism works is needed.
In this project, Dr. Bidichandani will look more closely at the two main mechanisms of FXN gene silencing to see if one mechanism precedes the other, or if they work in parallel. This information will inform if different therapeutic agents can work synergistically or limit the effectiveness of each other. Specifically, he will test the hypothesis that DNA hypermethylation acts as a barrier to efficient gene reactivation in FA, examining cells from people with FA and a humanized mouse model of the disease.
https://doi.org/10.55762/pc.gr.84543
Grantee: FA - Sanjay Bidichandani, PhD
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Grant - Winter 2019 - ALS - Samuel Alworth, MS, MBA
Samuel Alworth, MS, MBA, CEO and founder of AcuraStem, was awarded an MDA Venture Philanthropy (MVP) grant totaling $300,000 over two years to support preclinical development of a novel small molecule therapeutic for amyotrophic lateral sclerosis (ALS). MVP grants are awarded to researchers developing therapeutics for neuromuscular diseases to help lower the barriers and bridge the high-risk stages of drug development.
A team led by Justin Ichida, PhD, co-founder and chief scientific officer of AcuraStem and head of the Ichida Lab at the Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at the University of Southern California, published research in Nature Medicine in 2018 in which they discovered that inhibiting the action of a specific protein in ALS patient-derived motor neurons helped prevent their death in vitro (in a petri dish). While the target was discovered in cells from a patient with C9-ALS (or, C9ORF72 ALS; mutations in the C9ORF72 gene are the most common genetic cause of ALS), it may also be applicable to other forms of ALS, including the more common sporadic forms of the disease.
The MVP grant will allow AcuraStem to undertake proof-of-concept studies in mouse models of ALS, as well as develop biomarkers for its orally delivered, blood-brain-penetrating, preclinical development candidate, AS2015.
Grantee: ALS - Samuel Alworth, MS, MBA
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Grant - Winter 2019 - DMD - Roger Stromberg, PhD
"Hopefully more compounds will be developed (to benefit more patients) and better compounds will be developed (to benefit patients more). We expect that further developments of exon-skipping oligonucleotide constructs will lead to even more effective treatments."
Roger Stromberg, PhD, professor of Bioorganic Chemistry at Karolinska Institute, Sweden, was awarded an MDA research grant totaling $200,000 over two years to improve muscle cell penetrance and increase uptake of exon-skipping antisense oligonucleotides (ASOs) for treating Duchenne muscular dystrophy (DMD). Dr. Stromberg will collaborate with Annemieke Aartsma-Rus, PhD, professor of Human Genetics at Leiden University Medical Center, Netherlands, who will perform preclinical testing on the ASOs.
In 2016, the U.S. Food and Drug Administration approved the first drug to treat DMD, Sarepta Therapeutics’ Exondys 51. This drug is an exon-skipping ASO that specifically targets a section of genetic code within the dystrophin gene called exon 51. While ASOs like Exondys 51 can be used to treat some forms of DMD, there remain challenges to delivering these types of drugs to the right tissues in the right amounts. Current oligonucleotides have limited efficacy because they are not well delivered to muscle and delivery to heart is negligible. Improved delivery can have a major impact on treatment.
In this research, Dr. Stromberg will develop novel modified oligonucleotides that aim to enhance the structure and function of traditional ASOs. His work will include optimizing the backbone chemistry to improve muscle cell penetrance, adding peptides that prevent the endosomes in muscle cells from clearing them, and adding cardiac and skeletal muscle “homing peptides” that may increase uptake of the drug into the appropriate tissues.
Grantee: DMD - Roger Stromberg, PhD
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Grant - Winter 2019 - GAN - Puneet Opal, MD, PhD
"While GAN is rare, neurofilament accumulation is seen in a wide range of neurodegenerative disorders, including ALS, Parkinson’s disease, Alzheimer’s disease, and some CMT subtypes. By understanding the consequences of neurofilament accumulation in GAN, we hope to understand the broader role of neurofilaments in nervous system disorders."
Puneet Opal, MD, PhD, professor of Neurology and Cell and Molecular Biology at the Northwestern University Feinberg School of Medicine, Chicago, was awarded an MDA research grant totaling $304,601 over three years to better understand the role of neurofilaments in giant axonal neuropathy (GAN), a disease that affects the peripheral and central nervous system.
GAN causes impaired sensation, strength, and reflexes in the limbs as well as difficulty with coordination. Mutations in the gigaxonin gene (GAN), which encodes the protein gigaxonin, cause neurons to accumulate excess neurofilaments (skeletal-like proteins found within neurons). The “giant” neurons can no longer transmit signals properly and eventually deteriorate, resulting in the range of neurological problems associated with the disorder. In previous work, Dr. Opal discovered that neurofilaments are a major class of substrates for gigaxonin.
In this research, Dr. Opal will investigate whether one of the causes of GAN is, in fact, altered degradation of neurofilaments. His studies will provide insights into how gigaxonin works to degrade neurofilaments, which could be informative for other motor neuron and peripheral nerve diseases. He also will test whether reducing neurofilament levels could be beneficial in GAN using genetic and pharmacological approaches.
https://doi.org/10.55762/pc.gr.84561
Grantee: GAN - Puneet Opal, MD, PhD
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Grant - Winter 2019 - IBM - Ming Guo, MD, PhD
Ming Guo, MD, PhD, professor of Neurology and of Molecular and Medical Pharmacology at the University of California, Los Angeles, was awarded an MDA research grant totaling $300,000 over three years to study the molecular genetics of inclusion body myopathy (IBM) caused by mutations in the valosin-containing protein gene (VCP) in an animal model and human patient cells.
Mutations in the VCP gene cause IBM associated with Paget’s disease of the bone (PDB) and frontotemporal dementia (FTD). Almost all IBM patients show skeletal muscle weakness, half will develop PDB, and a third will develop FTD. In previous MDA-funded work, Dr. Guo created a fruit fly model to learn more about how VCP mutations lead to disease. In her studies, she found that disease mutations lead to hyperactivation of the VCP gene, which affects the expression of a mitochondrial membrane protein called mitofusion. By inhibiting this gene’s expression, she could reduce the symptoms of IBM in both the animal model and human patient cells.
In this work, Dr. Guo plans to carry out genetic screens on her animal model and patient cells, looking for other genes that might interact with the VCP gene and have a slowing effect on the progression of IBM. This work may increase understanding of the molecular pathology of the disease and identify potential therapeutic targets.
https://doi.org/10.55762/pc.gr.84551
Grantee: IBM - Ming Guo, MD, PhD
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