Grant - Winter 2019 - ALS - Junjie Guo, PhD
"The pathophysiological mechanisms underlying ALS and other neuromuscular diseases are still poorly understood. Only through systematic and mechanistic investigations of disease-relevant pathways can more novel therapeutic targets be discovered. More diverse therapeutic strategies will most likely accelerate the development of treatments."
Junjie Guo, PhD, assistant professor of Neuroscience at Yale University, was awarded an MDA research grant totaling $297,678 over three years to learn more about the process by which RNA from the C9ORF72 gene mutation in amyotrophic lateral sclerosis (ALS) forms complexes with proteins inside the cell and whether specific complexes are detrimental to the health of the motor neuron.
Although most cases of ALS are sporadic, meaning there is no family history of the disease, about 10 percent of cases are familial, meaning the disease runs in the family. Recently, it was discovered that a mutation 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 (this form is referred to as C9-ALS) and is found in some sporadic cases as well. It’s uncertain, however, if the disease is caused by reduced levels of normal C9ORF72 protein and/or by toxic RNA and proteins manufactured using instructions from the extra DNA.
Defects in cellular RNA metabolism have been shown to play important roles in a variety of sporadic and familial neuromuscular diseases, including familial ALS. In C9-ALS, RNA from the repeat expansion forms RNA foci (clump-like structures) inside the cell. Previous studies have shown that these RNA foci can alter the function of RNA-binding proteins, thereby affecting the function of cells. In this project, Dr. Guo will study how RNA foci are formed, what factors regulate their formation, and how these foci affect RNA metabolism in a C9-ALS motor neuron model. He aims to better understand the molecular mechanisms and pathophysiological roles of RNA foci in not only ALS but also other neuromuscular diseases associated with repeat expansions.
https://doi.org/10.55762/pc.gr.84550
Grantee: ALS - Junjie Guo, PhD
Grant type: Research Grant
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Grant - Winter 2019 - ALS - Jonathan Glass, MD
"Research into ALS cannot move forward without the participation of patients, who provide the needed clinical information, biosamples, and involvement in clinical trials. Our NEALS organization is the largest academic organization focused on promoting clinical trials in ALS and educating both investigators and patients/families on the science of clinical trials."
Jonathan Glass, MD, professor of Neurology and Pathology at Emory University in Atlanta and director of the Emory ALS Center, was awarded an MDA research infrastructure grant totaling $151,592 over three years to further develop the member services and activities of the Northeast ALS (NEALS) Consortium for the amyotrophic lateral sclerosis (ALS) research community. It builds upon a previous grant awarded to Dr. Glass from 2015 to 2018 for the development and support of the consortium.
The NEALS Consortium is an international organization of 125 research sites that collaborate to support and conduct clinical research in ALS and other motor neuron diseases. The mission of the NEALS Consortium is to translate scientific advances as rapidly as possible into new treatments for people with ALS and motor neuron disease.
This grant will help support the NEALS Consortium’s biorepository, which contains tissues and fluids that are widely used by the community — including MDA-funded researchers — to advance ALS research. The grant will also support the annual NEALS Consortium meeting, which is an opportunity for the sites to come together to share advances and receive training.
Grantee: ALS - Jonathan Glass, MD
Grant type: Infrastructure Grant
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Grant - Winter 2019 - ALS - John Landers, PhD
"I hope that we will identify several genes that, when inactivated, will lead to a beneficial effect in several models of ALS. Identifying such genes will progress several areas of research and the development of therapeutics."
John Landers, PhD, associate professor of Neurology at the University of Massachusetts Medical School, was awarded an MDA research grant totaling $300,000 over three years to identify novel therapeutic targets for both familial and sporadic amyotrophic lateral sclerosis (ALS) using an unbiased screening approach across the entire genome.
Although most cases of ALS are sporadic, meaning there is no family history of the disease, about 10 percent of cases are familial, meaning the disease runs in the family. To date, more than 40 genes have been identified to cause familial ALS; some of them also have been found in sporadic ALS patients. Still, there is no definitive genetic root for 90 percent of ALS cases.
Over the past 15 years, Dr. Landers’ lab has focused on identifying genes associated with ALS. Recently, he has transitioned to novel approaches for drug target discovery. In this research, he will use RNAi screens — RNAi, or RNA interference, uses RNA molecules to bind to and inactivate a gene — to discover novel drug targets for ALS. In these genome-wide RNAi screens, he hopes to discover genes that, when repressed or inactivated, may lead to an increased survival of ALS neurons. His lab previously screened approximately 200 of the 20,000 genes in the genome and identified a single gene that, when inactivated, yielded a beneficial effect on various neuronal cell cultures harboring a mutant ALS gene. In this study, he will screen all 20,000 genes to identify other additional genes that affect ALS motor neuron survival and then follow up on targets with validation studies in mice.
https://doi.org/10.55762/pc.gr.84554
Grantee: ALS - John Landers, PhD
Grant type: Research Grant
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Grant - Winter 2019 - FSHD - Jeffrey Miller, PhD
"We will attempt to identify drugs that prevent DUX4-induced changes in mRNA handling proteins and then determine, in model systems, if such pharmaceutical treatments could lessen loss of muscle function."
Jeffrey Miller, PhD, professor of Neurology at Boston University School of Medicine, was awarded an MDA research grant totaling $300,000 over three years to study the role of aberrant expression of double homeobox 4 protein (DUX4), the protein known to cause facioscapulohumeral muscular dystrophy (FSHD).
FSHD causes progressive degeneration of muscles, including muscles of the face, shoulder blades, and upper arms. FSHD is caused by aberrant expression of DUX4, which disrupts RNA and protein homeostasis and causes cell death. Dr. Miller previously found that DUX4 induces aggregation of TDP-43 and FUS, two proteins that are notably also aggregated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
In this study, Dr. Miller will identify mechanisms by which the presence of DUX4 changes the splicing of genes regulated by TDP-43. In addition, he will determine to what extent clumping of TDP-43 and FUS explain the appearance of FSHD characteristics in cells and how aggregation induced by DUX4 disrupts RNA homeostasis and ultimately leads to cell death. Finally, he will test drugs in cell culture models to identify targets that prevent these DUX4-induced changes and lessen loss of muscle function.
https://doi.org/10.55762/pc.gr.84559
Grantee: FSHD - Jeffrey Miller, PhD
Grant type: Research Grant
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Grant - Winter 2019 - Mitochondrial Myopathy/ALS - Giovanni Manfredi, MD, PhD
"CHCHD10 mutations are relatively rare causes of neuromuscular disease, but the disease mechanisms and the therapeutic approaches that can emerge from this work could be extended to a diverse group of neuromuscular diseases caused by mitochondrial dysfunction."
Giovanni Manfredi, MD, PhD, professor of Neuroscience, Mitochondria, and Neurodegeneration at Weill Cornell Medical College, was awarded an MDA research grant totaling $300,000 over three years to use a novel mouse model to study CHCHD10 protein mitochondrial diseases.
Mitochondrial are tiny energy factories found inside almost all our cells and are necessary for normal function. Mutations in the CHCHD10 gene, which codes for a mitochondrial protein, can cause multi-systemic mitochondrial diseases characterized by myopathy as well as motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and dementia. In previous MDA-funded work, Dr. Manfredi created a mouse model of CHCHD10 mutations to discover that mitochondrial CHCHD10 protein accumulates and clumps together with other proteins, ultimately resulting in degeneration of the heart and muscles.
In this research, Dr. Manfredi will investigate the specific organs and tissues involved in this disease, which may lead to insights about how to design rational therapies. Specifically, he will study the molecular mechanisms of mitochondrial mutations, determine if and how the nerves and brain are involved, and identify metabolic biomarkers that might help track prognosis of the disease.
https://doi.org/10.55762/pc.gr.84556
Grantee: Mitochondrial Myopathy/ALS - Giovanni Manfredi, MD, PhD
Grant type: Research Grant
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Grant - Winter 2019 - DMD - Foteini Mourkioti, PhD
"Knowledge gained from this MDA funded studies will reveal new mechanisms of cardiac dystrophy, providing fresh strategies for therapeutics to prevent or diminish the destructive cardiac processes in DMD patients."
Foteini Mourkioti, PhD, assistant professor of Orthopedic Surgery at the Perelman School of Medicine, University of Pennsylvania, was awarded an MDA research grant totaling $300,000 over three years to study the relationship between telomere shortening and dilated cardiomyopathy (DCM) in Duchenne muscular dystrophy (DMD) mice models.
Patients with DMD typically have cardiac complications, and heart failure is the major cause of death in DMD. Telomeres are sequences at the end of chromosomes that protect them from breaking down, similar to the plastic coating at the end of a shoelace. It has been previously shown that telomeric repeat-binding factor 2 protein (TRF2), which binds and protects chromosomes, is expressed less in people with dilated cardiomyopathy and in mice with DCM due to DMD.
In this work, Dr. Mourkioti will look at how oxidative stress causes DNA damage and telomere shortening. She will investigate a previously unknown mechanism in cardiac dystrophy and will determine if telomeric proteins in the dystrophic heart have other additional functions. Specifically, to determine whether loss of TRF2 is driving cardiomyopathy in DMD, Dr. Mourkioti will quantify the DNA damage in patient cardiomyocytes and then determine whether loss of TRF2 negatively impacts cardiac structure and function in DMD mice.
https://doi.org/10.55762/pc.gr.84560
Grantee: DMD - Foteini Mourkioti, PhD
Grant type: Research Grant
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Grant - Winter 2019 - DMD - Diego Fraidenraich, PhD
"A combination of pharmacological treatment that involves Cx43 peptide mimetics and gene editing in phosphorylation sites may synergistically increase the chances of a cure."
Diego Fraidenraich, PhD, assistant professor of Cell Biology and Molecular Medicine at Rutgers New Jersey Medical School, was awarded an MDA research grant totaling $300,000 over three years to study the relationship between the connexin 43 protein (Cx43) and cardiomyopathy in Duchenne muscular dystrophy (DMD) mice models.
Patients with DMD typically have cardiac complications, and heart failure is the major cause of death in DMD. Dr. Fraidenraich previously found connexin 43, a type of neuromuscular gap junction protein, to be expressed more in the DMD mouse heart, and that removal or inhibition of Cx43 protein could protect stressed DMD mice from arrhythmia, cardiomyopathy, and premature death.
To further investigate Cx43 as an important target for the treatment of DMD cardiomyopathy, Dr. Fraidenraich will use this grant to further characterize the role of Cx43 in mice and in human tissue by examining phosphorylation, expression levels, and effects on cardiac pathology and function. His previous research used engineered mice with a mutant version of Cx43 that mimicked full phosphorylation; in this project he will extend these studies to a more severe mouse model of DMD.
https://doi.org/10.55762/pc.gr.84546
Grantee: DMD - Diego Fraidenraich, PhD
Grant type: Research Grant
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Grant - Winter 2019 - FSHD - Davide Gabellini, PhD
"With our work, we hope to better understand how DUX4 is regulated and how we could control aberrant DUX4 in FSHD for therapeutic purposes."
Davide Gabellini, PhD, head of the Gene Expression and Muscular Dystrophy Unit at IRCCS Ospedale San Raffaele in Milan, Italy, was awarded an MDA research grant totaling $297,738 over three years to study how specific factors decrease double homeobox 4 protein (DUX4), the protein known to cause 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 DUX4, which causes toxicity and muscle cell death. Using a whole-genome approach, Dr. Gabellini previously identified one factor as an inhibitor of DUX4. This protein directly binds to DUX4, blocking its ability to activate certain genes that eventually cause cell death.
In this study, Dr. Gabellini aims to clarify the DUX4 biological pathway and the mechanism by which DUX4 causes cell death. Specifically, he will identify the minimal binding domain needed for the identified factor to inhibit DUX4 and determine if its overexpression can prevent FSHD mice and patient cells from dying. Interestingly, mutations in this protein’s gene are associated with familial amyotrophic lateral sclerosis (ALS), so Dr. Gabellini will also assess the impact of specific mutations found in ALS on their ability to inhibit DUX4.
Grantee: FSHD - Davide Gabellini, PhD
Grant type: Research Grant
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Grant - Winter 2019 - ALS - Csaba Konrad, PhD
"We believe finding biomarkers that stratify sporadic ALS patients into subgroups with shared cellular pathology may be the key to improving clinical trial design."
Csaba Konrad, PhD, postdoctoral associate in Neuroscience at Weill Cornell Medical College, was awarded an MDA development grant totaling $210,000 over three years to utilize a large bank of skin cells derived from sporadic amyotrophic lateral sclerosis (ALS) patients to determine if the cells can be clustered into groups based on changes in size and shape. He hopes to use these models to improve ALS patient stratification in clinical trials.
Developing drugs to treat ALS has proven difficult as there are many causes of the disease, resulting in a highly diverse patient population and a dearth of biomarkers. Biomarkers can be used for predicting disease progression and response to therapy, for early detection and accurate diagnosis, and for patient stratification in clinical trials — making biomarker discovery for ALS of high priority.
In previous work, Dr. Konrad showed that skin fibroblast cells are affected by the some of the same pathological changes as motor neurons. In this work, he will use his large bank of ALS patient-derived skin fibroblast cell lines to study differences in morphological features of these cells under stress. By using machine learning techniques, he will build models based on patterns of features that can be used to distinguish between healthy and ALS cells, models to predict clinical characteristics of the disease, and models to define subgroups of ALS patient cells that share similar abnormal features and cellular pathology.
https://doi.org/10.55762/pc.gr.84538
Grantee: ALS - Csaba Konrad, PhD
Grant type: Development Grant
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Grant - Winter 2019 - CMT - Charles Abrams, MD, PhD
"Unraveling the cause of a human disease requires having appropriate animal models for the disease being studied. This proposal will characterize models for CMT1X on the molecular level and use them to initiate studies that will shed light on the causes of this disorder."
Charles Abrams, MD, PhD, professor of Neurology at the University of Illinois, Chicago, was awarded an MDA research grant totaling $300,000 over three years to better understand how mutations in the connexin 32 gene (Cx32) lead to CMT1X, a form of Charcot-Marie-Tooth disease (CMT).
Mutations in the gene coding for the gap junction beta-1 protein (GJB1), also known as connexin 32 protein (Cx32), are associated with the X-linked form of Charcot-Marie-Tooth disease (CMT1X), which affects approximately 1 in 25,000 people and is the second-most-common form of CMT. Although scientists have known about these mutations for more than 25 years, information is still lacking about how they cause disease. In the case of CMT1X, animal models are inadequate — almost all studies have used the Cx32 gene knockout mouse, a loss-of-function model that may not accurately represent the full spectrum of the variety of mutations in Cx32 that can cause CMT1X.
This work will use a technique called RNA-Seq to characterize a variety of different CMT1X mouse models at the level of transcription (RNA), and it will then utilize this information for studies into the causes of this disease. Dr. Abrams will use these different knockout and mutant models to determine how gene expression in Schwann cells is affected by mutations, and how this change in gene expression leads to axonal death. Schwann cells are very important in that they generate the insulating myelin sheath around peripheral nerves. If successful, the project could provide insights into how genetic defects in supportive Schwann cells cause degeneration of the axons in CMT as well as identify which CMT1X patients may benefit from gene-replacement therapies under development.
https://doi.org/10.55762/pc.gr.84541
Grantee: CMT - Charles Abrams, MD, PhD
Grant type: Research Grant
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Grant - Winter 2019 - DMD - Chad Heatwole, MD
"At the completion of our work the DMD research community will have multiple validated outcome measures to aid in therapeutic assessment and encourage therapeutic development for DMD."
Chad Heatwole, MD, associate professor of Neurology at the University of Rochester Medical Center in N.Y., was awarded an MDA Human Clinical Trial Grant totaling $200,000 over two years to develop and validate a health index to be used as a patient-reported outcome (PRO) tool in clinical trials for Duchenne muscular dystrophy (DMD).
While the plethora of varied symptoms of DMD are well known to patients and their doctors, the prevalence and relative importance of the collective set of symptoms has never been found in a large study of DMD patients. The DMD research community lacks a PRO that satisfies all stakeholder groups and is in standard use. The FDA has clearly expressed a desire for such data, so it is critical that the field arrive at a consensus around a validated tool. Dr. Heatwole has previously developed and validated more than 30 disease-specific instruments currently being used in academic and government organizations and pharmaceutical companies around the world.
In this work, Dr. Heatwole will develop and validate PRO measures for DMD clinical trials. He will use patient interviews and a large cross-sectional study to identify the symptoms that are most important to DMD patients. Next, he will develop patient-centered, disease-specific outcome measures for DMD clinical trials using FDA guidelines, to be known as the DMD Health Indices. Finally, he will optimize DMD Health Indices using patient interviews and group testing, among others.
https://doi.org/10.55762/pc.gr.83904
Grantee: DMD - Chad Heatwole, MD
Grant type: Human Clinical Trial Grant
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Grant - Winter 2019 - Congenital & Other Myopathies – Alan Beggs, PhD
Alan Beggs, PhD, professor of Pediatrics at Harvard Medical School and director of the Manton Center for Orphan Disease Research at Children’s Hospital Boston, has been awarded an MDA research grant totaling $300,000 over three years to continue his previous research on the molecular genetics of congenital myopathies.
Congenital myopathies are a diverse group of inherited neuromuscular conditions caused by defects in skeletal muscle and include central core disease (CCD) and other core myopathies, nemaline myopathy, myotubular myopathy (MTM) and other centronuclear myopathies (CNMs), congenital myopathies with fiber-type disproportion (CFTDs), and others (some of these have not yet been identified). In previous MDA-funded work, Dr. Beggs built an extensive data registry and repository of samples from patients and their families. His screening for congenital myopathy-causing mutations in zebrafish led to the discovery of mutations in several genes that may be related to human neuromuscular diseases. His further analyses determined the nature of these mutations, their relationships to the muscle defects seen in zebrafish, and their relationships to the same genes in humans with analogous muscle findings.
In this new project, Dr. Beggs will use whole genome sequencing methods to discover the disease genes and genetic mutations that cause congenital myopathy in patients and families where the underlying cause has not yet been identified. Then, to better understand the biological pathways that lead to disease and search for effective therapies, Dr. Beggs will develop animal models with these mutations, which he will be able to use in validation studies (to test if the mutation actually causes the disease) and screening assays (to test small molecule libraries to identify new drugs to treat these conditions).
https://doi.org/10.55762/pc.gr.84542
Grantee: Congenital & Other Myopathies – Alan Beggs, PhD
Grant type: Research Grant
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Grant - Winter 2019 - Distal Myopathy - Aikaterini Kontrogianni-Konstantopoulos, PhD
“Although mutations in MyBP-C1 have been previously linked to severe and lethal forms of distal arthrogryposis, prior to our studies there was no evidence for causal association of MyBP-C1 mutations to myopathy. Continuing funding research in this area will therefore identify additional myopathic genes that have been potentially overlooked and accurately identify new forms of myopathies.”
Aikaterini Kontrogianni-Konstantopoulos, PhD, professor of Biochemistry and Molecular Biology at the University of Maryland School of Medicine, was awarded an MDA research grant totaling $300,000 over three years to investigate a novel form of myopathy associated with mutations in the myosin binding protein-C1 gene (MyBP-C1) using in vitro (in a petri dish) experiments and mice models.
Myosin binding protein-C is part of a family of proteins that regulates muscles’ ability to contract. Mutations in the genes for the cardiac and slow skeletal isoforms have been found to cause cardiac and neuromuscular disease. MyBP-C1 codes for myosin-binding protein C, slow-type, which is expressed in slow skeletal muscle and has very recently been shown to be associated with a new form of early-onset myopathy with muscle weakness, body deformities, and tremor.
Using well-developed in vitro experiments and a preclinical animal model carrying the mutation, Dr. Kontrogianni-Konstantopoulos hopes to determine what impact this mutation has on the biochemical and biophysical properties of MyBP-C1 protein and the molecular and cellular alterations underlying the development of this novel myopathy.
https://doi.org/10.55762/pc.gr.84553
Grantee: Distal Myopathy - Aikaterini Kontrogianni-Konstantopoulos, PhD
Grant type: Research Grant
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Grant - Summer 2018 - Myotonic Dystrophy – Eric Wang, PhD
“We are living in an extremely exciting time because of the explosion of technological and conceptual advances, both in the context of basic science as well as therapeutic development. Technologies such as high throughput sequencing, antisense oligonucleotides, gene therapy, and small molecule targeting of RNA are transforming the NMD landscape. Several drugs have been recently approved for NMDs and will undoubtedly pave the way for treatments for other NMDs.”
Eric Wang, assistant professor of Molecular Genetics & Microbiology at the University of Florida’s College of Medicine in Gainesville, was awarded an MDA Research Grant totaling $300,000 over 3 years to study the mechanisms of central nervous system (CNS) dysfunction in myotonic dystrophy.
Myotonic dystrophy is a neuromuscular disease with significant muscle, cardiac, and CNS symptoms. A significant amount of research on the skeletal muscle aspects of the disease has enabled clinical trials aimed at addressing muscle symptoms. CNS features of the disease can also be extremely debilitating, but the molecular basis is poorly understood. Building a solid foundation to understand molecular pathogenesis in the CNS, along with developing new animal models and therapeutics, are high priorities for this disease.
Dr. Wang and colleagues plan to identify RNA changes in mouse models of DM1, as well as from postmortem brains from DM1 individuals. The team will pattern its efforts after previous successes in identifying drivers of disease in muscle cells.
These studies will pave the way for future therapeutic development by identifying genes and pathways that are perturbed in the DM1 CNS, as well as by defining biomarkers that can be used to monitor therapeutic rescue in response to candidate therapies.
Grantee: Myotonic Dystrophy – Eric Wang, PhD
Grant type: Research Grant
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Grant - Summer 2018 - ALS – Ludo Van Den Bosch, PhD
“Amyotrophic lateral sclerosis (ALS) is a terrible disease, and despite all the research done in the past, patients still die (usually very fast). With our research, we want to contribute to the development of a cure! The proposed strategy can be translated relatively fast into a new therapy as the class of drugs that we are testing have already been tested in patients suffering from other diseases (e.g. cancer).”
Ludo Van Den Bosch, principal investigator at VIB in Leuven, Belgium, was awarded an MDA Research Grant totaling $300,000 over 3 years to study the role of histone deacetylase inhibitors in amyotrophic lateral sclerosis (ALS).
ALS is a neurodegenerative disease caused by the progressive failure of the motor system. Success in clinical translation of treatments for ALS has been poor and patients urgently need new therapeutic approaches.
Both in ALS patients and in mouse models of ALS, the motor axon is the most vulnerable compartment determining weakness and survival of the nerve cell. Histone deacetylase 6 (HDAC6) plays an important role in the regulation of axonal transport. Inhibition of HDAC6 can reverse the axonal transport deficits induced by mutant proteins. Previous work from the Van Den Bosch lab showed that inhibition of HDAC6 has a positive effect on mouse models of Charcot-Marie-Tooth disease (CMT), most likely due to reinnervation of the neuromuscular junctions.
Dr. Van Den Bosch and colleagues plan to inhibit HDAC6 in mouse models of ALS and to investigate the underlying mechanism of potential positive effects. Overall, the aim of this project is to find positive preclinical evidence for the use of HDAC inhibitors to treat ALS.
Grantee: ALS – Ludo Van Den Bosch, PhD
Grant type: Research Grant
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Grant - Summer 2018 - CMT – Vincent Timmerman, PhD
“If we can successfully validate our research hypothesis, reducing the expression of HSPB8 in vivo and decreasing the detrimental effects of the mutant protein, we may have found the first-ever treatment for dHMN patients having HSPB8 mutations. To reach this objective, we will focus on already-approved compounds and anti-sense oligonucleotides (ASOs).”
Vincent Timmerman, group leader at the University of Antwerp in Belgium, was awarded an MDA Research Grant totaling $300,000 over 3 years to study neuromuscular disease caused by HSPB8 mutations.
Patients with distal hereditary motor neuropathy, a variant of Charcot-Marie-Tooth neuropathy, have a progressive degeneration of their peripheral nerves resulting in muscle weakness and atrophy. Dr. Timmerman and colleagues were the first to report disease-causing mutations in the HSPB8 gene. The small heat shock protein B8 (HSPB8) belongs to the “stress protein family” and is expressed in various tissues and cells. HSPB8 acts as a molecular chaperone by clearing protein aggregates and reducing their toxic accumulation. This protective function has been studied in the context of cancer and neurodegenerative disease.
Building on the discovery, Dr. Timmerman’s team generated a mouse model mimicking the disease by introducing a mutation in the Hspb8 gene (a “knock-in” mouse). In addition, the team also made a model in which they deleted Hspb8 (a “knock-out” mouse), and these animals developed a mild myopathy.
The next step aims to identify therapeutic compounds that can rescue or delay the neurodegeneration observed in the knock-in model, or that can result in a milder phenotype as seen in the knock-out animals. The identified small-molecule compound acting on the expression of HSPB8 could be beneficial to treat patients affected with distal hereditary motor neuropathy and also patients with distal myopathies and related neuromuscular disorders.
Grantee: CMT – Vincent Timmerman, PhD
Grant type: Research Grant
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Grant - Summer 2018 - FSHD – Francis Michael Sverdrup, PhD
“I was inspired to start drug discovery research in FSHD when my daughter was diagnosed with the disease at the age of 10. Because no treatments are currently available, I have a strong motivation to help the field advance promising drug targets into clinical trials. With clinical trials for FSHD on the horizon, it is very exciting to see the rewards of the hard work by many talented scientists over the last 20 years. It is no longer just about the basic research but moving this knowledge to treatments.”
Francis Michael Sverdrup, associate professor of Biochemistry and Molecular Biology at Saint Louis University in Missouri, was awarded an MDA Research Grant totaling $300,000 over 3 years to study drugs targeting DUX4 expression in facioscapulohumeral muscular dystrophy (FSHD).
DUX4 protein produced in skeletal muscle is considered to be the key cause of muscle degeneration in FSHD. Therefore, suppressing DUX4 expression is a primary therapeutic approach for halting disease progression. Identifying drug candidates for this purpose is a critical step. Such drugs would prevent the many detrimental activities of this toxic protein and potentially provide the first candidate therapies for slowing or stopping disease progression in FSHD.
Dr. Sverdrup and colleagues recently identified 2 classes of drugs that suppress DUX4 using cell-based screens. Additionally, they have identified a class of modulators of intracellular signaling that similarly decrease DUX4 expression in differentiating FSHD muscle cells. Comparison of these 3 drug classes and understanding the mechanisms of DUX4 repression for each is a critical step in advancing the best therapy toward the clinic.
The proposed experiments will show which drugs are best at controlling DUX4 expression in animal muscles and therefore will be best suited for advancing to human clinical trials.
Grantee: FSHD – Francis Michael Sverdrup, PhD
Grant type: Research Grant
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Grant - Summer 2018 - DMD – Melissa Spencer, PhD
“One of the biggest barriers to success for gene therapies is the ability to deliver the cargo to the tissue of interest. In our case, the goal is to reframe the DMD gene in skeletal muscle and the heart. By developing a systemically injectable nanoparticle delivery platform, we hope to have a mechanism to use to deliver our CRISPR platform to multiple muscles in the body.”
Melissa Spencer, professor of Neurology at the University of California at Los Angeles, was awarded an MDA Research Grant totaling $300,000 over 3 years to work on the development of nanoparticles for the treatment of neuromuscular disorders.
For Duchenne muscular dystrophy (DMD), a primary goal of therapy development is to correct the DMD gene mutation. To that end, researchers are developing therapies such as micro-dystrophin (a smaller version of dystrophin) gene replacement and CRISPR Cas9 gene editing. In each case, they are relying on a small virus called AAV (adeno-associated virus) to deliver these therapies to the muscles and heart within the body.
However, AAV-based delivery of these therapies poses a couple of ongoing challenges. The first challenge with AAV-based delivery is that it is not completely efficient at targeting muscle cells and may target other cells. The second challenge is that AAV is a virus that exists in the environment. This means that some people may have already been exposed to AAV and could reject the AAV when it’s given as a therapy. Also, because of this immune response, AAV can be administered only one time to a person, which could be a problem if re-dosing is necessary.
To address these issues with the AAV-based approach, the Spencer lab is developing nanoparticles as an alternative method for delivering gene-editing and gene-replacement therapies. Nanoparticles are very small (1 nanometer) organic or inorganic molecules that can carry drugs or nucleic acids (DNA or RNA) and can be re-administered multiple times. Additionally, the nanoparticles are transient, so if unwanted side effects or safety concerns occur, nanoparticle administration could be discontinued. Using this approach, the investigators hope to develop a better delivery vehicle for systemically injected gene-replacement and gene-editing therapies to muscle.
Grantee: DMD – Melissa Spencer, PhD
Grant type: Research Grant
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Grant - Summer 2018 - LGMD – Dorianna Sandona, PhD
“In the last years, researchers understood that to fight orphan diseases the sole possibility is to join forces and share data. I think that people with NMDs must have hope in research. The way to identify an effective therapy is long and full of hurdles. We don’t want to create false hope; however, we are doing our best, and we need patients’ enthusiasm and support.”
Dorianna Sandona, research scientist at the University of Padova in Italy, was awarded an MDA Research Grant totaling $300,000 over 3 years to study novel zebrafish models of sarcoglycanopathy subtypes of limb-girdle muscular dystrophy.
The sarcoglycanopathies are a subtype of LGMD caused by defects in alpha-, beta-, gamma-, and delta-sarcoglycans (SGs). SGs are components of an essential complex for muscle integrity, as they help stabilize the muscle membrane during muscle contractions.
In order to screen for molecules able to restore a functional SG-complex, Dr. Sandona will mimic sarcoglycanopathy in zebrafish and develop an advanced in vitro model based on cells derived from patients. Both models will be utilized to assess efficacy and safety of the small molecules for use as potential therapeutics. Zebrafish are a versatile model organism that allows for simple functional assays to test any potential drug. On the other hand, the model based on patient’s cells allows researchers to evaluate the efficacy of compounds directly on human, pathologic samples. If successful, the work, combining data coming from the different models, may shorten the gap toward therapy testing in this class of LGMD.
https://doi.org/10.55762/pc.gr.81540
Grantee: LGMD – Dorianna Sandona, PhD
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Grant - Summer 2018 - ALS – Jeffrey D. Rothstein, MD, PhD
“Answer ALS is a nationwide consortium that is assembling the largest and most comprehensive ALS dataset to date, in which clinical, behavioral, and extensive cellular datasets will be collected from 1000 patients.”
Jeffrey D. Rothstein, 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, Maryland, was awarded an MDA grant totaling $550,000 over 3 years for Answer ALS, a tool for data integration and characterization of disease networks.
Amyotrophic lateral sclerosis (ALS) is a progressive disease of the nerve cells that leads to loss of voluntary muscle control, paralysis, difficulty speaking, swallowing, and, ultimately, breathing. Today, scientists recognize that ALS is unlikely to be one disease; rather, it may be a collection of subtypes and variants, each of which requires a different approach for optimal treatment.
Answer ALS is a nationwide consortium that is assembling the largest and most comprehensive ALS dataset to date, in which clinical, behavioral, and extensive cellular datasets will be collected from 1000 patients. This comprehensive dataset will allow, for the first time, in-depth study of the underlying disease mechanisms. Mining this rich, complex dataset with the goal of identifying ALS disease subtypes requires sophisticated computational tools.
The support for this project will facilitate the development of a series of these tools, known as probabilistic graphical models (PGMs), to specifically interrogate and interpret the combined Answer ALS datasets. PGMs have been used extensively in applications from finance to artificial intelligence and health care diagnostics. These flexible, interpretable models are able to identify and quantify changes in cellular pathways. Creation and application of PGMs to enable integrated models of this comprehensive dataset will enhance our understanding of disease mechanisms and advance the discovery of targets for effective therapy.
Grantee: ALS – Jeffrey D. Rothstein, MD, PhD
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Grant - Summer 2018 - DMD – Dr. Russell Rogers, PhD
“Many cutting-edge approaches to treating DMD are currently under development. Each offers distinct advantages over current standard care. It is without a doubt that the most hope would be placed into therapies that offer the most benefit (both therapeutically and in applicability) and are on the verge of clinical translation.”
Dr. Russell Rogers, postdoctoral research fellow at Cedars-Sinai in Los Angeles, California, was awarded an MDA Development Grant totaling $120,000 over 2 years to study cell-free therapy to treat Duchenne muscular dystrophy (DMD).
In DMD, skeletal and heart muscle are highly fragile and degenerate easily, leading to loss of independence and heart disease. There are currently limited treatment options available to address the disease.
Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that have been tested in preclinical and clinical studies in DMD. These studies suggest CDCs may someday be a safe and effective therapy. CDCs work by secreting nanosized particles that carry genetic information called exosomes (CDC-exos). A single dose of CDC-exos dramatically improved skeletal muscle and heart function in a preclinical animal model of DMD.
Dr. Rogers and colleagues plan to study whether CDC-exos could be beneficial in preventing the disease’s onset or delaying disease progression. The work proposed tests this hypothesis by treating DMD mice models with CDC-exos prior to significant skeletal muscle and heart disease. If the hypothesis is supported, the proposed work would be an important leap toward developing new therapeutic approaches to this refractory, progressive disease.
Grantee: DMD – Dr. Russell Rogers, PhD
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Grant - Summer 2018 - SBMA – Carlo Rinaldi, MD, PhD
“Better understanding of the underlying disease mechanisms, coupled with improvement of gene vector design, therapeutic gene selection, and methods of delivery, have made gene therapy a realistic option for neuromuscular conditions — and neurological diseases in general — for which no treatment option was available until few years ago. Many challenges still lie ahead, but we have good reasons to be very optimistic for the future.”
Carlo Rinaldi, associate professor and clinician scientist at the University of Oxford in England, was awarded an MDA Development Grant totaling $120,000 over 3 years to study the role of androgen receptor isoforms in SBMA pathogenesis and the potential as therapeutic targets. This grant is co-funded by the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM).
Mutations in the gene encoding the androgen receptor (AR) protein cause spinal and bulbar muscular atrophy (SBMA). SBMA is an adult-onset neuromuscular condition affecting males with unmet clinical need. It is not undestood how mutations in AR lead to primary degeneration of motor neurons and muscle in patients. The activity of AR and other hormone receptors can be modulated in human cells by isoforms and/or splice variants, which may block or enhance their functions.
Dr. Rinaldi and colleagues plan to investigate the role of AR alternative isoforms in mediating SBMA toxicity. By revealing how these isoforms regulate AR activity in health and disease, researchers expect to better understand the mechanisms of disease in SBMA and provide a novel rational therapeutic target. If successful, the work could pinpoint tissue-specific targets for therapy development, with implications not only for SBMA but for other diseases of the motor unit as well, including spinal muscular atrophy and amyotrophoic lateral sclerosis.
https://doi.org/10.55762/pc.gr.81520
Grantee: SBMA – Carlo Rinaldi, MD, PhD
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Grant - Summer 2018 - ALS – Joel Richter, PhD
“There are two outcomes we hope for. One outcome is basic understanding of how toxic peptides are generated from C9orf72. The second outcome – which is some distance in the future – will be to use our knowledge to inhibit the product ion of these toxic peptides and thereby mitigate or delay at least this one form of ALS.”
Joel Richter, Arthur F. Koskinas Chair in Neuroscience, and Fen-Biao Gao, Governor Paul Cellucci Chair in Neuroscience Research, both at the University of Massachusetts Medical School in Worcester, were awarded an MDA Research Grant totaling $300,000 over 3 years to study a potential inhibition of translation of G4C2-containing RNA as a novel therapy for C9orf72-ALS.
Amyotrophic lateral sclerosis (ALS) is a fatal disease caused by motor neuron degeneration and resulting muscle wasting. Most causes of ALS are unknown, but the most commonly known genetic cause is an aberrant C9orf72 gene expansion that leads to the toxic accumulation of dipeptide repeat proteins (DPRs).
Previous collaborative work in Drs. Richter and Gao’s labs has identified regions in C9orf72 RNA that could be blocked by binding to complementary DNA antisense oligonucleotides (AS-ODNs). Such AS-ODNs would inhibit DPR production, thereby slowing or inhibiting disease progression.
Drs. Richter and Gao propose to use human disease neurons in culture and C9orf72 model mice to test the efficacy and specificity of AS-ODNs to inhibit DPR synthesis and mitigate ALS pathophysiology. It’s hoped this work will have a major impact on the clinical treatment of ALS.
Grantee: ALS – Joel Richter, PhD
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Grant - Summer 2018 - ALS – Laura P.W. Ranum, PhD
“We are at an exciting time in the field of repeat expansion disorders because as a research community we are starting to understand there are common threads between these diverse disorders. The field is also progressing faster and faster toward clinical trials and a growing appreciation for how therapies for one disorder may lead to similar therapies for another disorder.”
Laura P.W. Ranum, professor of Molecular Genetics and Microbiology and director of the Center for NeuroGenetics at the University of Florida’s College of Medicine in Gainesville, was awarded an MDA Research Grant totaling $300,000 over 3 years to study the contributions of RAN proteins to C9orf72 ALS/FTD.
Expansion of a section of repetitive DNA in the C9orf72 gene is the most common genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This discovery linked C9-ALS/FTD to a larger group of more than 30 different repeat expansion mutations that also cause neurodegenerative diseases. These repeat expansions are also capable of producing novel toxic proteins in the absence of the regular starting sequences. These proteins have been found in human autopsy tissue of patients with C9-ALS/FTD and other repeat-associated diseases.
Understanding how these proteins contribute to C9-ALS/FTD will be important to developing effective treatment strategies. Dr. Ranum and colleagues have generated mice that successfully mimic the disease features of ALS/FTD patients and will use these mice to understand how the body reacts to these novel proteins and if this interaction contributes to disease. The researchers will also determine how certain cellular conditions lead to the production of these novel proteins and if these pathways can be manipulated to reduce the number of proteins produced.
These studies will result in a greater understanding of how the response to these proteins contributes to disease while also determining if scientists can modify this response to help combat this devastating disease.
Grantee: ALS – Laura P.W. Ranum, PhD
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Grant - Summer 2018 - MG – Kevin C. O’Connor, PhD
“Overall, this work will further our understanding of how MG initiates and progresses, and uncover fundamental disease mechanisms that have the potential to change the understanding of the immunopathology. In addition, we expect to develop clinically relevant disease models that will directly impact patient care.”
Kevin C. O’Connor, associate professor of Neurology at Yale University in New Haven, Connecticut, was awarded an MDA Research Grant totaling $300,000 over 3 years to study novel isolation and investigation of pathogenic cells in myasthenia gravis (MG).
Autoimmunity is a malfunction of the immune system where an immune response develops against one’s own tissues (self). MG is an autoimmune disease caused by circulating autoantibodies (antibodies against self), produced by a malfunctioning immune system, that interrupt signaling at the neuromuscular junction. Patients experience muscle weakness, which can be deadly when muscles involved in respiration are affected.
The human immune system is comprised of trillions of cells distributed throughout the body. Only a tiny fraction directly contributes to autoimmune disease. In MG, those that contribute are a subset of B cells, which produce the autoantibodies. In order to investigate this small subset and find ways to target it, researchers need a way to isolate these autoreactive B cells from other immune cells. This advance has yet to be achieved because the technology has not been established.
To this end, Dr. O’Connor’s team has developed a novel approach for isolating the specific B cells that cause MG. The team will investigate these cells to determine how they produce disease-causing autoantibodies and how they behave during treatment and disease exacerbation. Overall, this work will further the understanding of how MG initiates and progresses, and support the application and development of therapeutics that both repair dysfunction and specifically target disease-causing cells.
Grantee: MG – Kevin C. O’Connor, PhD
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