Innovations in Science
Understanding how VCP mutations cause Amyotrophic Lateral Sclerosis
ALS is a devastating neuromuscular disorder for which there is no current cure. Mutation in a number of genes are known to cause ALS, one of which is valosin containing protein (VCP). VCP is an important enzyme that regulates the destruction of many proteins within the cell and as such, its mutation perturbs many different cellular pathways. Most studies related to VCP mutation have been performed in cell lines not directly impacted in human disease. These two aspects have hindered our ability to understand how VCP mutations cause ALS. Our group has developed motor neurons and skeletal myocytes that have VCP mutations seen in individuals with ALS using induced pluripotent stem cells. We will investigate how VCP mutation impacts these two cell types. These studies will lay the foundation for our understanding of how VCP mutations cause the pathophysiology observed in ALS.
Digital Object Identifier (DOI)
Grantee: Malavika Raman, Ph.D
Grant type: Research Grant
Award total: $299,864.00
Institution: Trustees of Tufts College, Boston,MA
Country: United States
Targeting layered regenerative inflammation tissue zones in dystrophic muscle
Duchenne Muscular Dystrophy (DMD) is a serious and deadly disease that primarily affects children. It is a degenerative disease that leads to the loss of muscle tissue, which is replaced by fibrosis and fat, resulting in significant mobility impairments. There is currently no cure for DMD, but there are drug and gene therapy efforts to convert the disease to a milder form. One major challenge is finding effective treatments that can reduce inflammation without suppressing the immune system and prevent or reverse muscle loss. One novel approach we have been studying is to modify immune cells, particularly macrophages, to promote regeneration and the formation of new tissue. This project aims to evaluate the impact of various anti-inflammatory treatments on the formation of regenerative tissue zones that we found to be sensitive to glucocorticoid treatment. The study will also focus on the therapeutic efficacy of specific treatments that promote a pro-repair macrophage phenotype and restore the regenerative capacity of dystrophic muscle in aging DMD patients. Overall, in light of our recent compelling findings, the proposed work will re-evaluate the impact of current DMD standard-of-care drugs on muscle regeneration using state-of-art aproaches and has the potential to introduce new combination therapies for muscular diseases to support the growth of muscle tissue.
Grantee: Andreas Patsalos, Ph.D.
Grant type: Development Grant
Award total: $210,000.00
Institution: Johns Hopkins University School of Medicine
Country: United States
Metabolic therapies for dystrophic cardiomyopathy
Despite significant investments over the past >25 years to try to develop genetic therapies for Duchenne muscular dystrophy (DMD), to date only a few partially effective exon skipping therapies are approved for a small percentage of DMD patients. Gene-therapy development has been challenging due to limitations of delivery systems, the large size of the dystrophin gene and number of mutations, and the challenegs to achieve widely distributed gene delivery to all the muscle in the body. Many investigational gene therapies suffer from poor targeting of the heart, low efficiency in already diseased muscle, and immune responses to the therapy itself. Consequently, there is an unmet clinical need requiring new therapeutic strategies for the treatment of DMD, and particularly DMD associated cardiomyopathy. This proposal seeks to understand the unique metabolic changes that occur in DMD affected cardiac muscle cells. The overall goal is to use this information to test metabolic modulator drugs under investigation for other disease that could be repurposed for improving cardiac function, and also skeletal muscle function, in DMD patients. If successful, the proposed research will provide important preclinical evidence for new repurposed drugs that would have the potential to be relatively quickly repositioned as suitable investigational therapies for DMD patients.
Grantee: Daniel Michele, Ph.D.
Grant type: Research Grant
Award total: $299,542.00
Institution: The Regents of the University of Michigan
Country: United States
The molecular basis of muscular dystrophy caused by loss of MSTO1 function
Several patients with congenital myopathy and ataxia were recently reported to have mutations in MSTO1. MSTO1 patient fibroblasts possess shorter mitochondria than cells from healthy individuals and also have fewer copies of mitochondrial genomes, indicating that the function of MSTO1 must include maintenance of mitochondrial function. Mitochondria are best known as the powerhouse of the cell due to their vital role in energy production, which relies of their genome. Mitochondria also contribute to other aspects of cellular physiology including responding to viral infections and regulating cell death. Mitochondria form a dynamic tubular network that constantly fuses, divides and moves. These dynamic behaviors are essential to maintain mitochondrial function. Virtually nothing is known about the function of MSTO1 in vertebrate cells. The goal of this proposal is to understand how MSTO1 contributes to mitochondrial function in healthy cells and to establish all the cellular pathways that are changed in disease. Dysfunctional and disconnected mitochondria are often associated with neurological diseases and it has been shown that increasing mitochondrial connectivity can improve organismal health. Therefore, we will also determine how increasing mitochondrial fusion impacts the mitochondrial and cellular defects caused by loss of MSTO1.
Grantee: Suzanne Hoppins, Ph.D.
Grant type: Research Grant
Award total: $299,973.00
Institution: University of Washington
Country: United States
Longitudinal Endpoint Optimization to Provide an Assessment of Relevant Drugs
The Duchenne Muscular Dystrophy-Health Indices are novel, disease-specific patient and caregiver-reported outcome measures that were previously designed for use in Duchenne Muscular Dystrophy (DMD) clinical trials to track clinically meaningful changes in health in response to therapeutic intervention. The goal of this research is to implement the DMD-Health Indices in a longitudinal study to better understand how symptomatic burden changes over time, identify factors associated with faster or slower disease progression in DMD, and further optimize existing outcome measures for use in future therapeutic trials. Individuals with DMD will complete demographic questions, the Duchenne Muscular Dystrophy-Health Index, the Pediatric Quality of Life Inventory (PedsQL) DMD module (patient-reported), an instrument preference survey, and a global impression of change survey at baseline and 6, 12, 18, and 24 months. Caregivers of individuals with DMD will complete demographic questions, the Duchenne Muscular Dystrophy Caregiver Reported-Health Index, the PedsQL DMD module (caregiver-reported), an instrument preference survey, and a global impression of change survey at baseline and 6, 12, 18, and 24 months. This research will track patient and caregiver-reported disease burden over time, determine participant preferences with using the various instruments, identify high-risk patients, and optimize the DMD-Health Indices to facilitate future therapeutic trials for DMD patients.
Digital Object Identifier (DOI)
Grantee: Chad Heatwole, M.D.
Grant type: Research Grant
Award total: $299,800.00
Institution: University of Rochester
Country: United States
Disrupted nuclear pore complex surveillance as an initiating event in ALS
Maintenance of the protein complexes called nuclear pore complexes (NPCs) that control communication between the nuclear and cytoplasmic compartments of cells is essential for proper neuronal function and survival. Recent work has demonstrated that defects in a nuclear surveillance pathway initiate damage to these cellular communication channels as an early and significant event in sporadic and familial forms of Lou Gehrig’s disease or Amyotrophic Lateral Sclerosis (ALS). Critically, this damage cascade contributes to common pathological hallmarks of ALS such as altered function and mislocalization of specific proteins. Cumulatively, this NPC injury cascade can lead to impaired neuronal survival in ALS pathogenesis. This proposal will examine the contribution of proteins that comprise the fundamental nuclear surveillance pathway to these NPC injury cascades and therefore illuminate potential therapeutic targets and strategies for ALS and perhaps related neurodegenerative diseases.
Grantee: Alyssa Coyne, PhD
Grant type: Research Grant
Award total: $300,000.00
Institution: Johns Hopkins University School of Medicine
Country: United States
Preclinical Assessment of Gene Editing Efficacy in Periodic Paralysis
Periodic paralysis is a rare inherited disorder of muscle in which affected individuals have recurring transient episodes of weakness that may later progress to permanent muscle weakness. While life expectancy is normal in periodic paralysis, the transient attacks lasting hours to days severely impair quality of life and the permanent weakness may cause loss of ambulation. Interventions to reduce the frequency and severity of paralytic attacks have limited effectiveness. Avoidance of trigger factors (stress, strenuous exercise, cold environments, changes in blood potassium) helps somewhat, and medical management with carbonic anhydrase inhibitors has only modest response rates (50%) with adverse side effects such as kidney stones. Moreover, none of these interventions has been shown to reduce the risk of permanent muscle weakness. This project will develop more effective and durable treatments for periodic paralysis by using gene editing technologies that act directly on the primary cause of disease. We will establish a pre-clinical platform testing the safety and effectiveness of genetic tools (CRISPR) to either remove or to correct the mutation in our mouse models of periodic paralysis. Preliminary data show this approach reduces the susceptibility to attacks of weakness and may possibly prevent the late onset permanent weakness.
Grantee: Steve Cannon, MD, PhD
Grant type: Research Grant
Award total: $299,991.00
Institution: The Regents of the University of California, Los Angeles
Country: United States
Aberrant mitochondrial mRNA folding as mediator of Leigh's syndrome
Leigh syndrome is a rare inherited neurometabolic disorder due to defects in the mitochondrion, the powerhouse of the cell, that affects the central nervous system. Typically, this disorder begins in infants soon after birth, although a few juvenile-onset cases exist. Genetically heterogeneous, the disease can be caused by mutations in nuclear genes encoding proteins required for mitochondrial DNA expression. These proteins, such as LRPPRC, TACO1, and FASTKD5, have in common that they bind to the mitochondrial mRNAs to promote their stability, processing, or translation. Because mRNA binding proteins regulate the folding of mRNAs, and mRNA structure determines their function, we hypothesize that the Leigh syndrome proteins stabilize, disrupt, or require specific mitochondrial mRNA folds to act and promote mitochondrial gene expression. Here, we will test this hypothesis in fibroblasts from patients and human cell lines knockout for LRPPRC, TACO1, or FASTKD5. We expect to describe how mRNA folding and processing function in mitochondria and how they cause or contribute to mitochondrial disease.
Grantee: Antoni Barrientos, Ph.D
Grant type: Research Grant
Award total: $300,000.00
Institution: Miller School of Medicine of the University of Miami
Country: United States
Phase-2 Trial of 5m/kg/week Prednisolone in Young Boys with DMD
Duchenne muscular dystrophy (DMD) leads to weakness which, in infants and young boys manifests as slow motor development. Slow motor development means that boys with DMD walk and run later than other children. We recently showed that development could be improved by having the boys take liquid prednisolone at a dose of 10mg per kg per week in two divided doses of 5 mg per kg per day on two consecutive days. In that study of 24 infants and young boys (ages 3 months to 30 months), we showed this dose was safe. Only one boy stopped the prednisone because of side effects of irritability. All boys maintained normal linear growth using this intermittent dosing. The one important side effect was that about half of the boys gained more weight than expected for their age. Recently work in the mdx mouse (a good model of DMD) and older boys with DMD showed that smaller doses may work equally well. Here we plan to test a dose of 5mg/kg/week given on a single weekend dose. We will use a developmental scale called the Bayley-4 to assess the effects of this dose of prednisolone on motor development.
Grantee: Anne Connolly, M.D.
Grant type: Clinical Research Grant
Award total: $300,000.00
Institution: The Research Institute at Nationwide Children's Hospital
Country: Ohio, United States
Modulating ER-phagy thwart muscle diseases
Muscular dystrophies are genetic disorders characterized by progressive muscle degeneration. In the severe forms, muscle deterioration predisposes patients to a wheelchair and cardiorespiratory failure, as is the case with Duchenne Muscular Dystrophy (DMD) and Ullrich Congenital Muscular Dystrophy (UCMD). DMD and UCMD are widespread worldwide and currently has no cure. These diseases are degenerative and existing treatments only address some of the symptoms, offering no real delay in disease progression. Muscle wasting in patients is characterized by an impairment of the autophagy process that is responsible for the removal of altered organelles inside the myofibers. Moreover, muscles present an increase of ER stress markers suggesting that ER homeostasis is compromised too. Despite its irreplaceable role in muscle physiology, when dysfunctional, the sarcoplasmic reticulum (SR) progressively loses its beneficial role in dystrophic muscles and becomes detrimental promoting a stressful environment and the consequent myofibers’ death. The mechanisms responsible for the fitness of the SR are still poorly understood, which limits any therapeutic efforts in this area. Therefore, investigating SR dynamics and its turnover, in DMD and UCMD muscle, is required to develop alternative therapeutic approaches. This research aims to uncover the biological mechanisms responsible for SR homeostasis. So doing, we hope to reveal targets for future pharmacological treatments.
Grantee: Paolo Grumati, Ph.D
Grant type: Idea Award
Award total: $50,000.00
Institution: Fondazione Telethon
Country: Italy
Single cell transcriptomics to assess transgene related responses in DMD
Micro-dystrophin GT aims to replace the missing dystrophin protein to normalize myofiber fragility and repair in DMD. However, because micro-dystrophin has never been previously expressed in DMD recipients, a risk remains for its recognition by host immunity as a foreign entity, triggering immune attack of cells expressing the transgene. We developed and implemented technology for simultaneous single nuclei RNA sequencing of multi-and mononucleated muscle resident cells to characterize cellularity and gene expression differences between healthy and DMD muscle, creating a snRNAseq reference set. Here we propose to perform snRNAseq on muscle biopsies from post micro-dystrophin GT to assess intra-muscular cell composition and gene expression changes, inclusive of immune and myo-lineage cells, induced by long-term micro-dystrophin expression (Aim 1). Given recent findings linking some micro-dystrophin T cell responses with accelerated muscle weakness and other toxicities, we focus on T cell response to micro-dystrophin. Muscle infiltrating T cells will be additionally characterized by single cell RNA sequencing, determination of paired TCR usage and antigen specificity (Aim 2). These studies promise to better identify "at risk patient DMD genotypes", "the nature of dystrophin immunoreactive epitopes", inform "design of in vitro assays predictive of transgene-triggered immune response" and "development of immunosuppression strategies to minimize transgene-triggered responses".
Grantee: Carrie Miceli, PhD
Grant type: MDA Request for Applications
Award total: $199,962
Institution: The Regents of the University of California, Los Angeles
Country: California, United States
Expression of enhanced dystrophins via AAV
Gene therapy for DMD is aimed at treating the cause of the disorder: a lack of dystrophin. Currently, the only known method for dystrophin delivery to muscles bodywide is by infusion of adeno-associated viral (AAV) vectors carrying miniaturized dystrophin genes. These AAV-microdystrophin (µDys) vectors have shown dramatic effects in animal models and are being tested in clinical trials. However, the observation of serious adverse events (SAEs) in 5 patients who were missing (deleted for) a part of the gene that is carried by µDys vectors has shown that parts of dystrophin can lead to a serious immune response in some patients. The immediate consequence of this has been that such patients (10-15% of all DMD boys) are being excluded from gene therapy trials. Our group has been studying dystrophin immunity for many years due to concerns that such a situation might emerge, and we have developed a computational method to predict immunogenic regions of dystrophin and to redesign vectors to remove problematic parts of the protein. To date we have successfully redesigned several portions of micro/mini-dystrophin and shown that they can be functional, stable and non-immunogenic in animal models. Here we propose to extend these studies to the problematic region recently identified in the clinic. Our goal is to develop modified dystrophin clones that could be used in clinical trials and thus allow broad enrollment of patients regardless of their underlying genetic mutation.
https://doi.org/10.55762/pc.gr.159120
Grantee: Jeffrey Chamberlain, PhD
Grant type: MDA Request for Applications
Award total: $200,000
Institution: University of Washington
Country: Washington, United States
Utrophin Genome Editing for Duchenne's Muscular Dystrophy (DMD) Therapy
Duchenne's Muscular Dystrophy (DMD) is an incurable, genetic disease caused by mutations in the DMD gene leading to an absence of the dystrophin protein. Increased expression of a closely related gene called utrophin can rescue the disease, and increasing utrophin expression is considered a promising therapeutic strategy for DMD. Here we will harness post transcriptional mechanisms that regulate utrophin expression by gene editing to increase utrophin expression as a strategy for DMD gene therapy.
https://doi.org/10.55762/pc.gr.157006
Grantee: Tejvir Khurana, MD, Ph.D.
Grant type: Research Grant
Award total: $300,000
Institution: The Trustees of the University of Pennsylvania
Country: Pennsylvania, United States
Advanced Heart Failure Therapy Outcomes in Neuromuscular Cardiomyopathy
Muscular dystrophies affect not only the muscle but the heart and can result in severe heart failure. Heart transplant and heart pumps, which are called ventricular assist devices, are used in patients with advanced heart failure and improve their quality of life and survival. There have been concerns about involvement of multiple organs and the ability to do physical rehabilitation after heart transplant or heart pumps for patients with muscular dystrophies, which has limited the use of these life saving therapies in patients with muscular dystrophies. We currently have data on heart transplant in muscular dystrophies from databases showing that it is safe, however the database does not collect information that is important for consideration of patients with muscular dystrophies like lung function or use of a wheelchair. Also, there are only reports of heart pump use in patients with muscular dystrophies and no larger databases with this information. Here we combine data from large muscular dystrophy and advanced heart faillure centers to look at the outcome and survival of patients who have muscular dystrophies who undergo heart transplant or heart pump treatment. Multiple centers are needed to have enough patients to understand the outcome of heart failure treatment in muscular dystrophy patients. This work has the potential to have a direct benefit to patients with muscular dystrophy by addressing a gap in their current heart care.
https://doi.org/10.55762/pc.gr.157024
Grantee: Forum Kamdar, PhD
Grant type: Clinical Research Network Grant
Award total: $198,000
Institution: Regents of the University of Minnesota - Twin Cities
Country: Minnesota, United States
Ultrasound-induced access of therapeutics to peripheral nerves
One of the major challenges in developing therapeutics for inherited neuropathies is to achieve adequate access of drugs and gene therapy agents into the peripheral nerves throughout the body through a clinically applicable delivery route. The blood-nerve barrier (BNB) limits this distribution and the effectiveness of potential therapies. In order to overcome this, we propose to test an innovative method by transiently disrupting the BNB using a Focused-Ultrasound System (FUS). We will then test the efficacy of this method to facilitate penetration of viral vectors for gene therapy into peripheral nerves. As model disease, X-linked Charcot-Marie Tooth Disease (CMT1X) is a common inherited demyelinating neuropathy, characterized by progressive muscle atrophy, weakness and sensory loss in the limbs. CMT1X is caused by mutations affecting connexin32 (Cx32), a protein that is expressed specifically by myelinating cells in the nerves, the Schwann cells, and plays important role in nerve function and integrity. Using a previously developed gene therapy vector for treating CMT1X, we will examine the benefit of transient BNB disruption using FUS in order to maximize the gene delivery to Schwann cells and the therapeutic efficacy. Successful application of this technique can also benefit several other therapy approaches for inherited neuropathies as well.
https://doi.org/10.55762/pc.gr.157047
Grantee: Alexia Kagiava, PhD
Grant type: Idea Award
Award total: $50,000
Institution: The Cyprus Foundation for Muscular Dystrophy Research
Country: Cyprus
AMPK signaling defect in DM1 and its potential as a novel therapeutic target
Myotonic Dystrophy type 1 (DM1) is caused by a mutation affecting the normal function of the cell, causing the many symptoms characteristic of this disease. Our research led us to investigate AMPK signaling in DM1 muscle cells. We recently found that AMPK signaling is altered in DM1 muscle cells, and that the activation of AMPK with drugs and exercise is beneficial for the pathology. Here, we will build upon these initial findings and investigate the role of AMPK signaling in DM1. The characterization of this pathway in DM1 appears crucial and timely as this study will pave the way to a better understanding of the DM1 pathology while leading to the development of novel therapeutic strategies for DM1.
https://doi.org/10.55762/pc.gr.157012
Grantee: Bernard Jasmin, PhD
Grant type: Research Grant
Award total: $300,000
Institution: University of Ottawa
Country: Ontario, Canada
The role of DNAJ proteins and chaperone-chaperone interaction in muscle
Proteins are originally string-like polypeptide chains that are folded to form functional proteins. Chaperones help in the folding process or correct the folding of misfolded proteins. Therefore, when chaperones abnormality, the number of misfolded, non-functional proteins increases and eventually accumulates in the body. Many such chaperone diseases, called "chaperonopathies," are involved in neuromuscular diseases. Understanding the function of chaperones will lead to the development of treatments for chaperonopathies. Our group has shown that mutations in two genes, DNAJB6 and DNAJB4, cause muscle diseases. However, it is still unknown what "client" proteins the chaperones work on, how they correct the misfolding, and why only specific muscles are more severely impaired. I am trying to uncover the client proteins by manipulating cells to prevent a particular gene from working. In addition, since my preliminary experimental data suggest that the DNAJ proteins may interact with each other and work to correct folding, we will analyze this using cells and animal models in which the two DNA proteins are rendered inactive. In addition, we will explore why only specific muscles are strongly damaged using animal models and imaging techniques. If these things are clarified, it will lead to significant progress in developing therapies.
https://doi.org/10.55762/pc.gr.157003
Grantee: Michio Inoue, Ph.D.
Grant type: Development Grant
Award total: $209,510
Institution: Washington University in St.Louis
Country: Missouri, United States
Improving interpretation of variants in Sarcoglycanopathies
Muscular dystrophy is a group of diseases that cause progressive weakness and loss of muscle mass. Sarcoglycanopathies (SGPs) are a common but severe form of it, which affect hip and shoulder muscles. SGPs is an inherited disease with two mutations (variants) concurrently present in each of the chromosomes. Variants in four sarcoglycan (SG) genes can cause SGPs, named SGCA, SGCB, SGCG and SGCD. Currently, it is difficult to interpret a variant as pathogenic. Muscle biopsy or DNA sequencing is necessary for the patients to be diagnosed. Typically, variants predicted to produce no protein are easier to be interpreted as pathogenic, while missense, the most common type of variant in genes, are harder to interpret, leaving many suspected SGP patients without a definitive genetic diagnosis. The molecular feature of SGPs is the absence or reduced SG protein expression on the muscle cell membrane. We will use this feature to develop a high throughput functional assay and evaluate the pathogenicity of different variants. We will create a DNA library with all possible single nucleotide variants for an SG gene, then introduce them into cells. By flow cytometry, a technique used to detect the SG proteins on the cell surface, we will be able to predict the pathogenicity for each of the variants, especially difficult to interpret missense variants. This method will create a ‘look-up’ table to aid in the clinical interpretation of variants in patients with SGPs.
https://doi.org/10.55762/pc.gr.157030
Grantee: Shushu Huang, M.D.
Grant type: Development Grant
Award total: $210,000
Institution: Yale University
Country: Connecticut, United States
Nucleocytoplasmic GU-RNA gradients and TDP-43 mislocalization in ALS
Amyotrophic lateral sclerosis (ALS) is a fatal degenerative disease of motor neurons for which there is no curative therapies. Despite significant genetic and phenotypic variability, postmortem evaluation in 97% of ALS patients shows disruption of the essential RNA binding protein, TDP-43. TDP-43 critically regulates RNA processing within the nucleus of the cell, and its cytoplasmic mislocalization and aggregation in disease causes widespread RNA splicing defects and aggregate-mediated disruption of cellular homeostasis. TDP-43 is therefore an important therapeutic target, although the upstream causes that initiate the TDP-43 pathogenic cascade in ALS remain unknown. A major goal of our laboratory is to investigate the molecular regulation of TDP-43 trafficking in healthy cells and its disruption in disease. Our recent studies show a major role for TDP-43's normal, nuclear RNA binding partners in regulating TDP-43 localization. Surprisingly, we have also observed that a prolonged disruption of the cellular gradient of TDP-43 RNA targets can initiate aberrant TDP-43 cytoplasmic aggregation. Here, we will perform a detailed biochemical and molecular characterization of RNA-induced TDP-43 cytoplasmic aggregation in cell lines and human neurons, to advance our understanding of the beneficial versus deleterious interactions of TDP-43 with RNA.
https://doi.org/10.55762/pc.gr.157034
Grantee: Lindsey Hayes, M.D., Ph.D.
Grant type: Research Grant
Award total: $300,000
Institution: Johns Hopkins University School of Medicine
Country: Maryland, United States
Calcium regulation of ER stress and protein degradation in congenital myopathy
Muscle cells are constantly making new proteins that are needed to perform important skeletal muscle functions, like contraction and relaxation. Newly made proteins are carefully folded to ensure they function properly and can be transported to where they are needed in the cell. Normally when a protein misfolds it is removed before it can affect cellular health but in some muscle diseases these misfolded proteins remain in the cell. How these misfolded proteins affect the ability of muscle to function is poorly understood. Our work suggests that in some diseases the "garbage disposal" systems of muscle cells become overworked, allowing these misfolded proteins to buildup and cause cellular stress. This proposal will examine the factors that regulate protein folding and determine how the accumulation of misfolded proteins affects muscle contraction and relaxation. Our work will also determine whether these stress pathways are a viable target for alleviating muscle dysfunction in congenital myopathy.
https://doi.org/10.55762/pc.gr.157041
Grantee: Amy Hanna, Ph.D.
Grant type: Research Grant
Award total: $297,000
Institution: University of Queensland (UQ)
Country: Texas, United States
Clinical Research in ALS (CRiALS)
There is an enormous need for a better understanding of the clinical, demographic, and genetic features that underlie the phenotypic variability of ALS. Indeed, it may be more accurate to define ALS as a “syndrome” defined by the commonality of clinical features and progression. The syndrome of ALS may encompass a number disease mechanisms that will require different approaches for therapeutic intervention, and one could hypothesize that our failures in clinical trials for ALS are due to the inclusion of multiple disease types, some of which are not responsive to the experimental drug under investigation. Thus, we need to better understand whether multiple mechanisms of ALS truly exist, and to do that we need to better define the disease by documenting phenotypes along with genetic, serologic, and physiological features of disease. This improved categorization of disease will result in the definition of specific disease features that will allow for clinical trials targeting specific disease mechanisms. The CRiALS project, supported by MDA funding, has generated a world-class clinical database and biobank for use locally, nationally, and internationally for discovery research focused on better defining the mechanisms of ALS, which will lead to drug targets and directed therapeutics.
https://doi.org/10.55762/pc.gr.154583
Grantee: Jonathan Glass, PhD
Grant type: Restricted Research Grant
Award total: $16,255
Institution: Emory University
Country: Georgia, United States
Genetic and metabolic strategies for mutant CHCHD10 neuromuscular disorders
Mutations in a mitochondrial protein, coiled helix coiled helix domain containing protein 10 (CHCHD10) cause neuromuscular diseases including mitochondrial myopathy and amyotrophic lateral sclerosis. Mitochondrial abnormalities cause metabolic imbalance that contribute to these disorders. In this application, we propose to treat a mouse model of mutant CHCHD10 disorder that show mitochondrial myopathy, motor neuron degeneration, and cardiomyopathy. Disease altering strategies are needed for CHCHD10 disorders, since there are none to date. We propose to test two distinct strategies, one specifically targeting CHCHD10 with a genetic approach to reduce CHCHD10 levels, and the other to modulate metabolic imbalance observed in the mutant mice with nutritional approaches. We will investigate the effect of these strategies in the disease course of the mutant mouse. Importantly, metabolic therapy approaches tested in this application could be extended to a larger group of neuromuscular disorders involving similar metabolic dysregulation.
https://doi.org/10.55762/pc.gr.157007
Grantee: Hibiki Fujita, Ph.D.
Grant type: Research Grant
Award total: $300,000
Institution: Weill Cornell Medicine
Country: New York, United States
Microdystrophin Design for the Treatment of Dystrophin-Deficient Cardiomyocytes
Currently, there are three clinical trials testing microdystrophin in Duchenne muscular dystrophy (DMD) patients. Microdystrophins have shown promise in improving skeletal muscle function; however, little is known about efficacy in the heart as animal models used in preclinical testing do not manifest dilated cardiomyopathy. This is a critical gap in our knowledge, as dilated cardiomyopathy is the leading cause of death in DMD patients. My project capitalizes on cardiomyocytes differentiated from human induced pluripotent stem cells harboring dystrophin mutations. I will compare how well microdystrophin variants rescue functional deficits exhibited by dystrophin-deficient cardiomyocytes against minidystrophin, comprised of more domains of dystrophin. The outcome of this study will yield design principles for transgenes that can improve the functional deficits of DMD cardiomyocytes. This study will evaluate the efficacy of existing microdystrophin variants in the context of cardiomyocyte function and will establish a platform for assessing functional rescue in human cells, accelerating the development of therapies to delay the onset of heart failure.
https://doi.org/10.55762/pc.gr.157032
Grantee: Asuka Eguchi, Ph.D.
Grant type: Development Grant
Award total: $210,000
Institution: The Board of Trustees of the Leland Stanford Junior University
Country: California, United States
Gene therapy for large muscle disease genes
Childhood genetic muscle diseases affect at least 250, 000 North Americans and significant quality of life and life expectancy. Despite their prevalence and impact, few therapies have been developed. Many NMDs are caused by genetic mutations that result in the loss of a critical protein. An attractive therapeutic strategy is to replace the missing or mutated gene through gene replacement therapy. This approach has been extremely successful for a small number of conditions, such as spinal muscular atrophy, where gene therapy dramatically increases survival. Currently, viral vectors such as adeno associated viruses (AAVs) are the main gene therapy delivery system. AAVs can only carry genes of limited size. However, nearly half of all human genes exceed this size restriction, and It therefore is not feasible to use AAVs for gene replacement therapy for a large proportion of genetic muscle diseases. This proposal will directly address and seek to overcome this critical therapeutic barrier. We hypothesize that lipid nanoparticles can deliver large genes in a safe and effective manner. We will test this hypothesis for a disease called RYR1 related myopathy, a severe genetic childhood muscle diseases. We will use lipid nanoparticles to deliver RYR1, one of the largest genes in the genome, to rescue a mouse model of the human disease. Our study’s success will open the door not only for gene therapy for RYR1, but for the whole group of disorders caused by large gene mutations.
https://doi.org/10.55762/pc.gr.157051
Grantee: James Dowling, M.D., Ph.D.
Grant type: Idea Award
Award total: $50,000
Institution: The Hospital for Sick Children
Country: Ontario, Canada
Pathophysiology and Treatment of Tubular Aggregate Myopathy
Tubular aggregate myopathy (OMIM #160,565 and #615,883) is an inherited skeletal muscle disease characterized by weakness, cramps, myalgia, and fatigue that primarily affects proximal muscles of the lower limbs. The aberrant presence in skeletal muscle of tubular aggregates, regular arrays of highly-ordered and densely packed tubules, represents the key histopathological hallmark of this disease. There is currently no cure or effective treatment for this debilitating muscle disease. This project will use a newly generated mouse model of tubular aggregate myopathy with characteristics that mimic the human disease (including age-dependent muscle weakness, increased fatigue, and tubular aggregates in skeletal muscle) to provide needed insight into the underlying pathophysiological mechanisms and to assess therapeutic potential of early intervention with an Orai1 inhibitor treatment and endurance exercise in mitigating disease progression.
https://doi.org/10.55762/pc.gr.157013
Grantee: Robert Dirksen, Ph.D.
Grant type: Research Grant
Award total: $300,000
Institution: University of Rochester
Country: New York, United States
Find MDA
in your Community
-
Search for Clinical Trials
Learn More -
Grants at a Glance
Read More
