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
Combining oxytocin with corticosteroid therapy in DMD patients
Duchenne muscular dystrophy, is a muscular degeneration characterized by the absence of a cytsoskeletal protein, dystrophin, leading to death around the age of 35 from cardio-respiratory failure. Without curative treatment, corticosteroid therapy is the only treatment currently used. Serious side effects are described as depression or muscle weakness. Our preliminary results on the oxytocin (OT) levels of patients before and after corticosteroid therapy) strongly support the hypothesis that the addition of OT could have beneficial effects on cardiac function, muscle regeneration and social behaviors in patients. Using the Mdx mouse model, we will assess the combination of OT and corticosteroid therapy on these parameters. As oxytocin is FDA approved, the feasibility of rapid clinical application is strong.
https://doi.org/10.55762/pc.gr.157050
Grantee: Sabine De La Porte, HDR
Grant type: Idea Award
Award total: $50,000
Institution: Institut National de la Santé et de la Recherche Scientifique
Country: France
Unraveling the contribution of local translation to ALS pathogenesis
Despite identification of ALS-associated RNA binding proteins (RBPs) including TDP-43 and FUS (which also cause the second most frequent dementia, frontotemporal dementia or FTD), the disease mechanism(s) are unknown. The effort proposed here seeks to uncover this mechanism to support therapy development in familial ALS forms and beyond. Key questions to be tackled will be to understand the emerging critical functions of TDP-43 and FUS within motor neuron projections called axons and at their synapses, where the mutant forms are known to accumulate. We will thus investigate how mutations cause axonal degeneration and loss of their neuromuscular junctions (NMJs), which are the earliest hallmarks of ALS pathogenesis. In particular we will identify the FUS/TDP-43 mRNA targets along axons and NMJs and unravel the mechanisms underlying their local protein synthesis in health and ALS pathogenesis.
https://doi.org/10.55762/pc.gr.157008
Grantee: Sandrine Da Cruz, Ph.D.
Grant type: Research Grant
Award total: $300,000
Institution: VIBvzw
Country: Belgium
Therapeutic significance of FKRP’s regulation of glycosylation within the Golgi
Although a significant number of new genes and new mutations in known genes are being identified as the cause of congenital muscle diseases why and how these mutations cause disease is often less than clear. Specifically, the relationship between the congenital muscle disease symptoms and the genetic lesion is often complex. Some muscle diseases with the same clinical phenotype result from mutations in several different genes but, by contrast, mutations in the same gene can lead to different congenital muscle diseases with a different clinical outcomes. The disparity found in disease presentations is perhaps no more apparent than when considering the disease spectrum evident in patients with FKRP deficiency, which can present as a mild muscular dystrophy diagnosed late in life, through to a severe pathology of the newborn affecting sight, mental capacity and ambulation. We have therefore generated zebrafish models of this muscular dystrophy to fill this knowledge gap. Combining studies in zebrafish genetics, patient cell lines and biochemical approaches we surprisingly revealed that FKRP acts on a second novel muscle pathway, directing alterations on fibronectin an important muscle attachment protein. This study aims to understand the clinical significance of this finding and to determine if this mechanism can explain the different types of disease that mutations in FKRP cause. In addition we wish to explore the possible therapy options our new findings have provided.
https://doi.org/10.55762/pc.gr.157035
Grantee: Peter Currie, PhD
Grant type: Research Grant
Award total: $295,614
Institution: Monash University
Country: Australia
Long-read genome sequencing to diagnose neuromuscular disorders
Neuromuscular disorders (NMDs) comprise a heterogenous group of conditions associated with impaired nerve and muscle function that affect 1-10/100,000 individuals worldwide, the vast majority of which result from one or more genetic factors. Despite successes from single gene, gene panel, and exome or genome sequencing tests, there remains a large portion of patients suspected to have genetic NMDs but for whom no precise diagnosis can be made using current clinical or laboratory information; such patients often undergo a “diagnostic odyssey” in which many tests are conducted over many years without success. We hypothesize that many genetic variants that cause NMDs are missed by standard DNA testing methods. We will apply an exciting “long-read” genome sequencing technology called Circular Consensus Sequencing (CCS, also called “HiFi”) recently developed by PacBiosciences to a group of undiagnosed children suspected to have a congenital NMD. Preliminary data indicate that CCS/HiFi sequencing is far more accurate than standard sequencing, especially for complex genetic variants, and has great potential to detect pathogenic, diagnostic genetic variants that were previously overlooked. We aim to refine data and process quality and establish methods suitable for routine research and clinical use. Our study has potential to improve diagnostic yield and provide better information, and ultimately improve outcomes, for patients and families affected by NMDs.
Grantee: Greg Cooper, Ph.D.
Grant type: Research Grant
Award total: $294,803
Institution: HudsonAlpha Institute for Biotechnology
Country: Alabama, United States
Investigating a link between ER stress and nucleocytoplasmic transport in ALS
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons, leading to paralysis and death within 2-5 years for most patients. There is a growing consensus that disruption of the nuclear pore complex (NPC) which shuttles proteins and RNAs in and out of the nucleus, contributes to the disease, but both the cause and consequences of this impairment remain unclear. A key finding in motor neurons in ALS is that they have protein aggregation and upregulation of endoplasmic reticulum (ER) stress pathways. While the ER stress pathway may initially protect motor neurons against accumulating toxic protein aggregates, chronic ER stress is believed to contribute to toxicity and cell death in ALS. Indeed, the Amylyx drug AMX0035 being reviewed by the FDA for treatment of ALS, is believed to protect neurons by inhibiting ER stress. ER stress induces activation of the “unfolded protein response” (UPR), which relies on the communication between the nucleus and cytoplasm (NCT). Our proposal aims to study how NCT impairment—a state of incommunicado between the nucleus and cytoplasm—affects ER stress and UPR in ALS models. Furthermore, ER is an important organelle that helps assemble the NPC, and we will also examine how ER stress affects NCT. Establishing how NCT and ER stress interact in ALS have the potential to identify new therapeutic target for ALS.
https://doi.org/10.55762/pc.gr.157027
Grantee: Chang Geon Chung, Ph.D.
Grant type: Development Grant
Award total: $210,000
Institution: Johns Hopkins University School of Medicine
Country: Maryland, United States
Maximizing dystrophin functionality
Gene therapy for Duchenne muscular dystrophy is an extremely promising approach to therapy as it directly addresses the cause of the disorder- a lack of functional dystrophin protein. Our group has spent more than 30 year studying the structure and function of dystrophin and developing approaches for gene therapy. This work includes development of numerous micro-dystrophin clones, several of which are being tested in clinical trials. We also showed that AAV vectors could be used for systemic delivery of new genes to muscles, bodywide. However, while current AAV-microdystrophin vectors are showing significant benefit in the clinic, several limitations have been identified. Among these are a lack of full function from micro-dystrophins, lower levels of dystrophin production than are ideal, and some vector dose limitations due to adverse events. Our proposal explores a new way to make larger mini-dystrophins and even full-sized dystrophin by co-delivery of current and novel AAV vectors. Here we explore the potential of this system to improve upon approach for gene therapy of DMD and other neuromuscular disorders.
https://doi.org/10.55762/pc.gr.158724
Grantee: Jeffrey Chamberlain, PhD
Grant type: Restricted Research Grant
Award total: $233,243
Institution: University of Washington
Country: Washington, United States
HSPB3: a promising candidate for the maintenance of the neuromuscular system
Motor neuropathies (dHMNs) and ALS share common underlying mechanisms, including degeneration of peripheral nerves. Dysfunction at the junction between nerve and muscle, the neuromuscular junction (NMJ), is an early event contributing to motor neuron (MN) loss in dHMNs and ALS, with active denervation/reinnervation occurring during the disease. Importantly, the regeneration of nerves and muscles occurs also during adulthood to enable the repair of NMJs and damaged muscles; however, the regenerative abilities decline with aging, when these diseases develop. It is fundamental to better understand how dysfunctions of the neuromuscular system lead to dHMNs and ALS. This project aims to unravel players and mechanisms responsible for MN and NMJ vulnerability in dHMNs and ALS. We focus on the gene HSPB3, which is a promising candidate because: 1) rare HSPB3 variants have been found in dHMNs and ALS patients; 2) we have shown that HSPB3 is a specialized chaperone engaged in muscle and MN differentiation; 3) we found that HSPB3 induction is impaired in MNs carrying a mutation linked to ALS. We hypothesize that deregulation of the pro-differentiation functions of HSPB3 may contribute to NMJ deterioration with aging and in disease. Using human MNs and muscle cells and neuromuscular organoids derived from iPS cells we will study how HSPB3 dysfunction leads to degeneration and assess if its targeting increases the regenerative capacity of the neuromuscular system.
https://doi.org/10.55762/pc.gr.157046
Grantee: Serena Carra, Ph.D.
Grant type: Research Grant
Award total: $299,910
Institution: University of Modena and Reggio Emilia (Università degli Studi di Modena e Reggio Emilia)
Country: Italy
DMD-Related Cardiomyopathy Beyond Dystrophin Deficiency in Skeletal Muscle
Duchenne muscular dystrophy (DMD) is a devastating disease affecting the musculature of young kids and boys caused by mutations in the dystrophin gene, this in turn cause the absence of dystrophin protein, a protein that is essential to keep the muscle intact. DMD is characterized by a progressive replacement of musculature by fibrotic and fat tissue, this replacement causes dramatic loss of contractile function of the muscle. This disease causes kids to be wheelchair bound in their early teen years and death within the second/third decade of their life. Current therapeutic approaches have improved life expectancy; however, there is not yet a definitive cure of the disease. In this project I propose a novel approach to understand if reintroduction of dystrophin in muscles is able to repair all the damages that muscles have acquired. Understanding this, will allow to identify future therapeutic targets to cure DMD.
https://doi.org/10.55762/pc.gr.157010
Grantee: Luca Caputo, PhD
Grant type: Development Grant
Award total: $210,000
Institution: Sanford Burnham Prebys Medical Discovery Institute
Country: California, United States
Restoring membrane trafficking in CMT neuropathies with aberrant myelin
(Co-funded with CMT Research Foundation)
Charcot-Marie-Tooth (CMT) neuropathies are generally characterized by progressive muscular atrophy and weakness, with an age at onset usually comprised between the first and the second decade of life. Among CMT neuropathies, CMT4B1 is a very severe demyelinating neuropathy with childhood onset, characterized by myelin outfoldings, redundant loops of myelin in the nerve that degenerate causing axonal problems. This form of aberrant myelin is also a pathological feature of other forms of demyelinating CMT, such as CMT4B2, B3, CMT4C and CMT4H. Our laboratory demonstrated that loss of MTMR2 (Myotubularin-related 2) phosphatase is the cause of the disease. MTMR2 dephosphorylates phospholipids, important regulators of membrane trafficking, which is a key process in Schwann cells, the glial cells forming myelin in the peripheral nervous system. Our laboratory also generated in vitro and in vivo models of CMT4B1, which have been instrumental over the years to study the pathophysiology of this neuropathy. By investigating why loss of MTMR2 in Schwann cells provokes aberrant myelin, we identified a novel mechanism by which MTMR2 and its lipid substrate coordinate cytoskeleton dynamics and membrane growth within myelin-forming cells. In this project, we will further explore this mechanism of relevance in cell biology. We will also test whether pharmacological and/or genetic modulation of these pathways can represent an effective strategy for the therapy of CMT4B with aberrant myelin.
https://doi.org/10.55762/pc.gr.157015
Grantee: Alessandra Bolino, Ph.D.
Grant type: Research Grant
Award total: $263,450 (Co-funded with CMT Research Foundation)
Institution: San Raffaele Hospital (Ospedale San Raffaele)
Country: Italy
ASM-AAV Gene Therapy as a Treatment for Limb Girdle Muscular Dystrophy 2B
LGMD2B is a progressive late adolescent onset disease with development of functional limitations in running and climbing stairs within 3 years of diagnosis, and requirement of wheel-chair assistance for mobility within 20 years, on average. These rates of disease progression are hastened by increased physical activity and exercise. The relationship between physical activity, muscle degeneration, and functional mobility deficits in LGMD2B, is thought to derive, in-part, from poor membrane repair and inadequate dysferlin-mediated ASM secretion in response to frequent myofiber membrane injury with activity and exercise. This deficit identifies extracellular ASM supplementation as a potential treatment to improve myofiber repair for LGMD2B and preserve functional mobility. ASM enzyme replacement therapy offers an alternative, but there are currently no approved drugs to address this or other disease etiology of dysferlinopathy. However, liver gene transfer with AAV vectors has successfully treated hemophilia B in humans, by inducing liver expression and secretion of therapeutic concentrations of circulating FIX protein. A similar treatment approach may be leveraged to bypass deficient injury triggered ASM secretion in LGMD2B, by providing myofibers with an increased pool of extracellular ASM for repair, derived from the transduced liver. Optimizing the pre-clinical efficacy and safety of a liver-targeted ASM-AAV treatment in LGMD2B is required for integration into the clinic.
https://doi.org/10.55762/pc.gr.157028
Grantee: Daniel Bittel, Ph.D., D.P.T.
Grant type: Development Grant
Award total: $209,811
Institution: Children's Research Institute (CNMC)
Country: DC, United States
Developing a bioassay for GJB1 variants causing CMTX1
Charcot-Marie-Tooth disease (CMT) is a common and debilitating disorder, affecting about 130,00 people in the United States and several million throughout the world and the X-linked form cased by mutations the GJB1 gene is the second most common. With the widespread availability of genetic testing, over 700 variants in GJB1 have been identified. However many of these are likely not disease causing. This leads to great difficulty with advising patients when results of genetic testing are obtained, because there is currently no way to reliably identify which of these variants are disease causing. This proposal aims to address that problem by studying a subset of these not characterized variants to allow us to develop an algorithm for determining pathogenicity of GJB1 variants.
https://doi.org/10.55762/pc.gr.157043
Grantee: Charles Abrams M.D., Ph.D.
Grant type: Research Grant
Award total: $299,865
Institution: The Board of Trustees of the University of Illinois - University of Illinois at Chicago
Country: Illinois, United States
Identification of genetic modifiers for C9ORF72-ALS/FTD
A hexanucleotide repeat expansion in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two adult-onset progressive neurodegenerative diseases. One of the major hypotheses for toxicity is the accumulation of dipeptide repeat (DPR) proteins produced by RNA repeats. There were many studies unraveling the toxicities by different DPRs. In particular, poly-GR is one of the most toxic DPRs and is found to correlate with neurodegeneration in C9ORF72-related ALS, implicating the contribution of poly-GR to the disease etiology. Therefore, we performed a genetic screening in human neurons to identify modifiers that regulate the poly-GR mediated toxicity. I identified and validated one candidate modifier, knockdown of which strongly improved the survival of the poly-GR expressing neurons. I now propose to further decipher the neuroprotection mechanism, and validate the rescue efficacy in both C9ORF72-ALS patient-derived neurons and the mouse model. This study will provide novel insights on disease mechanisms and potential therapeutic target.
https://doi.org/10.55762/pc.gr.157004
Grantee: Zhe Zhang, Ph.D
Grant type: Development Grant
Award total: $210,000
Institution: Johns Hopkins University School of Medicine
Country: Maryland, United States
Engineering CAR-Tregs for the induction of immune tolerance in gene therapy
In some Duchenne muscular dystrophy (DMD) patients the development of transgene-specific immunity raises safety concerns and the need for novel approaches to study and mitigate these unwanted immune responses. The recognition of dystrophin-expressing muscle cells by dystrophin-specific T cells may result in the rejection of muscle cells that express dystrophin. Our studies will explore a new approach to re-educate the DMD patient's immune system to understand that it should not mount a response to the dystrophin protein that is expressed after gene therapy. To achieve this, we will use regulatory T cells (Tregs), which normally instruct the immune system to not attack self-proteins. We will engineer a muscle-specific Treg that will be used to inhibit the activation of dystrophin-specific T cells in a novel mouse model of dystrophin immunity our lab developed. Muscle-specific Tregs, thus represent a novel approach for addressing the recent observation in dystrophin gene therapy trails that SAEs are partly attributed to dystrophin-specific T cells, and have great potential for transforming the approaches used to inhibit immunological responses to gene therapy in DMD patients.
https://doi.org/10.55762/pc.gr.157011
Grantee: Armando Villalta, PhD
Grant type: Research Grant
Award total: $200,000
Institution: The Regents of the University of California (Irvine)
Country: California, United States
A Designer HMGB1 as a Drug Candidate for Duchenne Muscular Dystrophy
Muscular dystrophies are a family of genetic diseases characterized by progressive muscle degeneration. Duchenne muscular dystrophy is the most common and lethal muscle-wasting disease of childhood, which is still incurable. Pharmacological corticosteroid therapy is the standard of care for patients affected by Duchenne muscular dystrophy to control symptoms and slow disease progression through potent anti-inflammatory action. However, these current treatments have limited efficiency and a major concern is the significant adverse effects associated with long term-treatment. In our laboratory, we study a protein, called HMGB1, which is a key player in inflammatory and regenerative processes. We generated a designer HMGB1 protein devoid of inflammatory activity but endowed with potent regenerative properties in muscle. We recently demonstrated that administration of our designer protein stimulates regeneration and ameliorates the muscle function, aside from reducing degeneration, inflammation, and fibrosis, in mouse models of muscular dystrophies. Our objective is to conduct a preclinical evaluation of this novel molecule as drug candidate for patients affected by Duchenne muscular dystrophy. Hence, our study is oriented towards a translational approach to develop an innovative therapeutic strategy for patients affected by Duchenne muscular dystrophy and preliminary data indicate that in future, these results might be extended to other forms of muscular dystrophy.
https://doi.org/10.55762/pc.gr.157017
Grantee: Emilie Venereau, Ph.D
Grant type: Research Grant
Award total: $300,000
Institution: San Raffaele Hospital (Ospedale San Raffaele)
Country: Italy
Contribution of variable number tandem repeats to Amyotrophic Lateral Sclerosis
The number of people in our world over 60 years old is estimated to more than double by 2050. As life expectancy increases, so will the prevalence of age-related neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS). The genetic contributions that lead to ALS are still not fully clear despite intensive sequencing efforts, necessitating further studies into genes that cause or modify ALS. We hypothesize that a significant genetic contribution to disease comes from regions of the human genome that are still challenging to characterize using standard sequencing technology. Some of these regions contain repetitive stretches of DNA can expand in patient populations and often can manifest in different neurodegenerative disorders. We have established techniques to characterize these genetic regions in a multiplexed high-throughput manner. We propose to use our approaches to determine the contributions of these repeats to ALS, determine how they aggregate in cells and what additional factors they can bring into these aggregates. Our proposed work will provide insight into novel mechanisms of ALS and help bridge genes associated with disease for the purpose of devising novel therapeutics.
https://doi.org/10.55762/pc.gr.157016
Grantee: Paul Valdmanis, Ph.D
Grant type: Research Grant
Award total: $300,000
Institution: University of Washington
Country: Washington, United States
Leveraging microglia states to understand ALS disease
Although most therapeutic avenues for Amyotrophic lateral sclerosis (ALS) have focused on neurons, recent studies suggest that microglia, the immune cells of the brain, are key players in pathogenesis, pointing toward alternative approaches to therapeutic development. Many genetic risk factors for ALS are expressed in microglia and recently, a distinct subpopulation, or “state”, has been identified in ALS patients. Interestingly, microglia have also been involved in other neurodegenerative diseases like Alzheimer’s disease. In this study, we used human cell culture models and single-cell-resolution analyses to identify how ALS genetics affect microglia states and functions and understand how microglia affect motor neuron health. This project will identify pathways of neurodegeneration specific to ALS and open the door for new therapeutic avenues.
https://doi.org/10.55762/pc.gr.156998
Grantee: Martine Therrien, Ph.D
Grant type: Development Grant
Award total: $208,027
Institution: Broad Institute (Eli and Edythe L. Broad Institute of MIT and Harvard)
Country: Massachusetts, United States
Molecular characterization of hippocampal neurons in Duchenne Muscular Dystrophy
Duchenne Muscular Dystrophy (DMD) is more than just a muscle disease. Boys with DMD have a distinct cognitive profile including lower intelligence quotient, executive function problems, working memory deficits, communication and language difficulties. Second to the muscle, the highest expression of dystrophin protein is in the central nervous system underscoring the importance of dystrophin in neuronal and glial function. To more deeply understand the role of dystrophin in hippocampal neurons, it is imperative to delve deeply into the molecular mechanisms that go awry. Towards this goal, we will use the preclinical mouse model of DMD, the mdx52 mouse, and a cutting-edge technique -- single nuclei RNA sequencing -- to specify the neuronal transcriptome. This knowledge has two immediate outcomes. First, we will have a detailed account of neuronal transcriptome. Second, using this knowledge, we would be able to identify what genetic pathways are abnormal so we can design mechanistically-driven therapeutic agents. This MDA Idea Development Award will offset cost for the single nuclei RNA sequencing.
https://doi.org/10.55762/pc.gr.157053
Grantee: Mathula Thangarajh, PhD
Grant type: Idea Award
Award total: $50,000
Institution: Virginia Commonwealth University
Country: Virginia, United States
Advancing equitable access to clinical trials in rare diseases
In recent years, health disparities in accessing health and opportunities to clinical trials have emerged as critical unmet needs not only in the general population but also in rare diseases. Barriers to equitable access to healthcare opportunities includes difficulty accessing information, geographic location, financial burden due to work productivity loss. Our prior research knowledge and experience has demonstrated that mitigating financial burden can be a powerful incentive for families to consider participation in clinical research. We will advance this approach using our recently funded R21 award to investigate a technology-enabled platform to assess cognition in dystrophinopathy. This application will serve to support travel and travel-related costs, so that families and research participants, regardless of socioeconomic status and geographic location will have equitable access to our study.
https://doi.org/10.55762/pc.gr.156495
Grantee: Mathula Thangarajh, PhD
Grant type: Clinical Trial Travel Grant
Award total: $69,460
Institution: Virginia Commonwealth University
Country: Virginia, United States
LEMS-induced disruption of the nanoscale organization of the active zone
Many neuromuscular diseases result in functional disruptions at the neuromuscular junction (NMJ); the site of communication between motor neurons and muscle fibers. Lambert-Eaton Myasthenic Syndrome (LEMS) is caused when a patient’s own immune system attacks and removes calcium channels from transmitter release sites at the NMJ, causing muscle weakness. Previously, the simple loss of calcium channels was thought to result in the muscle weakness seen in LEMS, but recently it has become apparent that the pathophysiology of LEMS is more complicated. In fact, the organization of many proteins at the neurotransmitter release site is significantly disrupted in LEMS, indicating a more complex pathophysiology. Unfortunately, exploring the specific proteins whose organization is disrupted in LEMS has not been possible because of the technical limitations of imaging these very small regions of the NMJ. However, recent advances in super-resolution microscopy can now provide the resolution necessary to observe the changes that occur at transmitter release sites in LEMS. This proposal aims to identify the specific proteins that are altered in LEMS, which will provide new potential targets for the development of alternative therapies. The data generated from this project will also enhance our understanding of neurotransmitter release sites at the NMJ, which may prove beneficial for the development of treatments for other neuromuscular diseases.
https://doi.org/10.55762/pc.gr.156997
Grantee: Tyler Tarr, Ph.D.
Grant type: Development Grant
Award total: $208,212
Institution: University of Pittsburgh
Country: Pennsylvania, United States
Design and evaluation of drug-like small molecules targeting repeat expansion
Repeat expansions are a class of disease causing RNAs causing more than 30 different diseases including myotonic dystrophy type 1 (DM1). These disease causing RNA molecules have structured regions with biological functionality. In a structure based approach, small molecules, can target these structured regions, called binding pocket. DM1 is caused by an expanded CTG repeat. After being transcribed into RNA this expanded repeat forms a hairpin structure with multiple repeating 1x1 UU internal loops. These internal loops provide a high affinity binding pocket for proteins like muscleblind-like 1 (MBNL1) and sequester them in nuclear foci. Small molecules with high binding affinity toward these binding pockets can either liberate MBNL1 or inhibit its interaction with the binding pocket and restore the MBNL1 activity. Finding small molecules with high binding affinity toward the binding pocket is the first and most challenging step in the process of restoring MBNL1 activity and therefore alleviating the DM associated defects. Virtual screening approaches such as docking and 2D fingerprint similarity searches provide the opportunity to screen millions of small molecules, identifying the lead compounds with highest affinity toward the binding pocket. Lead compounds found through these approaches will then be subject to a barrage of experimental studies for their selectivity and potency in DM1 cellular models including patient derived cells.
https://doi.org/10.55762/pc.gr.157023
Grantee: Amirhossein Taghavi, PhD
Grant type: Development Grant
Award total: $210,000
Institution: University of Florida
Country: Florida, United States
SARM1 antagonism as adjunct therapy in SMA
New gene targeting treatments that increase survival motor neuron (SMN) protein expression can substantially improve motor function in spinal muscular atrophy (SMA) patients when given before disease onset, but have modest effects when given post-symptomatically. Unfortunately emerging data indicates that for the most common and severe SMA type I, precipitous motor axon neurodegeneration is ongoing neonatally. We postulate that temporarily halting axonal degeneration could enhance the efficacy of SMN induction therapeutics. The sterile-a and Toll/interleukin 1 receptor (TIR) motif containing protein 1 (SARM1) is a NADase that triggers motor axon degeneration. Our preliminary data indicate that genetic knock out of SARM1 is associated with prevention of proximal motor axon loss neonatally in SMA mice. In this study, we will assess the durability of this effect and the therapeutic potential of SARM1 inhibition together with SMN induction in severe SMA mice. These studies will provide proof of concept to support the development of a novel combinatorial treatment for SMA patients.
https://doi.org/10.55762/pc.gr.157037
Grantee: Charlotte Sumner, M.D.
Grant type: Research Grant
Award total: $300,000
Institution: Johns Hopkins University School of Medicine
Country: Maryland, United States
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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
