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
tRNA sequestration as a pathogenic mechanism of tRNA synthetase-associated CMT
Unravelling the molecular mechanism underlying an incurable disease Charcot-Marie-Tooth (CMT) is an incurable disease in which motor and sensory nerves degenerate, leading to muscle weakness and sensory deficits. CMT is a genetic disease, and changes in many different genes can cause CMT. It is incompletely understood how these changes in CMT genes ultimately result in degeneration of motor and sensory nerves. Currently, no effective drug treatment is available for any genetic form of CMT. Among the CMT genes, mutations in 6 distinct genes that produce so-called ‘transfer RNA (tRNA) synthetases’ cause CMT. Scientists recently elucidated a novel mechanism that underlies CMT caused by mutations in one of these tRNA synthetases, the glycyl-tRNA synthetase. Now, they wish to evaluate whether a similar mechanism applies to CMT caused by mutations in the other tRNA synthetase genes. If so, this would imply that administration of tRNA may constitute a novel therapeutic approach for these incurable diseases.
Image Source: Prinses Beatrix Spierfonds
https://doi.org/10.55762/pc.gr.157000
Grantee: Erik Storkebaum, Ph.D.
Grant type: Research Grant
Award total: $300,000
Institution: Stichting Radboud Universiteit
Country: Netherlands
Muscular Dystrophy Clinical Trial Research Network
Advances in our understanding of muscular dystrophies (MDs) have identified targets for treatment for facioscapulohumeral muscular dystrophy, myotonic dystrophy, and limb girdle muscular dystrophy. Indeed, several clinical trials of new gene targeted drugs are underway for each MD. Despite that, companies have identified several barriers to drug development including the need for biomarkers, outcome measures to support drug registration, and standardized site training to prepare for clinical trials. We formed clinical trial research networks to hasten therapeutic development for many of the MDs. In the current proposal, we plan to consolidate the project management and oversite of the research networks into a single MD Clinical Trial Research Network. This network of 15 core United States centers brings together national leaders in MD research, sets the stage for common site training and patient engagement, and allows for us to also advance patient care, by providing training and online resources related to MD. Such a research network can work with patients and their family members, industry, academics, and drug companies to overcome lingering barriers to drug development, including trial preparedness studies to validate better biomarkers and clinical outcome assessments for drug approval. Finally, by having such a large national effort we can train the next generation of MD researchers, to ensure continuity and excellence in care in the future.
https://doi.org/10.55762/pc.gr.157025
Grantee: Jeffrey Statland, M.D.
Grant type: Clinical Research Network Grant
Award total: $1,517,502
Institution: University of Kansas Medical Center Research Institute, Inc
Country: Kansas, United States
Restoration of motor neuron function via potassium channels in SMA mice
Movement and muscle control are regulated by the activity of motor neurons which are located in the spinal cord. Spinal motor neurons convey central commands to their peripheral targets, the skeletal muscles. Pre-motor neurons make synaptic contacts with motor neurons and regulate their function. However, the molecular mechanisms underlying synaptic-mediated motor neuron function are unknown. To address this, we use in vivo and in vitro models of spinal muscular atrophy a neurodegenerative disease caused by deficiency of the ubiquitously expressed SMN protein. Proximal muscles are preferentially affected during the progression of this disease, compared to more distal muscles. In our proposal, we aim to investigate enzymatic effects on the molecular and cellular function of potassium channels expressed on the motor neurons. Potassium channels are essential to elicit repetitive firing of motor neurons and subsequent muscle contraction. Utilizing enzyme inhibitors that regulate the activity of potassium channels, we aim to uncover the cascade of molecular events leading to the enhancement of motor neuron function. Our study has the potential to reveal salient principles in the restoration of neuronal function in spinal muscular atrophy and offer novel therapeutic avenues.
https://doi.org/10.55762/pc.gr.157009
Grantee: Nandhini Sivakumar, Ph.D.
Grant type: Development Grant
Award total: $210,000
Institution: Columbia University Medical Center
Country: New York, United States
Inherited Neuropathy Consortium
The Inherited Neuropathy Consortium is dedicated to developing the infrastructure necessary to evaluate therapies for patients with Charcot-Marie-Tooth disease. We have developed CMT specific clinical outcome assessments to measure the effects of CMT on adults and children. We have identified markers of disease severity in blood, from skin biopsies and also by MRI imaging of muscles. We have had a Critical Path Innovation Meeting with the FDA on how best to use our measures to bring successful clinical trials to our patient population. Developing rational therapies for patients requires knowing the cause of their CMT. We have identified 23 novel genetic causes of CMT. We have initiated the CMT Variant Browser which promotes sharing of genetic information on CMT for patients, their families, caregivers and researchers. We have successfully trained 14 young investigators to carry on future CMT research, many of whom have obtained faculty positions in fields related to CMT. We are applying to continue MDA support through 2024 which coincides with the end of our currently funded NIH five year cycle to continue natural history studies with various CMT subtypes, continue gene identification and genetic modifier studies using whole genome sequencing, develop the use of remote evaluations of patients and train future investigators.
https://doi.org/10.55762/pc.gr.157060
Grantee: Michael Shy, M.D.
Grant type: Infrastructure Grant
Award total: $439,250
Institution: The University of Iowa
Country: Iowa, United States
Obesity as a modifier of disease progression caused by dystrophin deficiency
Obesity and insulin resistance (IR) commonly accompany dystrophin deficiency; however, how they potentiate disease progression and severity is unknown. Indeed, dystrophin deficiency and obesity/IR cause a host of cellular dysfunctions that in some cases overlap and in some cases are distinct. This raises the likelihood of additive and even synergistic effects. Further, glucocorticoids are commonly prescribed to boys with DMD but may also alter cellular metabolism particularly in the case of obesity/IR. To address this gap in knowledge, we will measure muscle function parameters in lean and obese healthy mice and mice with DMD, with or without glucocorticoid treatment. We will also investigate how obesity alters dystrophic metabolism and assess glucose transport, mitochondrial function, and the metabolome and proteome of these mice. We expect to discover that obesity/IR further erodes muscle function and antagonizes muscle metabolic function. This work will provide important information about disease progression in humans as well as about nutritional management of boys with DMD. Further, as the commonly used DMD mouse model, the mdx mouse, is quite lean, outcomes may also improve the utility and predictive power of mdx mice. This would enable treatment strategies to be tested in a physiological and metabolic context that more closely resembles that of humans with DMD.
https://doi.org/10.55762/pc.gr.157040
Grantee: Joshua Selsby, Ph.D.
Grant type: Research Grant
Award total: $300,000
Institution: Iowa State University of Science and Technology
Country: Iowa, United States
Linker-based gene therapy of LAMA2-related muscular dystrophy using AAVMYO
Extracellular matrix (ECM) acts as scaffold to provide essential structural support to the surrounding cells. Laminins are essential components of the ECM connecting it tightly with the underlying cell layer, just like the binds between scaffolding and a building. Mutations in this protein family cause a range of severe disorders that affect different organs. The rope-like laminin-211 protein, composed of three intertwined laminin chains, is the main isoform in skeletal muscle. Mutations in the LAMA2 gene, encoding one of the chains in laminin-211, leads to its loss and causes a rare, severe and early-onset muscular dystrophy, called MDC1A or LAMA2 MD. Affected children show muscle wasting and weakness and eventually die from respiratory insufficiency. There is no treatment for LAMA2 MD. We have shown that two specifically designed linker proteins strongly improve the pathology and lifespan in LAMA2 MD mice, which lack laminin-211 like LAMA2 MD patients and display very similar symptoms. In ongoing research, we are developing a gene therapy approach to deliver the two linkers to LAMA2 MD mice by using an adeno-associated viral vector (AAV9). Our initial results show that this gene therapy approach is indeed possible. We now aim to optimize linker delivery using newly developed AAV9 variants (myotropic AAVs) that are even more efficient at infecting skeletal muscles. We are hopeful these experiments will pave the way to a gene therapy treatment for LAMA2 MD patients.
https://doi.org/10.55762/pc.gr.157038
Grantee: Markus Ruegg, Ph.D.
Grant type: Research Grant
Award total: $293,810
Institution: University of Basel (Universität Basel)
Country: Switzerland
Mobilizing Muscle Stem Cells to Treat DMD
Duchenne Muscular Dystrophy (DMD) is a muscle wasting disease that leads to premature death. We discovered that muscle stem cells in DMD are defective and regeneration is unable to keep pace with the muscle damage. We have developed a drug that overcomes this deficit and observed that treated DMD mice show a large improvement in muscle function. We will determine the optimal dose that promotes the best response without adverse effects, we will evaluate the efficacy of long-term treatment in preventing disease progression, and we will evaluate whether drug stimulation of regeneration can repair existing dystrophic damage. We will treat mice with drug and gene therapy to evaluate combination therapy. Finally, we will validate that the drug works the same in human muscle tissue. Together, these experiments will provide important proof-of-concept data that a drug that stimulates muscle regeneration is potentially effective as a treatment for DMD.
https://doi.org/10.55762/pc.gr.156999
Grantee: Michael Rudnicki, PhD
Grant type: Research Grant
Award total: $300,000
Institution: Ottawa Hospital Research Institute
Country: Ontario, Canada
CSF1R inhibitors as therapeutics for Duchenne Muscular Dystrophy
The standard of care for Duchenne Muscular Dystrophy (DMD) includes corticosteroids that, while partially effective at delaying disease progression, are associated with significant side effects, due to which they often need to be interrupted. Despite therapeutic interventions, patients with DMD become wheelchair bound during adolescence and by early adulthood they need assistance for eating and drinking and require assisted ventilation. Therefore, the identification of safer alternative therapies, or therapies that would cooperatively enhance the effect of corticosteroids would greatly benefit DMD patients. Our recent findings in a mouse model of DMD suggests that CSF1R inhibitors, a class of drugs recently approved by The United States Food and Drug Administration (FDA) as anti-cancers in human patients, have the potentials to reduce muscle damage in DMD. Here, we propose a preclinical trial of a CSF1R inhibitor in dystrophic rats, a newly developed animal model that better represents human DMD. We will assess the efficacy of this drug by itself, as well as in the context of current standard therapies given to DMD patients. This is a prerequisite to engage the regulatory path leading to clinical trials in human patients.
https://doi.org/10.55762/pc.gr.157019
Grantee: Fabio Rossi, M.D., Ph.D.
Grant type: Research Grant
Award total: $300,000
Institution: University of British Columbia
Country: British Columbia, Canada
Cannabidiol for the treatment of Duchenne Muscular Dystrophy
It is clear that exposures to cannabidiol (CBD) are increasing. It is also clear that CBD possesses therapeutic benefit, and in some cases, the beneficial effects of CBD are for diseases for which other available treatments have not been efficacious. The new perspective is to combine different therapeutic approaches to improve the efficacy of the single treatment, CBD combined with current steroid treatment may improve the anti-inflammatory effects of those therapies. These observations suggest that CBD has potential and there is a critical need to assess the efficacy of CBD in improving skeletal muscle function, pulmonary function, and immunological function in DMD.
https://doi.org/10.55762/pc.gr.157021
Grantee: George Rodney, Ph.D.
Grant type: Research Grant
Award total: $300,000
Institution: Baylor College of Medicine
Country: Texas, United States
Antigen-Specific Treatment of Myasthenia: Chimeric Autoantibody Receptor T Cells
Myasthenia gravis (MG) is an autoimmune (AI) disease, i.e., disorders in which control of the immune system becomes dysfunctional, allowing production of antibodies (Abs) that attack the body itself. In MG the target of AI attack is the crucial connection between nerve and muscle, which leads to the muscle weakness that characterizes the disease. Currently available treatments of AI diseases in general, and MG in particular, involve drugs that nonspecifically reduce the activity of the entire immune system, both the abnormal AI portions and the normally functioning portions. Use of these agents requires balancing the disease-directed effect with the side effects resulting from nonspecific blockade of normal immune function. The current project aims at developing a treatment for MG (and possibly other AI diseases) that affects only the abnormal AI portion of the immune system by targeting the production of the abnormal Abs directed at the nerve-muscle connection. Some of the patient’s immune cells (T cells) will be engineered to attack the subset of Ab-generating cells (B cells) that produce the AI Abs, leaving all other B cells untouched. This is possible because each B cell displays on its surface the single Ab it is capable of making. The engineered T cells target the AI Abs on the surface of the abnormal B cells, stopping the production of the auto-Abs, potentially terminating the disease – while leaving the rest of the immune system intact.
https://doi.org/10.55762/pc.gr.157005
Grantee: David Richman, M.D.
Grant type: Research Grant
Award total: $300,000
Institution: The Regents of the University of California (University of California Davis)
Country: California, United States
Fetal and neonatal gene therapy for DMD through homology directed repair
We propose to develop a novel form of gene therapy for Duchenne muscular dystrophy which will have greater durability and broader applicability than therapies currently in clinical trials. Our approach would enable neonatal or even fetal gene therapy, and would eliminate the risk of gradual loss of efficacy that might complicate standard gene therapy approaches. We will test our novel gene therapy for safety and efficacy in mice with Duchenne muscular dystrophy, and look for potential problems caused by modification of the genome.
https://doi.org/10.55762/pc.gr.157045
Grantee: William Pu, MD
Grant type: Research Grant
Award total: $299,979
Institution: Boston Children's Hospital
Country: Massachusetts, United States
Metabolic imaging of muscular dystrophy and cardiomyopathy
Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are the most common types of neuromuscular diseases that are resulted from mutations in the dystrophin genes. Patients develop progressive muscle weakness and atrophy, and most of them die of heart failure. Currently, there is no cure for the diseases and no standard method for monitoring the disease progression. Muscular dystrophy is accompanied by apparent metabolic alterations such as tissue inflammation and mitochondrial dysfunction. These metabolic shifts typically precede development of muscular atrophy and have potentials to be developed as early biomarkers for muscular dystrophy. In this proposed study, we will develop in-vivo biomarkers for inflammation and mitochondrial dysfunction in muscular dystrophy using a quick (few minutes), safe, and powerful metabolic imaging method. The method, so-called ‘hyperpolarized 13C MRI’, uses a bolus injection of pyruvate, a natural metabolite, and has been already tested with more than 200 injections in healthy volunteers and patients at UT Southwestern without having any adverse effects over the last few years. In this study, we will recruit patients with DMD or BMD, and acquire metabolic images of the heart and the skeletal muscle during a single MRI session. In the future, these tools may help identify the start of heart failure, develop therapeutic targets, or detect early metabolic response to therapy.
https://doi.org/10.55762/pc.gr.157052
Grantee: Jae Mo Park, PhD
Grant type: Idea Award
Award total: $50,000
Institution: The University of Texas Southwestern Medical Center (UT Southwestern)
Country: Texas, United States
Development of lipid nanoparticles for antisense delivery to dystrophic muscle
Mutations in dystrophin gene leads to Duchenne muscular dystrophy (DMD). Use of exon skipping antisense oligonucleotide (AO) drugs designed to skip over the mutations in the dystrophin gene helps express a shorter version of the dystrophin protein, helping reduce muscle pathology in the DMD patients. Despite the great potential of AO drugs for DMD and other neuromuscular diseases, their clinical expectations for DMD have not been met due to the inefficient delivery of these drugs to skeletal and cardiac muscle. The work presented here aims to address this bottleneck, through an approach that encapsulates AO within lipid nanoparticles (LNP). This enhances drug bioavailability in the bloodstream and within the muscle tissue, allowing for greatly reduced drug loads as compared to current AO dosing strategies. Investigations proposed here will build on these features of LNPs by harnessing the potential of LNP encapsulated AOs to improve delivery and retention of these drugs, leading to their enhanced efficacy for DMD therapy.
https://doi.org/10.55762/pc.gr.157049
Grantee: James Novak, Ph.D.
Grant type: Idea Award
Award total: $50,000
Institution: Children's Research Institute (CNMC)
Country: DC, United States
Developing treatments for Duchenne Muscular Dystrophy
Healthcare providers routinely prescribe glucocorticoid steroids to help control the symptoms of DMD. However, there are an inherent number of significant side effects associated with long-term steroid use leading to dose reduction or suspension and ultimately decreased efficacy. It is well recognized that new treatments for DMD with better safety and efficacy profiles are required. We have developed several potent and selective drug compounds that block a key inflammatory pathway, one of which has been shown to reduce muscle damage in mouse models of DMD. We aim to optimize our candidate compounds in pre-clinical testing in animal models of DMD, so as to progress our best lead drug compound towards human clinical trials. Our proposed pre-clinical experiments in DMD model mice (mdx mice) will generate the required data to guide selection of a preferred candidate that will ultimately be taken forward to Investigational New Drug (IND) enabling studies and into the clinic.
https://doi.org/10.55762/pc.gr.157039
Grantee: Peter Noakes, Ph.D.
Grant type: Research Grant
Award total: $293,667.27
Institution: University of Queensland (UQ)
Country: Australia
Assessing the role of Fibro-Adipogenic Progenitors in EDMD
Our project focuses on fibro-adipogenic progenitors (FAPs), a population of muscle-resident cells that support the formation of new muscle during skeletal muscle regeneration but also give rise to fibrotic and fat cells that accumulate in degenerating muscles. We aim here to study whether this population of cells plays a pathogenic role in Emery-Dreifuss Muscular Dystrophy, a rare genetic muscle disease caused by mutation in a gene encoding for Lamin A/C a protein that resides in the nuclear envelope. In particular, our goal is to understand how mutations in Lamin A/C affect the capacity of FAPs to differentiate into fibrotic and fat cells by studying whether their genome is re-configured in the absence of a functional Lamin A/C. Our ultimate objective is to find new therapeutic cellular targets to develop strategies to block the loss of muscle tissue and the formation of fat and fibrotic scars in EDMD muscles.
https://doi.org/10.55762/pc.gr.157036
Grantee: Chiara Mozzetta, Ph.D.
Grant type: Research Grant
Award total: $279,300
Institution: CNR-Institute of Molecular Biology and Pathology
Country: Italy
Developing Gene Therapy Approaches for mtDNA Deletions
Mitochondrial DNA deletions are a relatively common cause of myopathy among the mitochondrial diseases population. We have generated tools to eliminate mtDNA deletions, but have not been able to test them in vivo because no mammalian models exist. Here we propose to develop a mouse model with high levels of mtDNA deletions and treat these mutant molecules with DNA editing enzymes. We will also explore non-viral delivery system of these enzymes to muscle and liver.
https://doi.org/10.55762/pc.gr.157044
Grantee: Carlos Moraes, Ph.D.
Grant type: Research Grant
Award total: $300,000
Institution: Miller School of Medicine of the University of Miami
Country: Florida, United States
Advancing clinical trial readiness in TRPV4 neuropathy
Charcot-Marie-Tooth disease (CMT) includes a group of inherited peripheral neuropathies that cause symptoms of progressive weakness and loss of sensation. CMT is the most common inherited neurological condition worldwide, but there are currently no available treatments to slow progression of any forms of this disease. A subtype of CMT, known as CMT type 2C, is caused by mutations in TRPV4, which is an ion channel that can open or close to allow calcium to enter cells. Our work in animal models of this condition has shown that disease mutations in TRPV4 cause the channel to be overactive, and drugs that block the channel are highly effective as treatments in these animal models. This suggests that available TRPV4 blocking drugs are a promising potential treatment for patients with TRPV4 mutations. However, there are still important barriers that need to be overcome in order to facilitate a clinical trial for this condition. In particular, the natural progression of CMT2C and readouts of disease progression must be better defined to determine the specific outcome measures that would be used in a clinical trial. This proposal will use a comprehensive clinical approach to define markers of disease severity and progression in patients, an essential step in the process of moving towards a clinical trial and ultimately establishing a treatment for CMT2C. If successful, this would be a ground-breaking accomplishment and pave the way for clinical trials for other forms CMT.
https://doi.org/10.55762/pc.gr.157002
Grantee: Brett McCray MD., Ph.D
Grant type: Clinical Research Grant
Award total: $497,011
Institution: Johns Hopkins University School of Medicine
Country: Maryland, United States
Manipulating muscle growth and oxidative metabolism to improve pathology in DMD
Although micro-dystrophin gene therapy offers promise as a treatment for DMD, the current lack of full gene correction means shortcomings in addressing all aspects of the pathology. For DMD, counteracting wasting and weakness and improving the pathology requires a strategy that ideally produces larger (and stronger) muscles, without causing fatigue, and protects them from injury. This requires simultaneously manipulating signaling pathways that promote hypertrophy and oxidative metabolism. Although exercise has many health benefits for improving muscle strength and endurance, most DMD patients cannot exercise. A solution may come from ‘exercise mimetics’ that can confer exercise-like improvements in muscle structure, function, and metabolism. Powerful pharmacologics are available that can alter muscle phenotype; beta-agonists (like formoterol), can promote muscle mass and strength; and adenosine monophosphate-activated protein kinase (AMPK) activators (like MK-8722), can enhance oxidative metabolism. This proposal will interrogate the therapeutic potential of simultaneously manipulating growth and oxidative metabolism through a combined formoterol-MK-8722 strategy, with potential to confer improvements in muscle function without compromising metabolism or injury susceptibility. If successful, this would represent a novel repurposing of approved drugs as a treatment for DMD and provide strong support for this novel adjuvant combination to be advanced to the clinic.
https://doi.org/10.55762/pc.gr.157018
Grantee: Gordon Lynch, Ph.D.
Grant type: Research Grant
Award total: $299,872.32
Institution: University of Melbourne (Melbourne University)
Country: Australia
Investigation of Skeletal Muscle Calcium Dysregulation in Myotonic Dystrophy
DM1 is an autosomal dominant disease characterized by muscle weakness and myotonia, often leading to premature death from respiratory failure. Presently there is no treatment to reverse or slow the progressive decline. DM1 is caused by expansion of a CTG repeat in the 3’ untranslated region of DMPK. The repeat expansion containing RNA expressed, exhibits a toxic gain-of-function that results in misregulated alternative splicing of specific transcripts and the inappropriate expression of neonatal transcript isoforms in mature muscle. DM1 is estimated to affect >100,000 people in the U.S. alone, many of whom experience decades of progressive disability. Our preliminary results demonstrate that oral feeding of an already FDA approved voltage-gated calcium channel drug significantly rescues phenotypes and extends the lifespan of a reductionist DM1 mouse model with targeted missplicing events. Here we will use a RNA toxicity DM1 mouse that models severe DM1 myopathic features, including the full spectrum of aberrant splice events, and shortened lifespan. We will target the muscle voltage-gated calcium channel in two ways to determine its role in DM1 pathophysiology and provide proof-of-concept for repurposing an FDA approved drug for treatment of DM1 for rapid transition into the clinic.
https://doi.org/10.55762/pc.gr.157033
Grantee: John Lueck, Ph.D.
Grant type: Research Grant
Award total: $300,000
Institution: University of Rochester
Country: New York, United States
Contribution of metabolic abnormalities to spinal muscular atrophy
Our laboratory has been at the leading edge in the identification of non-neuronal defects in spinal muscular atrophy (SMA). We have shown that SMN depletion leads to defects in fatty acid metabolism. This novel finding raises the intriguing question of whether liver metabolic alterations are an important facet of SMA disease pathogenesis. Here we will perform a more in-depth investigation to examine fatty acid metabolism in SMA. The proposed experiments will address the triggering events in liver steatosis in SMA and whether the liver is an important player in the overall picture of SMA disease etiology. The research will have important implications in the care and disease management of patients with SMA.
https://doi.org/10.55762/pc.gr.157042
Grantee: Rashmi Kothary, Ph.D.
Grant type: Research Grant
Award total: $300,000
Institution: Ottawa Hospital Research Institute
Country: Canada
NF-kB signaling in muscle regeneration and disease
The NF-kB pathways form a signaling complex that is critical for normal skeletal muscle function and is important in promoting recovery in response to muscle injury. Furthermore, there is strong evidence that prolonged NF-kB activation is detrimental to normal skeletal muscle function and can contribute to diseases such as the common genetic disorder, Duchenne muscular dystrophy (DMD). As such, NF-kB has become an attractive drug target for the treatment of muscle diseases. It has been shown that cellular inhibitor of apoptosis 1, cIAP1, can modify NF-kB signaling in skeletal muscle in a beneficial manner. This discovery has raised the exciting possibility that cIAP1 may be a potential therapeutic target for various muscle diseases that are caused or worsened by prolonged NF-kB signaling. Since there are several drugs and reagents that potently and specifically eliminate cIAP1 expression, I will evaluate their therapeutic potential in mdx mice, the mouse model for DMD. I will also clarify the role that cIAP1 plays in the disordered muscle structure and function associated with DMD and how cIAP1 regulates NF-kB signaling in dystrophic muscle. Findings from this study have the potential to improve muscle structure and function and thus the quality of life of patients living with DMD.
Institution: Children's Hospital of Eastern Ontario Research Institute Inc
Institution Country: Canada
https://doi.org/10.55762/pc.gr.157031
Grantee: Neena Lala-Tabbert, Ph.D.
Grant type: Development Grant
Award total: $199,842.22
Institution: Children's Hospital of Eastern Ontario Research Institute Inc
Country: Canada
Unveiling the pivotal disease-associated mechanisms in TPM3-related myopathy
TPM3-related myopathy is a muscular disorder caused by genetic defect in the tropomyosin-3 (TPM3) gene. Patients typically experience lifelong muscle weakness, eventually requiring the use of a wheelchair and nocturnal non-invasive ventilatory (NIV) support. So far, there is no treatment or cure for TPM3-related myopathy. Using the CRISPR-Cas9 genetic scissors, our lab developed mouse and zebrafish models of the disease that mirror the pathology seen in patients. In mouse, we aim to study the molecular events in muscle that contribute to the disease and to better drive the development of therapeutic strategies. Zebrafish also offers many advantages (small size, large number, rapid development ex utero, ability to absorb drugs) to complement studies in mouse. We aim to use the zebrafish as a straightforward and cost-effective platform to design targeted therapeutics using small compounds or mRNA strategies that reverse the pathology. Our long-term goal is to better understand the disease and provide efficient therapies for patients.
https://doi.org/10.55762/pc.gr.157029
Grantee: Matthias Lambert
Grant type: Development Grant
Award total: $210,000
Institution: Boston Children's Hospital
Country: Massachusetts, United States
Mirabegron in Treating Muscle Dystrophy
Duchenne muscular dystrophy (DMD) is a fatal disease affecting around 1 in 3500 to 1 in 5000 live male births. Boys with DMD usually lose the ability to walk and feed in their teens, and die from respiratory insufficiency or cardiomyopathy in early adulthood. There is no cure for this disease at this time. In our previous studies, we found that a group muscle stem cells, named Fibro/adipogenic progenitors (FAPs) can differentiate into a brown fat-like cells to prevent muscle degeneration and promote muscle regeneration, under the stimulation of a group of drugs, called beta3 adrenergic receptor (B3AR) agonists. Mirabegron is a FDA approved B3AR agonist currently used for treating patients with hyperactive bladders, including kids. In our pilot study, we have shown that Mirabegron significantly improved the health and extended the life span of mice with DMD. In this study, we will determine the optimal dose of Mirabegron in treating DMD in a preclinical DMD mouse model. We will also define the role of Mirabegron in reducing heart and skeletal muscle fibrosis, a critical pathological change that leads heart failure and muscle weakness. Results from this study will provide essential preclinical data that allows the filing of clinical trials application of Mirabegron for treating DMD. Considering the fact that Mirabegron is a FDA approved drug, successful accomplishment of this study may lead to an expedite transition of clinical use of Mirabegron on DMD patients.
https://doi.org/10.55762/pc.gr.157014
Grantee: Xuhui Liu, MD
Grant type: Research Grant
Award total: $300,000
Institution: The Regents of the University of California, San Francisco
Country: United States
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