Developing novel chemical and genetic regulators of Stathmin-2 in ALS
Amyotrophic lateral sclerosis (ALS) is a devastating, terminal neurodegenerative disease for which few biologically modifying therapies are available. There is therefore a vast unmet need for target-specific therapies capable of rectifying underlying disease pathology, as opposed to treating generalized cellular deficits. The protein Stathmin-2 (STMN2) has recently been identified as one such target. Loss of STMN2 in mice results in progressive shrinking of nerve axons and retraction of nerve end terminals from muscles, which are both features of human disease. Increasing the level of STMN2 is therefore a pertinent therapeutic approach which would be applicable to nearly all cases of ALS as well as patients with other neurodegenerative diseases including frontotemporal dementia (FTD) and Alzheimer’s disease. Through screening, we have identified drugs and genes capable of significantly increasing STMN2 expression, with all results pointing to the modulation of one specific, targetable, cellular pathway being responsible for this increase. In this project, we propose to validate these findings in human cultured neurons and mice in order to inform the design of future clinical trials in patients with ALS/FTD, but also potentially other diseases where STMN2 is disrupted, including Alzheimer’s disease.
Funded in collaboration with the ALS Network
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Grantee: Matthew Nolan PhD
Grant type: Development Grant
Award total: $210,000.00
Institution: Massachusetts General Hospital (Mass General)
Country: USA
Investigating MAM domains and neuronal function in Coenzyme Q10 deficiency
Mitochondrial diseases are a group of rare disorders that affect about 1 in 4,300 people in the United States. This group of disorders includes Primary Coenzyme Q10 (CoQ10) deficiencies, caused by defects in the CoQ10 synthesis pathway. CoQ10 is essential for many biological processes, including mitochondrial function. Patients with CoQ10 deficiency typically present neurological involvement, isolated or associated with other organs involvement, such as heart and kidney. Unfortunately, there is no cure for the neurological manifestations. One major challenge is that CoQ10 supplementation cannot cross the blood-brain barrier to reach the brain, thus alternative therapies need to be developed. Our goal is to gain a comprehensive understanding of the mechanisms responsible for the neurological manifestations of CoQ10 deficiency to develop novel therapies. We found alterations in lipids, as cholesterol, in neurons from patients with defects in CoQ10 synthesis and in mouse models of CoQ10 deficiency. In this project, we will study how these abnormalities in lipids alter the shape and function of neurons, causing their death. Our studies might help identifying potential new targets and develop therapies for CoQ10 deficiency and other mitochondrial diseases.
Funded in collaboration with United Mitochondrial Disease Foundation (UMDF)
Grantee: Alba Pesini Martin Ph.D.
Grant type: Development Grant
Award total: $210,000.00
Institution: Columbia University Irving Medical Center
Country: USA
SOCE modulation as a potential therapeutic for LGMD R1/2A
LGMD R1/2A is caused by defects in Calpain 3 (CAPN3), which is a protein that cleaves many targets in muscles for remodeling in response to high calcium levels. Our group recently found that CAPN3 loss also causes complication with how muscles combat fatigue. This process called store-operated Calcium entry (SOCE) brings calcium into cells when they need it for generating force, particularly during prolonged activity. In the absence of CAPN3, SOCE is abnormally high at rest, and then turns off inappropriately during exercise. There are inhibitors that have been developed to reduce SOCE activity. We propose to test these inhibitors in mouse models for LGMDR1/2A, as well as in human muscle cells isolated from people with LGMDR1, to determine if this will improve the muscle function at rest and in exercise. If successful, this will aid in the development of new treatments for this disease.
Co-funded with the Coalition to Cure Calpain 3
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Grantee: Elisabeth Barton Ph.D.
Grant type: Research Grant
Award total: $293,911.00
Institution: University of Florida
Country: USA
LEOPARD-DM2
The Myotonic Dystrophy Type 2 Health Index (MD2HI), is a novel, disease-specific, regulatory-grade outcome measure that was developed for use in myotonic dystrophy type-2 (DM2) clinical trials to give patients a tool to report clinically meaningful changes in health in response to therapeutic interventions. This research will conduct a longitudinal study with DM2 patients to better understand how symptomatic burden changes over time, identify what factors are associated with faster or slower disease progression in DM2, and further optimize existing outcome measures for use in future therapeutic trials and patient monitoring. Individuals with DM2 will complete a demographic questionnaire, the MD2HI, and the Patient-Reported Outcomes Measurement Information System-57 (PROMIS-57). In addition, participants will complete an instrument preference survey at baseline and the 30-month time point, as well as a detailed global impression of change survey at 6, 12, 18, 24, and 30 months. This research will determine how patient-reported disease burden changes over time, identify participant preferences for clinical trial outcome measures, identify potentially treatable factors associated with faster or slower disease progression, and optimize patient-centered clinical trial tools to facilitate future therapeutic trials for DM2 patients.
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Grantee: Chad Heatwole M.D.
Grant type: Research Grant
Award total: $297,393.00
Institution: University of Rochester
Country: USA
Somatosensory dysfunction in a Friedreich’s ataxia mouse model
Sensory deficits are a major neurological component in Friedreich ataxia (FA) individuals. Areflexia and sensory loss are present at clinical presentation, and early clinical observations supported the view that somatosensory pathways were affected early in the disease. While historically many studies focused on dorsal root ganglia and cerebellum pathology, the somatosensory cortex was overlooked. However, functional MRI studies in FA individuals proved lower activation of somatosensory cortices during motor-sensory tasks. Despite this evidence, basic research on the somatosensory circuitries in laboratory models of FA is lacking. We propose to investigate in vivo in a mouse model of Friedreich ataxia (FA) the earliest events leading up to sensory deficits in FA and to determine the neuronal types (sensory neurons and pyramidal cells) affected first. These studies will provide evidence for synaptic pathology and dysregulated somatosensory circuitry as potential contributors to sensory ataxia in FA.
Co-funded with Friedreich's Ataxia Research Alliance
Grantee: Jordi Magrane Ph.D.
Grant type: Research Grant
Award total: $313,508.28
Institution: Weill Medical College of Cornell University
Country: USA
Genetic and Extrinsic Mechanisms in Metabolic Myopathies
Metabolic myopathies (MM) are a diverse and complex group of genetic disorders. Clinical episodes in affected individuals are triggered by external factors combined with underlying genetic susceptibility, significantly impacting daily quality of life and potentially leading to life-threatening complications. However, no systematic methods currently exist to evaluate the effects of extrinsic triggers on skeletal muscle pathology in genetically predisposed individuals. To address this gap, we propose the development of a comprehensive database capturing MM's genetic and environmental susceptibility in human patients. Additionally, we will investigate disease pathways and biomarkers in response to common external triggers across various genetic forms of MM and explore therapeutic interventions using small molecules and replacing the defective copy of the disease-causing gene with a normal copy. These studies will provide fundamental and clinical insights into the key regulators of disease onset and progression, guiding the development of targeted therapies and informing strategies to prevent the transition from health to disease.
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Grantee: Vandana Gupta Ph.D.
Grant type: Research Grant
Award total: $299,374.40
Institution: Brigham and Women's Hospital, Inc.
Country: USA
The ECM-macrophage axis promotes disease progression in Muscular Dystrophy
Cells, including muscle cells, are surrounded by a matrix. In muscular dystrophy, the matrix surrounding muscle cells expands, taking the place of the muscle cells themselves. In muscular dystrophy, the diseased matrix contains increased protein content which results in negative effects on local cells, affecting the ability of muscle to regenerate. Local inflammation is also increased in muscular dystrophy and influences this abnormal matrix-protein composition. In Duchenne muscular dystrophy, patients are treated with steroids, although how steroids work in DMD is not fully known. In DMD, steroid use can have many side effects. This research project aims to better understand the role that inflammation has on matrix composition and whether steroid or other therapies can promote a more pro-regenerative matrix, shifting from the pro-inflammatory matrix. To study how abnormal matrix composition differs following treatment, we will use muscle tissue from a mouse model of DMD, following a process to remove all cells, leaving only the intact matrix behind. We will add immune cells to these matrix scaffolds and determine how treatments affect local inflammatory responses and protein production to determine how the different treatments influence their behavior. Together, these studies will enhance our understanding of how inflammation and abnormal matrix-protein content contribute to DMD progression and the effects of potential therapeutics.
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Grantee: Ashlee Long Ph.D.
Grant type: Development Grant
Award total: $210,000.00
Institution: Northwestern University - Chicago Campus
Country: USA
Investigating skeletal muscle mediated non-cell autonomous neurodegeneration
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease with no cure and limited treatment options. The symptoms of the disease usually manifest late, yet its progression is rapid, often leading to death from respiratory failure within an average of 2-5 years following diagnosis. The mutation in the C9orf72 gene is the most common genetic cause of Amyotrophic lateral sclerosis (ALS). Recent failures in clinical trials for C9orf72 ALS highlight the need for a deeper understanding of the disease for the development of new therapies. This proposal aims to understand the role of skeletal muscle in pathophysiology of ALS, by using multiple model systems complemented by an array of molecular, biochemical, and imaging techniques. This integrative approach seeks not only to unravel the intricate molecular mechanisms underpinning the ALS development but also to pinpoint potential targets for therapeutic intervention.
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Grantee: Janani Parameswaran Ph.D.
Grant type: Development Grant
Award total: $210,000.00
Institution: Emory University
Country: USA
MICU1 loss-related myopathy: Role of mitochondrial fusion
Patients carrying mitochondrial disease show muscle weakness due to defects in mitochondrial fusion and calcium (Ca2+) regulation, among other defects. Mitochondria are essential for muscle repair and function, and their ability to fuse is crucial for maintaining muscle health. The mitochondrial calcium uniporter (mtCU) controls Ca2+ uptake, with MICU1 as a key regulator. Patients carrying mutations in MICU1 usually develop muscle fatigue, weakness, and atrophy. Our preliminary data shows that MICU1 loss disrupts mitochondrial fusion, increases resting mitochondrial Ca2+, and impairs cellular proliferation, suggesting that its role is not restricted to the Ca2+ function. We discovered that MICU1 also regulates mitochondrial fusion independently of its Ca2+ role, and this function on fusion is key for the mitochondrial network to respond to different metabolic challenges. We speculate that the role of MICU1 on mitochondrial fusion is key to maintaining muscle health. To explore this, we will study muscle-specific MICU1-deficient mice, analyzing mitochondrial fusion, muscle regeneration, and function. We will also test MICU1 mutants and drugs targeting mtCU as potential treatments. This study will clarify the MICU1 role in fusion is required for muscle health. Our findings could improve the understanding and treatment of MICU1-related myopathies and other mitochondrial diseases affecting muscle function.
Grantee: Benjamin Cartes Saavedra Ph.D.
Grant type: Development Grant
Award total: $210,000.00
Institution: Thomas Jefferson University
Country: USA
Molecular Genetics and Therapies for Congenital Myopathies
The congenital myopathies are a diverse group of inherited neuromuscular conditions that result in skeletal muscle weakness of variable onset and severity. To better understand the causes of these disorders, which are commonly seen in MDA neuromuscular clinics, we are building an extensive registry and biorepository of cases and specimens from patients and their families. Through new genetic methods such as whole genome sequencing and RNA sequencing of patients' DNA and RNA, we are completing the identification of disease genes and genetic mutations that has been ongoing since the 1980’s. These studies are leading to discoveries of new neuromuscular disease genes and many new genetic diagnoses for patients, some of whom have been undergoing a diagnostic odyssey for many years. We will continue and expand this work to define the natural history and prepare for clinical trials by more fully defining the genetic and clinical findings in participants with congenital myopathies. To study the causes of weakness and provide model systems with which to develop therapies, we have developed mouse models for two of these conditions caused by mutations in the SELENON and ADSS1 genes and will use these to test novel gene therapies. Success will lead to a better understanding of the causes of weakness in congenital myopathies, and to the development of new treatments for these conditions.
Funded in collaboration with Cure ADSSL1 and Cure CMD
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Grantee: Alan Beggs Ph.D.
Grant type: Research Grant
Award total: $312,567.00
Institution: Boston Children's Hospital
Country: USA
Mutation-independent prime editing as a novel therapeutic approach for COL6-RD
Collagen VI-related dystrophies (COL6-RD) are a group of inherited muscle diseases that cause progressive muscle weakness, joint stiffness, and breathing problems. There is currently no cure for COL6-RD. These diseases are caused by mutations in the three genes that make collagen VI, a protein important for muscle function. Currently there are treatments under development that can address individual mutations. However, there are many different mutations that can cause COL6-RD, making it difficult to develop a treatment that works for everyone. Here we propose a new approach to treat COL6-RD that could potentially work for a larger number of patients. This approach uses a gene editing technique called prime editing to specifically target and silence the mutated copy of the gene specifically but independent of the actual mutation. By introducing a premature stop signal in the gene, the mutated protein will not be produced. This approach will be tested in patient cells and in a new humanized mouse model of COL6-RD. This research has the potential to develop a mutation-independent therapy for COL6-RD, which could benefit a large number of patients.
Grantee: Carsten Bonnemann M.D.
Grant type: Restricted Research Grant
Award total: $318,000.00
Institution: National Institute of Neurological Disorders and Stroke, NIH NINDS
Country: USA
A pilot study of Forodesine Treatment for Patients with GUK1 deficiency
Mitochondrial disease comprises an important group of disorders that are challenging to biomedical investigators and clinicians because they are among the most heterogeneous human conditions at every level: clinical, biochemical, and genetic. There are currently no FDA-approved therapies for mitochondrial disease. Our group has recently identified a new debilitating mitochondrial disease, guanylate kinase 1 (GUK1) deficiency, characterized by mitochondrial myopathy with ptosis, chronic progressive external ophthalmoplegia (CPEO), and limb weakness as well as variable hepatopathy, cardiopathy, and altered T-lymphocyte profiles. GUK1 deficiency causes mitochondrial DNA (mtDNA) depletion/deletions syndrome (MDDS) by decreasing intramitochondrial levels of deoxyguanosine triphosphate (dGTP). Treatment of GUK1-deficient cells with deoxyguanosine, forodesine (an inhibitor of degradation of deoxyguanosine), or both ameliorates the mitochondrial DNA depletion and mitochondrial functions. We propose to assess forodesine in patients with GUK1 deficiency as an important step towards developing a treatment for this and potentially other MDDS disorders.
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Grantee: Valentina Emmanuele M.D., PH.D.
Grant type: Research Grant
Award total: $300,000.00
Institution: The Trustees of Columbia University in the City of New York
Country: USA
Therapeutic Targeting of TAK1 in Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is a genetic disease characterized by muscle weakness and loss of function, resulting in severe complications and premature mortality. Current treatment options are limited to symptom management, often accompanied by significant side effects. Our research has revealed the role of the protein TGF-ß-activated kinase 1 (TAK1) in maintaining skeletal muscle mass and function in animals. Loss of TAK1 protein leads to muscle atrophy, whereas its activation promotes muscle growth in mice. TAK1 also plays a critical role in preserving metabolic homeostasis and the stability of neuromuscular junctions, which are vital for skeletal muscle function. In a mouse model of DMD, we have observed that TAK1 also contributes to muscle damage and temporal regulation of TAK1 levels ameliorates disease progression. This underscores the significance of TAK1 in DMD pathology. We hypothesize that TAK1 activates unique mechanisms promoting muscle damage, which are distinct from mechanisms controlling normal muscle growth and function in DMD. In this project, we aim to elucidate the underlying mechanisms, potentially leading to the identification of novel drug targets. Furthermore, we are investigating the effects of pharmacological TAK1 inhibitors, previously used in preclinical studies for inflammatory diseases, in DMD mouse models. Successful completion of this research may offer innovative therapeutic avenues against DMD.
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Grantee: Anirban Roy Ph.D
Grant type: Research Grant
Award total: $300,000.00
Institution: University of Houston
Country: USA
Modeling ALS cortical neuron influences on corticospinal connectivity
Changes in cell signaling between corticospinal neurons (CSN) and spinal motor neurons (SpMN) are source of disability in amyotrophic lateral sclerosis (ALS). Moreover, the “corticofugal hypothesis” proposes that the spread of disease in ALS may occur through the connections between the CSN and SpMN neuron cell subtypes. People living with ALS have different connections amongst these cells that are not fully reproduced in ALS animal models—suggesting that developing corticospinal networks using human induced pluripotent stem cells (hiPSC) may offer advantages for disease modeling. In this proposal, we grow these cells in a newly designed microfluidic chamber to accurately model the complexity of these cell-subtype interactions. This model is unique because electrophysiological activity can be recorded in real-time over a period of months. Using a specific set of molecular tools, we can also manipulate the TDP-43 protein in CSN to influence the electrophysiological and network connectivity between CSN and SpMNs. What we learn from manipulating this protein will then be applied to the study of hiPSC-CSN and SpMN from familial forms of ALS. Taken together this model system will offer a platform to study ALS corticospinal networks and offer insights into the mechanisms by which TDP-43 mediated cortical pathology influences corticospinal synaptic biology and electrophysiology.
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Grantee: Nicholas Maragakis M.D.
Grant type: Research Grant
Award total: $299,340.00
Institution: Johns Hopkins University School of Medicine
Country: USA
Monitoring FSHD with Antibody to SLC34A2
Facioscapulohumeral Muscular Dystrophy (FSHD) is the 3rd most common form of muscular dystrophy in man, affecting about 1 in 15,000 people worldwide. It typically affects young adults and leads to wheelchair dependence in the 3rd to 4th decade of life. The underlying cause of FSHD is the sporadic expression of DUX4, a gene that is normally not expressed in muscle. In FSHD, DUX4 is expressed in only a small number of muscle fibers at a time. When it is expressed, it leads to the expression of a number of other genes. This cascade causes the death of the fibers and ultimately a severe loss of muscle tissue, but how it does so is still unknown. Although identifying those muscles where loss has already occurred is possible by physiological testing and magnetic resonance imaging (MRI), identifying affected muscles early in disease progression, as loss just begins, has not yet been possible. This makes it challenging to follow the progression of the disease and, perhaps more importantly, to assess therapies, now being developed, early on. Our methods are designed to detect diseased FSHD muscle fibers just as DUX4 begins to exert its devastating effects. We have also tentatively identified one of the genes activated by DUX4 that, when expressed alone, kills muscle fibers. We propose that this is a key contributor to FSHD pathology. If our ideas are correct, our method should be readily translated to the clinic, for use in clinical trials of new treatments for FSHD.
Grantee: Robert Bloch Ph.D., Harvard University, 1972
Grant type: Research Grant
Award total: $300,000.00
Institution: University of Maryland, Baltimore
Country: USA
Modulating ER stress-induced lipotoxicity to ameliorate mitochondrial myopathy
Mitochondrial myopathies are inherited metabolic disorders caused by impairment of energy production and manifest with fatigue and muscle weakness. Effective drug treatments for mitochondrial myopathy are currently limited largely due to the lack of metabolic targets. We have identified a progressive muscle accumulation of lipids in mouse models and human patients resulting in the generation of toxic lipid species which we hypothesized can contribute to the disease by triggering cellular stress. Therefore, we propose two different approaches to target pharmacologically this pathway leading to muscle lipotoxicity in a mouse model, to provide proof of concept of a new metabolic target for mitochondrial myopathies.
Funded in collaboration with United Mitochondrial Disease Foundation (UMDF)
Grantee: Marilena D'Aurelio Ph.D.
Grant type: Research Grant
Award total: $299,973.00
Institution: Weill Medical College of Cornell University
Country: USA
In-depth characterization of immune dysfunction in inclusion body myositis
Inclusion body myositis (IBM) presents with asymmetric weakness of hands and thigh muscles leading to impaired hand function and difficulty with walking. There is no cure for IBM but research is ongoing. Unfortunately, last three major clinical trials in IBM failed to show any definitive benefit. Not having a clear idea regarding the underlying process leading to IBM is a major obstacle in developing new therapy in IBM. Based on the previous research, we know that there are aggressive T cells in the muscle tissue of patients with IBM along with a type of B cells which makes immuglobulin protein, also known as plasma cells. Similarly, there are evidence for abnormal protein deposition in muscle tissue of IBM and abnormal mitochondrial function. However, the role of the plasma cells in the muscle tissue is not clear. These cells can have many role, starting from protecting the muscle tissue, or helping the aggressive T cells to make more muscle damage. In this study, we propose to study the interaction of these B cells and T cells in muscle and also in the peripheral blood using a method where we can look into the gene expression of individual B and T cells, also known as single cell analysis. This study will help us to understand the differences in B and T cells when they move to the muscle tissue from the periphery and will guide us to understand the disease process better. Such in-depth analysis of IBM will help us to identify potential new therapies.
Co-funded with The Myositis Association
Grantee: Bhaskar Roy MD
Grant type: Research Grant
Award total: $299,991.60
Institution: Yale University
Country: USA
Gene therapy in a porcine model for DMD
Gene therapies are showing significant potential to treat many muscular dystrophies. In 2024, the US Food and Drug Administration gave the first approval anywhere in the world to a gene therapy treatment for a muscle disease, which was Elevidys, an AAV delivery vector based gene therapy that delivers a miniaturized “micro-dystrophin” gene to patients with Duchenne muscular dystrophy (DMD). While Elevidys is showing promise for slowing the development of DMD symptoms, significant improvements are needed. Our group has been exploring next generation gene therapies that have potential to improve therapeutic outcomes. One approach, that will be explored here, is to use multiple AAV delivery shuttles to produce larger and more functional versions of the dystrophin protein in patients with DMD. The approach is showing significant promise in initial studies in mice. Here we propose to test the method in a large new animal model of DMD that closely resembles the human disorder. Consequently, we hope to develop data in this new model that can be used to support transfer of the technology into clinical trials.
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Grantee: Jeffrey Chamberlain PhD
Grant type: Restricted Research Grant
Award total: $375,000
Institution: University of Washington
Country: USA
NY-DMC: Expanding horizons for the diagnoses and treatment of myotonic dystrophy
The New York Myotonic Dystrophy Center (NY-DMC) serves as a research and training hub for scientific discovery, clinical progress, and therapeutic development on the leading cause of adult-onset muscular dystrophy – myotonic dystrophy (DM). This proposal by the UAlbany NY-DMC team will focus on advancing the diagnostic and treatment horizons of myotonic dystrophy while promoting increased public awareness of this disease which is the leading cause of adult-onset muscular dystrophy. This project will help better understand the disease process and how changes in the underlying repeat expansion DNA can be used to predict how the disease affects individual patients. Using our internal expertise alongside advice from global experts, this project will help us better understand how to predict and treat the disease and to ensure the disease impact is better understood by the public and policymakers.
Grantee: Andrew Berglund Ph.D.
Grant type: Restricted Research Grant
Award total: $85,691.00
Institution: Research Foundation of SUNY - University at Albany
Country: USA
Identifying genetic modifiers of TDP43 loss-of-function mediated toxicity (Wings)
Amyotrophic lateral sclerosis (ALS) is a devasting disease with muscle weakness, atrophy, and eventually fatal paralysis in adults. TDP-43 is an RNA-binding protein mainly localized in the nucleus. However, its mislocalization or aggregation is found in about 97% of ALS cases. Loss of the normal function (LOF) of TDP-43 in the nucleus is an essential pathogenic factor that could contribute to disease progression. Therefore, reducing the toxicity caused by TDP-43 LOF has therapeutic potential for a broad patient population. In this proposed study, We will perform the genome-wide screening on human-derived neurons to identify novel genetic modifiers that can alleviate the toxicity of TDP-43 LOF. This study will provide important insights into the molecular mechanisms of disease pathogenesis and identify potential therapeutic targets for ALS.
Grantee: Jeffrey Rothstein MD, PhD
Grant type: Restricted Research Grant
Award total: $119,756.00
Institution: Johns Hopkins University School of Medicine
Country: USA
NY-DM: Advancing knowledge and practices for myotonic dystrophy (Albany)
The New York Myotonic Dystrophy Center serves as a research and training hub for scientific discovery, clinical progress, and therapeutic development on the leading cause of adult-onset muscular dystrophy – myotonic dystrophy (DM). The Center is built around the regional expertise of The RNA Institute at the University at Albany, SUNY (UAlbany) and the University of Rochester Medical Center (URMC). The Center’s will provide resources for building interdisciplinary research, training, and leadership into the biology, clinical, health, and policy implications of myotonic dystrophy. This proposal will supports research efforts focused on understanding the changes to the molecular mechanisms behind myotonic dystrophy that parallel patient disease progression and heterogeneity. This project will focus on: (1) better understanding changes to the molecular disease complexity of myotonic dystrophy through characterization of the transcriptomic heterogeneity of DM across different muscle type, time and cellular landscape; and (2) developing artificial intelligence enhanced transcriptomic analysis tools for myotonic dystrophy to dissect the molecular and disease complexity of DM. This project will advance our understanding of fundamental aspects of disease pathogenesis and heterogeneity in myotonic dystrophy while leveraging these findings to identify molecular outcomes that can serve as much needed molecular biomarkers of disease for future clinical and therapeutic applications.
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Grantee: Andrew Berglund Ph.D.
Grant type: Restricted Research Grant
Award total: $112,666.00
Institution: Research Foundation of SUNY - University at Albany
Country: USA
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.
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Grantee: Jonathan Glass M.D.
Grant type: Restricted Research Grant
Award total: $130,966
Institution: Emory University
Country: USA
Advanced analysis of remote assessments
The New York Myotonic Dystrophy Center focuses on research, training, and treatment development for myotonic dystrophy (DM), the leading cause of adult-onset muscular dystrophy. It leverages the expertise of The RNA Institute at UAlbany and the University of Rochester Medical Center. The Center supports interdisciplinary research and training in the biology, clinical care, and policy aspects of DM. This proposal aims to improve remote clinical assessments for DM1 by developing AI tools to automate movement tests and analyze gait patterns. The goal is to enhance disease monitoring and prepare for evaluation of treatment effects from patients' homes.
Digital Object Identifier (DOI)
Grantee: Johannna Hamel M.D.
Grant type: Restricted Research Grant
Award total: $92,181.00
Institution: University of Rochester
Country: USA
Molecular and cellular mechanisms of cardiac fibrosis in Friedreich ataxia
"Friedreich ataxia (FA) is a genetic disease that frequently results in serious cardiac complications, primarily due to myocardial fibrosis, a form of heart muscle damage due to inflammation and scarring. In FA, the deficiency of a key mitochondrial protein called frataxin leads to swelling and eventual death of cardiomyocytes, which are heart muscle cells. This cell loss triggers inflammation and activates fibrotic pathways, resulting in the buildup of stiff scar tissue that impairs the heart's ability to fill and pump blood effectively. As fibrosis progresses, it contributes to heart failure and atrial arrhythmias that contribute to morbidity. Although imaging and post-mortem studies have revealed these structural changes in the heart, it remains unclear whether atrial arrhythmias are directly caused by the fibrosis or are secondary to changes happening in other chambers of the heart.
This research project seeks to better understand the mechanisms underlying cardiac fibrosis in FA, with a particular focus on identifying the specific cell types, such as cardiac fibroblasts, that drive the response. Using mouse models of FA, the study investigates the molecular signaling pathways that activate fibroblasts and will dissect both the damaging and compensatory molecular signals involved in FA-related cardiomyopathy. Through these studies, the researchers aim to uncover novel therapeutic targets that could mitigate or prevent cardiac dysfunction in individuals with FA."
(Co-funded with Friedreich's Ataxia Research Alliance)
Grantee: Giovanni Manfredi M.D., Ph.D.
Grant type: Restricted Research Grant
Award total: $150,879.00
Institution:
Country: USA
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