NYS-DM: Building the next generation of DM therapeutics and researchers

The New York State Myotonic Dystrophy Center (NYS-DMC) is a growing hub of research and clinical experts focused on the leading cause of adult-onset muscular dystrophy – myotonic dystrophy (DM). This proposal by the University at Albany’s RNA Institute NYS-DMC team will support research and training efforts focused on building the next generation of DM therapeutics and researchers. Research efforts for this proposal will focus on better understanding the mechanism of action and therapeutic potential of novel small molecules that target the toxic repeat RNA that underlying DM. The training efforts will focus on support for a Young DM Investigator meeting in New York (October 3-6, 2023), which will train the next generation of DM researchers to strategically drive their research, careers, and by extension, the DM field, on a path towards finding a cure for this devastating disease. These parallel research and training efforts will build a foundation of future therapeutics and the researchers to guide them along the clinical trial path towards finding a cure for this devastating disorder.

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Grantee: Andy Berglund, PhD

Grant type: Restricted Research Grant

Award total: $97,749.78

Institution: Research Foundation of SUNY - University at Albany

Country: USA

Establishing a global certification standard for evaluating CMT

PI Burns and colleagues have established a suite of clinical outcome measures to evaluate the effectiveness of therapies for children and adults with Charcot-Marie-Tooth disease (CMT) and related neuropathies. These outcome measures have been well-validated and are ready to be used in clinical trials and cohort studies. However, a barrier to progressing to multicenter trials is the lack of well-trained clinical evaluators around the world to collect these measures. We were awarded a 2021 MDA Ideas Grant to develop an e-training and quality assurance system to promote accurate collection of these CMT-specific measurement tools, which are freely available online at www.ClinicalOutcomeMeasures.org. In this MDA Research Infrastructure Grant, we aim to establish a global certification standard to enable accurate measurement and avoid delay to testing rational therapies. A cadre of CMT Master Trainers in partnership with Patient Advocacy Groups in the USA, UK, Europe, Asia, South America and Australia will expand clinical evaluator training resources to sites and countries where trials are likely to occur. We will scale-up trial capacity by building a global certification standard and remote data monitoring system to activate a global network of reliable trial-ready clinical evaluators.

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Grantee: Joshua Burns MD

Grant type: Infrastructure Grant

Award total: $300,000.00

Institution: The University of Sydney

Country: Australia

Extracellular vesicle metabolome in Myotonic dystrophy 1

The process that the body uses to regulate the use of energy is called metabolism, while the intermediate compounds produced during this process are known as metabolites. In myotonic dystrophy type 1 (DM1), progressive muscle weakness is associated with whole-body insulin resistance and elevation of several metabolites in the blood. However, the molecular pathways responsible for elevation of metabolites in DM1 and their relationship to muscle weakness are uncertain. Extracellular vesicles (EVs) are tiny bubble-like structures that are released from all cell types. EVs carry gene expression information and metabolites as a form of communication between cells. The EV metabolite content, or "metabolome," in DM1 is unknown. In this project we will 1) compare the metabolite composition in urine EVs from DM1 and unaffected individuals, 2) determine a relationship between the gene products and metabolites found in EVs, and 3) monitor EV metabolites over time in relation to clinical measures of muscle function. If successful, this project would promote major advancement in the understanding of the DM1 disease mechanism that could accelerate therapeutic development and expand non-invasive biomarker options. The insights that we gain have the potential to benefit all DM1 patients and may extend more generally to DM type 2 and other muscular dystrophies.

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Grantee: Preeti Kumari, Ph.D

Grant type: Development Grant

Award total: $206,189.00

Institution: Massachusetts General Hospital (Mass General)

Country: United States

Dissecting lysosomal signals to fight Pompe disease

Pompe disease (PD), is the rare genetic disorder caused by an inactivating mutation in the gene coding for acid maltase, the enzyme that usually breaks down glycogen to glucose inside lysosomes. Due to the impairment in the function of these organelles, PD has been the first described lysosomal storage disease (LSD), affecting 1 in 40,000 live births. In the infantile form, lysosomal glycogen accumulation is causing a severe cardiomyopathy that can be successfully reversed by enzyme replacing therapy (ERT); however, both in infantile forms and late onset ones (LPOD), a severe, ERT resistant and progressive skeletal muscle wasting and weakness is forcing patients to wheelchairs and mechanical ventilation. Unfortunately, to date, respiratory failure is still the main cause of death in LOPD patients, even if in treatment. In the past years scientific breakthrough paved the basis for the development of next-generation ERT; however, no clear advancements have been made in understanding the misregulated signals in the organelle where the pathology originates due to technological limitations in the characterization of lysosomes. With this project, I propose to fill the gap setting up a ground-breaking methodology for unraveling these hidden signals at the onset of Pompe pathogenesis, with the expectation to find novel potential targets exploitable for boosting the current traditional enzyme replacing therapy.

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Grantee: Andrea Armani, Ph.D.

Grant type: Development Grant

Award total: $210,000.00

Institution: University of Zurich (Universität Zürich, UZH)

Country: Switzerland

Mechanisms of fatty liver disease and impaired drug metabolism in DM1

Myotonic Dystrophy type 1 (DM1) is a multi-systemic neuromuscular disorder affecting 1 in 3000 people. Much of the focus in DM1 research has been on the effects within the muscle and neurological tissues. However, DM1 patients also suffer from increased levels of various metabolic and liver-specific symptoms, such as non-alcoholic fatty liver disease, metabolic syndrome, and liver damage. Additionally, DM1 patients are abnormally sensitive to a wide range of analgesics and muscle relaxants, resulting in prolonged anesthesia recovery, heightened pulmonary dysfunction, and in some cases, death. So far, these symptoms have been attributed to the disruption of neurological and muscular functions associated with DM1 but could also be explained by the malfunctioning of the liver, a major site for nutrient and drug metabolism. This proposal aims to understand the precise effects of DM1 on the liver; determine to what extent DM1 diseased livers exhibit susceptibility to risks from lifestyle choices such as diet and drugs; and investigate how the interference with MBNL activity causes metabolic and drug clearance pathologies which can jeopardize the health of DM1 patients and complicate their treatment.

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Grantee: Auinash Kalsotra PhD

Grant type: Research Grant

Award total: $300,000.00

Institution: The Board of Trustees of the University of Illinois Urbana-Champaign

Country: United States

Clinical Research in ALS (CRiALS): A comprehensive resource for human research

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.

Grantee: Jonathan Glass, MD

Grant type: Restricted Research Grant

Award total: $154,797.00

Institution: Emory University

Country: United States

Astrocyte-microglia crosstalk in C9orf72 ALS/FTD

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are now recognized as a spectrum disease with approximately 50% of ALS patients exhibiting cognitive impairments and about 15% of FTD patients developing motor deficits. Most studies aimed at elucidating mechanisms of cognitive impairments in this spectrum disease focused on disease mechanisms of neuronal cells in the brain, while non-neuronal cells, so called glial cells, have been largely ignored and overlooked. The development of induced pluripotent stem cell (iPSC) technologies has facilitated the generation of disease models for ALS/FTD. This technology allows us to create a ‘brain in a dish’, which consists of patient-derived iPSCs converted into brain-like cells. To better understand how patients with C9orf72 ALS/FTD, the most prevalent genetic mutation leading to this disease spectrum, develop cognitive impairments and most importantly, how we can provide specific treatments for these patients, we propose to focus our studies on glial cell-to-cell communication and regulation using iPSCs derived from C9orf72 ALS-FTD patients. In specific, we aim to study how astrocytes and microglia, two distinct glial cell types in the brain, co-regulate each other using molecular and cellular techniques. We will also test how this regulation impacts neuronal function, but most importantly, how this glia-glia co-regulation goes rouge during disease and contributes to neuronal dysfunction in C9orf72 ALS/FTD.

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Grantee: Rita Sattler, Ph.D.

Grant type: Research Grant

Award total: $300,000.00

Institution: Dignity Health dba St. Joseph's Hospital & Medical Center, Phoenix, AZ

Country: United States

Contributions of genetic variation to LMNA-associated muscular dystrophy

Mutations in the LMNA gene cause 16 different diseases including three that affect muscle, Emery-Dreifuss, Limb-Girdle, and congenital muscular dystrophy. Currently, there are no cures for these diseases. When individuals are diagnosed with a mutation in the LMNA gene it is challenging to predict what type of muscle disease they will get, the disease severity, and the long-term prognosis. In part, this is because mutations in genes other than LMNA called modifier gene influence how the disease will affect an individual, yet no modifier genes have been identified to date. We have used genome sequencing of closely related individuals with the same LMNA mutation that have different disease phenotypes to identify candidate modifier genes. We propose to test these candidate modifiers using our fruit fly models of LMNA-associated muscular dystrophy. Fruit flies share 75% of human disease genes and have muscle biology like that of humans. We can perform genetics using fruit flies that is not possible with humans. The identification of these modifier genes will aid in the diagnosis, prognosis, and treatment of individuals with LMNA-muscular dystrophy.

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Grantee: Lori Wallrath, Ph.D.

Grant type: Research Grant

Award total: $296,044.00

Institution: The University of Iowa

Country: United States

Repair of the ALS Nuclear Pore and associated TDP-43 misregulation by CHMP7 ASO

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease. The majority of cases are sporadic in nature. Defects in processes that maintains communication between nuclear and cytoplasmic compartments of the cell (nucleocytoplasmic transport, NCT) have emerged as a cause of ALS and other neurodegenerative diseases. The nuclear pore complex (NPC), is made up of individual proteins (Nups) and regulates NCT. We identified a subset of Nups that are altered as an early event in disease pathogenesis by using patient-derived induced pluripotent stem cells and validated these results in patient autopsy tissue. We discovered the mechanism for this early cellular event, the abnormal nuclear localization of the nuclear pore surveillance protein CHMP7. Using antisense oligonucleotide (ASO) treatment, we can repair this problem and its consequences. The current program will advance the CHMP7 ASO through the necessary steps to eventually make it rapidly ready for human ALS trials.

Grantee: Jeffrey Rothstein, M.D., Ph.D.

Grant type: Research Grant

Award total: $300,000.00

Institution: Johns Hopkins University School of Medicine

Country: United States

Unraveling the contribution of local translation to NMJ degeneration in FUS-ALS

Amyotrophic lateral sclerosis (ALS) is a devastating disease which is characterized by the loss of motor neurons of the motor cortex and spinal cord. Most of the ALS cases are unpredictable, but several genetic causes have been found in the population accounting for mutations in genes encoding SOD1, TDP-43, FUS and C9ORF72 proteins. All the different ALS forms have in common denervation of the neuromuscular junctions (NMJs), the contacts between the axons and the muscle, which are critical for our most basic functions including breathing and walking. The mechanisms through which this structure is non-functional and eventually lost during disease are currently unknown. Recently, we demonstrated that in animals modeling inherited forms of disease the production of proteins along the axons, called axonal local translation, is impaired and this correlates with aberrant composition of the axonal and synaptic translation machinery and ribosomes, all of which are responsible for protein production. This project will unveil the local translation events in a healthy NMJ and will investigate at the same time the contribution of aberrant local translation to NMJ demise driven by ALS-causing mutations in FUS and other forms of ALS. This work ultimately will uncover the local mechanisms leading to disease pathogenesis for the identification of synaptic targets whose translation can be modulated to rescue disease phenotypes, with the promise to translate these findings to the clinic.

Grantee: Diana Piol, Ph.D.

Grant type: Development Grant

Award total: $210,000.00

Institution: Vlaams Instituut voor Biotechnologie (Flanders Institute for Biotechnology, VIB)

Country: Belgium

Investigation of ALS caused by mutant KIF5A

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder characterized by selective loss of upper and lower motor neurons resulting in paralysis and finally death within 2 to 5 years after symptom onset. There is no effective drug to cure or even slow disease progression. Motor neurons rely on proper communication between the cell body and neurites through cargo trafficking. Deficits in such communication are one of the early events of disease pathogenesis. This is further supported by the recent identification of mutations in the KIF5A gene, which is a major motor protein for cargo transport, in ALS patients. This proposal will determine the molecular mechanisms underlying ALS caused by KIF5A mutants using human motor neurons and novel mouse models. Results from this study will help understand what causes this dreadful disease and identify new therapeutic approaches.

Grantee: Devesh Pant, Ph.D

Grant type: Development Grant

Award total: $210,000.00

Institution: Emory University

Country: United States

Mechanisms and treatment of muscle pathology in spinal muscular atrophy

Spinal muscular atrophy (SMA) is a neuromuscular disorder thought of as arising primarily from the deficiency of the SMN protein in motor neurons. Accordingly, current treatments focus on restoring the protein to these cells or the central nervous system. However, recent data suggests that protein deficiency in skeletal muscle also contributes to disease. This proposal investigates the manner in which SMN ensures healthy muscle, examining the cellular and molecular consequences of low protein in the tissue. In particular, experiments center on the role of SMN in muscle stem cells. If successful, the project will cast important light on the role of muscle in SMA and how SMN functions in this tissue to maintain its health. This could lead to new and improved treatments for this most devastating of pediatric diseases.

Grantee: Umrao Monani, Ph.D.

Grant type: Research Grant

Award total: $299,999.25

Institution: Columbia University Medical Center

Country: United States