Grant - Summer 2018 - CMT – Alessandra Bolino, PhD
“Our research is aimed at unravelling how myelination is regulated in the PNS and how perturbation of these mechanisms can cause disease in humans.”
Alessandra Bolino, head of the Human Inherited Neuropathies Unit at IRCCS Ospedale San Raffaele in Milano, Italy, was awarded an MDA Research Grant totaling $300,000 over 3 years to study the targeting of phospholipid and cytoskeleton dynamics to ameliorate CMT neuropathies.
Charcot-Marie-Tooth type 4B1 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. Dr. Bolino’s research previously demonstrated that loss of MTMR2 (Myotubularin-related 2) phosphatase is the cause of the disease. MTMR2 acts on phospholipids, important regulators of membrane trafficking, which is a key process in Schwann cells, the glial cells forming myelin in the peripheral nervous system. Dr. Bolino and colleagues 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 the mechanism by which loss of MTMR2 leads to altered membrane trafficking and myelin outfoldings in Schwann cells, they identified a novel signaling pathway that regulates the cytoskeleton dynamics and membrane growth within myelin-forming cells. In this project, they will further characterize this novel pathway and test whether this pathway is a good drug target. These approaches can be extended to other forms of CMT that are characterized by myelin outfoldings (CMT4B2, B3, CMT4C, CMT4H).
https://doi.org/10.55762/pc.gr.81538
Grantee: CMT – Alessandra Bolino, PhD
Grant type: Research Grant
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Grant - Summer 2018 - CMT – Bogdan Karl Beirowski, MD, PhD
“Axon degeneration is a central component of irreversible neurological disability in many neuromuscular diseases. There is accumulating evidence that enwrapping glia provide metabolic support to axons, and perturbed metabolic functions in these glia can result in axon degeneration.”
Bogdan Karl Beirowski, assistant professor at the University at Buffalo in Buffalo, New York, was awarded an MDA Research Grant totaling $300,000 over 3 years to study metabolic support of axons by LKB1 signaling in Schwann cells. Dr. Beirowski was the recipient of an MDA development grant in 2012.
Degeneration of long axons is a hallmark in neuropathies and neuromuscular diseases like Charcot-Marie-Tooth (CMT), Friedreich’s ataxia (FA), amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (SMA). Axonal losses lead to the debilitating neurological symptoms in these conditions, but underlying mechanisms are only poorly understood. Axons do not exist in isolation but are intimately associated with Schwann cells (SCs), which provide metabolic support to axons. When metabolic functions in these cells are disrupted, it can result in axon degeneration. In CMT neuropathies, it remains unknown how malfunction in SCs results in axon degeneration.
The Beirowski lab recently showed that SCs support integrity of long axons by virtue of their metabolism. Disruption of metabolic function in SCs from transgenic mice results in progressive axon degeneration, recapitulating a key component of human neuromuscular disease. Using genetic mouse models in his laboratory, together with the application of novel technologies to study SC metabolism, Dr. Beirowski and colleagues plan to identify glial metabolic pathways important for regulation of axon integrity and to investigate if abnormalities in such pathways may contribute to nerve damage and axon demise in CMT neuropathy models.
https://doi.org/10.55762/pc.gr.81537
Grantee: CMT – Bogdan Karl Beirowski, MD, PhD
Grant type: Research Grant
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Grant - Additional Grant 2018 - Nicholas Johnson, M.D.
“We believe that the absence of tools to measure disease progression is a major barrier to conducting drug trials in this underserved population,” Nicholas Johnson said. “This is critically important given the exciting progress in gene therapy. “We are focused on developing these tools, with a particular focus on those assessments that may be used across different LGMD types, and which assessments are unique to specific subtypes. Progress in these areas is best suited for a research network that is geographically distributed and includes investigators with varied expertise in clinical and laboratory methods.”
The Muscular Dystrophy Association awarded an MDA clinical research network grant to Nicholas Johnson, vice chair of research and associate professor of neurology at Virginia Commonwealth University in Richmond, to establish the Limb-Girdle Muscular Dystrophy (LGMD) Clinical Research Network.
The investment, totaling $700,000 over two years, supports seven centers with expertise in LGMD research and clinical care and is targeted to facilitate the development of tools and infrastructure needed to efficiently and effectively conduct clinical trials and accelerate treatments for LGMD.
Therapy development in LGMD can significantly benefit from rich natural history data to describe the clinical course of the different forms of LGMD, as well as from validated clinical outcome assessments which can be used to determine whether a drug or intervention has provided treatment benefit.
Through the coordinated activities and enhanced communication among this new network of LGMD clinics, Johnson and colleagues aim to standardize approaches and develop the clinical outcome assessments to be for used in future clinical trials.
If successful, the LGMD Clinical Research Network could facilitate the development and testing of a number of promising new LGMD therapeutic approaches.
https://doi.org/10.55762/pc.gr.80679
Grantee: LGMD - Nicholas Johnson, M.D.
Grant type: Clinical Research Network Grant
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Grant - Additional Grant 2018 - Mary M. Reilly
“We are grateful to MDA for its support of this extremely important work,” Mary Reilly said. “The results from our pilot study of an MRI neuromuscular protocol in CMT1A are promising and we anticipate we will be able to confirm responsiveness with a refined protocol in children with CMT1A and in the other three common types of CMT.”
Mary M. Reilly, professor of clinical neurology and consultant neurologist, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, was awarded an MDA human clinical trials grant totaling $1 million to evaluate a new magnetic resonance imaging (MRI) protocol designed to detect disease-related changes in muscles over time in Charcot Marie Tooth disease (CMT).
In CMT, damaged motor nerves are unable to send adequate signals to muscles. This leads to muscle weakness and wasting, as well as other abnormal changes including the accumulation of fat in muscle tissue, which can be detected by MRI.
Reilly’s team has developed an MRI protocol to measure fat accumulation in thigh and calf muscles. In a pilot study to determine the protocol’s effectiveness at measuring fat infiltration in adults with CMT1A, Reilly’s team showed that the presence of calf muscle fat increased significantly over a 12-month time period.
With the new MDA funding, the team will work to refine the new protocol to include foot muscles, which could make it effective in mild cases of CMT where fat accumulation occurs more often in the feet than in calves. The team will study the refined protocol in children with CMT1A, as well as in the other three most common types of CMT: CMT1B, CMT2A and CMTX.
If successful, Reilly’s work could result in a sensitive, validated outcome measure in multiple forms of CMT, in both children and adults, that could allow researchers conducting clinical trials to reliably detect any positive effects of a candidate treatment within a 1- to 2-year timeframe.
https://doi.org/10.55762/pc.gr.79107
Grantee: CMT - Mary M. Reilly, M.D., FRCP, FRCPI
Grant type: Human Clinical Trial Grant
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Grant - Additional Grant 2018 - Jeffrey Statland, M.D.
“Meetings with industry leaders, advocacy groups and FSHD researchers have identified several gaps in our clinical trial arsenal and have pinpointed clinical trial planning as a major goal for the community,” Jeffrey Statland, M.D., said. “Not only will the FSHD CTRN help close gaps in trial readiness, but a network of sites will be created with a centralized streamlined regulatory process, specific common expertise in FSHD and an engaged patient population ready to conduct efficient, high-quality clinical trials.”
Jeffrey Statland, assistant professor of neurology at University of Kansas Medical Center in Kansas City, was awarded an MDA clinical research network grant totaling $1.2 million to expand the facioscapulohumeral muscular dystrophy (FSHD) Clinical Trial Research Network.
With colleagues, Statland is building a team of trained clinical evaluators who will all work with standardized approaches and developing regulatory strategies optimized to streamline high-quality drug trials.
The network will help ensure that clinical trials can be conducted quickly and efficiently to test potential treatments coming out of a rapidly growing pipeline of FSHD drugs in development. Ultimately, it may speed therapy development for FSHD.
Grantee: FSHD - Jeffrey Statland, M.D.
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Grant - Additional Grant 2013 - ALS – Nazem Atassi, M.D., MSSc
“One of the main roadblocks for ALS drug development is the lack of markers that tell us about drug efficacy in patients,” Nazem Atassi says. “With the recent science explosion and the exciting potential ALS treatment targets, we now need efficient tools that will allow us to quickly test many treatments.”
MDA has awarded a human clinical trial grant totaling $750,000 to ALS ONE to explore the potential for a type of imaging called positron emission tomography (PET) to measure inflammation in the brain that could serve as a biomarker for ALS.
ALS ONE is an alliance between four institutional leaders in ALS treatment development: Massachusetts General Hospital (MGH), ALS Therapy Development Institute (ALS TDI), University of Massachusetts Medical School, and Compassionate Care ALS (CCALS). The partnership was formed with the goal of speeding the discovery of treatments for ALS and developing new approaches to improve care for individuals living with the disease.
The new project, led by Nazem Atassi, M.D., MSSc, will use PET imaging to track inflammation in healthy people who carry a known ALS gene and in symptomatic people with early-stage ALS. Atassi is a member of the ALS ONE science team, associate director for the Neurological Clinical Research Institute at Massachusetts General Hospital and associate professor of neurology at Harvard Medical School.
Early data from previous studies conducted by Atassi and colleagues have shown significantly increased inflammation in the motor regions in people with ALS. The team also found that ALS patients who have more inflammation tend to have more advanced disease and worse functional status. Implementing PET technology potentially could reduce both the duration of future trials as well as the number of participants required to enroll. This would add enormous efficiency to ALS drug development.
“This project is poised to change the paradigm of ALS drug development and have a direct impact on the design of future treatment trials for both familial and sporadic ALS,” Atassi says.
Grantee: ALS – Nazem Atassi, M.D., MSSc
Grant type: Human Clinical Trial Grant
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Grant - Winter 2018 - Myofibrillar Myopathy – Robert Bryson-Richardson, Ph.D.
“We are testing multiple drugs in our animal model,” Robert Bryson-Richardson said. “Some of these, if effective, could be suitable for clinical use. Those that are not suitable for clinical use will help us to identify pathways that could be targeted in future therapies.”
Robert Bryson-Richardson, associate professor at the School of Biological Sciences, Monash University, in Victoria, Australia, was awarded an MDA research grant totaling $273,962 over three years to investigate potential approaches to treating myofibrillar myopathy (MFM) caused by a mutation in the Filamin C gene.
With colleagues, Bryson-Richardson has generated zebrafish models for MFM caused by a Filamin C mutation that reproduce key symptoms of the disease including accumulation of Filamin C protein into aggregates (clumps) and loss of muscle integrity, leading to muscle weakness. Using the models, the team is investigating two potential approaches to treat the disease: increasing the level of functional Filamin C protein overall so that there is more present in the muscle to compensate for the loss of some of it to aggregates, and removing the protein aggregates to slow down the sequestration of Filamin C.
In addition, the team is using CRISPR/Cas9 gene editing technology to develop new zebrafish models for the disease and screen for drugs that potentially could provide clinical benefit by increasing the level of functional protein or removing protein aggregates.
https://doi.org/10.55762/pc.gr.79226
Grantee: Myofibrillar Myopathy – Robert Bryson-Richardson, Ph.D.
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Grant - Winter 2018 - LGMD + other NMDs – Daniel MacArthur, Ph.D.
The low prevalence of similar rare muscle disease patients means that recruiting for a study with in-person visits is often infeasible, Daniel MacArthur said. Working with MDA, we have developed the Rare Genomes Project to give patients the opportunity to participate in a research study no matter where they live.
Daniel MacArthur, co-director of medical and population genetics at the Broad Institute of Harvard and MIT in Cambridge, Mass., was awarded an MDA research infrastructure grant totaling $110,000 to create a neuromuscular disease-specific platform for the Rare Genome Project, which will provide more individuals living with neuromuscular diseases access to a definitive diagnosis, through advanced genome sequencing techniques.
This new partnership between the Broad Institute and MDA will focus on two groups: individuals with rare diseases for which onset occurred before the age of 13 years, and those who have gone through MDA’s LGMD genetic testing program and did not receive a definitive diagnosis.
Two MDA co-branded web portals will be developed through which participants can complete questionnaires. Information will be collected on demographics, symptoms and affected family members.
Grantee: LGMD + other NMDs – Daniel MacArthur, Ph.D.
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Grant - Winter 2018 - Inclusion Body Myositis (IBM) + Pompe disease + CNM/MTM - Marta Margeta, M.D., Ph.D.
“Both autophagy impairment and excessive autophagy activation play a role in many human diseases including cancer and Parkinson disease,” Marta Margeta said. “In the neuromuscular disease field, autophagy impairment plays a role in centronuclear myopathies and lysosomal storage myopathies. Our work has a potential to affect all these disparate research areas.”
Marta Margeta, associate professor of pathology at University of California San Francisco School of Medicine, was awarded an MDA research grant totaling $200,000 over two years to improve understanding of the cellular and molecular pathways by which dysregulation of a process called autophagy impairs skeletal muscle function and leads to muscle injury in sporadic inclusion-body myositis (IBM) and other neuromuscular diseases.
Autophagy is a fundamental metabolic process with many important cellular functions, one of which is to degrade damaged cellular organelles and misfolded proteins whose presence otherwise would lead to cell dysfunction.
Evidence of autophagy dysregulation is present in a number of inherited and acquired skeletal myopathies, including the lysosomal storage disorder Pompe disease (AMD), sporadic IBM, centronuclear myopathies, and inherited as well as drug-induced autophagic vacuolar myopathies. However, the underlying molecular and cellular mechanisms are poorly understood.
With colleagues, Margeta is working to uncover the mechanisms by which autophagy dysregulation impairs skeletal muscle function and leads to muscle injury in both in vitro and in vivo models of drug-induced autophagic myopathy.
If successful, this work could facilitate the development of pharmacologic therapies for inclusion body myositis and other autophagic myopathies.
Grantee: Inclusion Body Myositis (IBM) + Pompe disease + CNM/MTM - Marta Margeta, M.D., Ph.D.
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Grant - Winter 2018 - FA – David Lynch, M.D., Ph.D.
“Several therapies in clinical trials have shown an unexpected immediate benefit — of days to a few weeks — especially improvement in fatigue and speech, very different from the slow disease progression based on neuronal loss,” David Lynch said. “These results imply that our understanding of Friedreich’s ataxia neuropathology is limited, in that some neurological deficits in FA are more readily modifiable at the early stage of disease.”
David Lynch, professor of neurology at the Children’s Hospital of Philadelphia, was awarded an MDA research grant totaling $300,000 over three years to improve understanding of neurological dysfunction in Friedreich’s ataxia (FA).
FA is caused by deficiency of the mitochondrial protein frataxin. To date, a number of clinical trials to test mitochondrial enhancers and frataxin restoration drugs in FA have shown an unexpected short-term response, particularly in speech dysfunction and fatigue. However, speech dysfunction in FA does not stem from brain regions in which cell loss occurs early in the disease. Instead, such deficits may be caused by early synaptic abnormalities. If this is the case, it may be possible to therapeutically target these abnormalities and ameliorate symptoms of speech deficit and fatigue.
In previous studies, Lynch and colleagues have identified early impaired cerebellar mitochondrial biogenesis and synaptic deficits in a mouse model with neurobehavioral deficits analogous to the clinical manifestations observed in people with FA. The team hypothesizes that deficiency of frataxin protein in the cerebellum leads to cerebellar mitochondrial and synaptic deficits that contribute to cerebellar dysfunction and ataxia in FA patients.
Now the team is working to determine if rescuing mitochondrial biogenesis or synaptic deficits can reverse cerebellar dysfunction and neurobehavioral deficits in the FA mouse models.
If successful, this work could improve the understanding of neurological dysfunction in FA, which could immediately translate to novel treatment strategies for FA patients.
Grantee: FA – David Lynch, M.D., Ph.D.
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Grant - Winter 2018 - DMD – Matthew Alexander, Ph.D.
“Many drugs for neuromuscular diseases fail to win FDA approval, resulting in a large amount of wasted time and resources,” Matthew Alexander said. “Our approach to rigorously test compounds in multiple disease-relevant DMD animal models — mainly zebrafish and mice — can eliminate some of the false-positive drug hits and speed up approval for drug compounds.”
Matthew Alexander, assistant professor of pediatric neurology and genetics at the University of Alabama at Birmingham School of Medicine and Children’s of Alabama, was awarded an MDA research grant totaling $298,650 over three years to evaluate the effects of an experimental compound called KPT-350, developed by Karyopharm Therapeutics, on Duchenne muscular dystrophy (DMD)-affected muscle.
In studies, results have shown that KPT-350 blocks inflammation and neurotoxicity, and extends life span in animal models of neurological and neuromuscular disease. Now, in collaboration with Karyopharm Therapeutics, Alexander is continuing preclinical development of the compound for DMD, establishing optimal dosing and characterizing the drug’s efficacy in mouse heart and skeletal muscle.
The team will perform rigorous long-term testing and pharmacokinetic preclinical analysis of the systemic effects of KPT-350 on DMD mice at key developmental timepoints throughout the progression of disease. The will perform analysis on skeletal muscle, heart and other tissues affected by DMD in an effort to identify the optimal time point at which KPT-350 should be administered to DMD mice and determine whether there is a point of no return after which the drug cannot improve muscle pathology because the disease progression is too severe.
If successful, Alexander’s work could lend strong support to advancing the development of KPT-350 for the treatment of DMD.
Grantee: DMD – Matthew Alexander, Ph.D.
Grant type: Research Grant
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Grant - Winter 2018 - DMD – David Hammers, Ph.D.
“The development of effective therapeutics to target fibrosis is greatly needed to increase both the quality and quantity of life for current DMD patients,” David Hammers said. “This need will continue, even when advancements in gene therapy or gene editing are capable of turning DMD into a milder form of disease, of which fibrosis will still be a feature.”
David Hammers, research assistant professor at the College of Medicine, University of Florida in Gainesville, was awarded an MDA development grant totaling $180,000 over three years to improve understanding of fibrosis in Duchenne muscular dystrophy (DMD)-affected muscle.
In DMD, skeletal muscle degenerates and is replaced with non-functional connective tissue in a process called fibrosis.
To better understand fibrosis in DMD, Hammers and colleagues are investigating the role of cells in the muscle stroma (connective tissue cells) that appear to be in an inappropriate state of senescence, or growth arrest. In other diseases, senescent cells can secrete repair-inhibiting factors and drive fibrosis.
Using a DMD mouse model, Hammers is working to characterize the senescent cells, including determining their numbers, their ability to grow and whether they secrete factors that affect fibrosis. Additionally, he plans to assess whether an enzyme called NOX4 plays a role in causing cellular senescence, and whether it could be targeted with a drug to treat muscle fibrosis in DMD.
If successful, Hammers’ work could provide detailed information about a novel mechanism of muscle fibrosis and help pinpoint new therapeutic targets for the development of anti-fibrotic therapeutics in DMD.
Grantee: DMD – David Hammers, Ph.D.
Grant type: Development Grant
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Grant - Winter 2018 - CMT – Stephan Zuchner, M.D., Ph.D.
An open Charcot-Marie-Tooth genetics data resource could help expedite CMT research, from gene identification to drug discovery and development.
Stephan Zuchner, chairman of the Dr. John T. Macdonald Foundation of Human Genetics at the University of Miami School of Medicine in Florida, was awarded an MDA research infrastructure grant totaling $384,967 over three years to expand and make more widely available resources to streamline gene identification and therapy development efforts for Charcot-Marie-Tooth disease (CMT).
Approximately 40 percent of people with CMT do not have a confirmed genetic diagnosis, highlighting the need for a continued focus on gene identification efforts for CMT. Since the most common causative genes for CMT have already been identified, there exists a need for genetic analysis across larger cohorts of patients to find rare causes of disease.
In collaboration with the Inherited Neuropathy Consortium, Zuchner is working to develop a genomic data infrastructure platform. This open CMT genetics data resource will allow for aggregation, archiving, analysis, comparison and sharing of genetic data among many laboratories and institutions. The resource could speed CMT research from gene identification to therapy discovery and development.
Making such data available to CMT researchers in the United States and around the world, could improve diagnostic processes, guide functional studies and drug discovery, and build the foundation for the patient selection process necessary for well-designed clinical trials.
Grantee: CMT – Stephan Zuchner, M.D., Ph.D.
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Grant - Winter 2018 - CMD – Dwi Kemaladewi, Ph.D.
“Successful completion of this project will provide us with the necessary preclinical data and comprehensive strategy to bring CRISPR/Cas9-mediated gene correction closer to clinical application,” Dwi Kemaladewi said.
Dwi Kemaladewi, research associate in the Program of Genetics and Genome Biology at SickKids Research Institute, Toronto, Canada, was awarded an MDA development grant totaling $180,000 over three years to explore the potential of gene correction therapy in merosin-deficient congenital muscular dystrophy (MDC1A), which is caused by a mutation in the LAMA2 gene.
In studies conducted in an MDC1A mouse model, Kemaladewi and colleagues are working to determine whether CRISPR/Cas9 gene editing technology can restore LAMA2 gene expression and in turn, production of LAMA2 protein, an important component in the stability and organization of skeletal muscle and nerves.
If successful, Kemaladewi’s work could provide the necessary preclinical data and comprehensive strategy to bring CRISPR/Cas9-mediated gene correction closer to clinical application.
Grantee: CMD – Dwi Kemaladewi, Ph.D.
Grant type: Development Grant
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Grant - Winter 2018 - CCD – Amy Hanna, Ph.D.
Hanna’s work is aimed at shedding light on how ryanodine receptor and calsequestrin mutations that alter calcium handling and cause protein aggregation lead to muscle myopathies such as central core disease.
Amy Hanna, postdoctoral associate at Baylor College of Medicine in Houston, was awarded an MDA development grant totaling $180,000 over three years to increase understanding of the pathways that lead to muscle myopathy in central core disease (CCD).
The release of calcium from a storage compartment inside the muscle fiber plays a crucial role in muscle contraction — and is itself controlled by the ryanodine receptor (RyR1) protein. Mutations in the ryanodine receptor can lead to the accumulation of misfolded protein inside the muscle fiber, which in turn causes the myopathy seen in CCD. However, it’s unknown how an RyR1 mutation can lead to the accumulation of misfolded proteins.
Based on new evidence supporting a role for calsequestrin, a protein that regulates the ryanodine receptor, Hanna and colleagues are working to determine whether calsequestrin is redistributed in CCD muscles, triggering the activation of signaling pathways that cause muscle myopathy. The team is now working to use a new animal model of calsequestrin-linked myopathy to directly test if abnormal calsequestrin can trigger the endoplasmic reticulum (ER) and oxidative stress pathways in muscle.
If successful, this work could lead to a greater understanding of the pathways that lead to muscle myopathy and inform the development of new therapeutic options that restore muscle size and strength and improve the quality of life for people with CCD and other forms of neuromuscular disease where ER and oxidative stress contribute to muscle dysfunction.
Grantee: CCD – Amy Hanna, Ph.D.
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Grant - Winter 2018 - ALS – Target ALS
An urgent need exists in ALS research for biological indicators called biomarkers that can be used for diagnostic purposes, to measure disease progression and to assess drug performance in clinical trials.
MDA and the Target ALS Foundation announced a partnership in September 2016. Now, MDA has partnered again with Target ALS to provide $100,000 in support to advance the collaborative work of the Target ALS precompetitive biomarker initiative.
A recent poll of top pharmaceutical and biotech companies working in the ALS (amyotrophic lateral sclerosis) space ranked biomarker validation as a top priority in efforts to make ALS research more attractive to industry partners. This new collaboration between MDA, Target ALS and other organizations will leverage biofluids collected from ALS patients in the National Institutes of Health-supported CReATe consortium to independently validate a list of leading biomarkers.
Data will be shared in an open-access manner to benefit industry as well as the wider ALS community.
If successful, the work could help attract industry partners to the ALS therapy development space, accelerating the search for treatments and cures.
Grantee: ALS – Target ALS
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Grant - Winter 2018 - ALS – Kristi Wharton, Ph.D.
“It is likely that success in identifying a therapeutic intervention, as well as a cure, will only come when the ability to suppress ALS-associated degeneration is evaluated in the context of the whole organism, with an intact nervous system and motor circuit,” Kristi Wharton said.
Kristi Wharton, professor of biology at the Brown University Institute for Brain Science in Providence, R.I., was awarded an MDA research grant totaling $103,750 over six months. In this new academic-industry partnership, Wharton is working to identify novel drug targets for ALS (amyotrophic lateral sclerosis) that might quickly be developed using the resources available at Pfizer.
Wharton and colleagues are using fruit fly and worm models of ALS to perform chemical screens for factors that alleviate motor neuron degeneration. The team aims to optimize screening design and establish feasibility for screens using the Pfizer chemogenomics library.
The proposed Brown/Pfizer collaboration takes advantage of each team’s respective strengths and expertise, Wharton said. Brown researchers contribute their experience in generating and evaluating human disease models and screening, while Pfizer researchers contribute their deep knowledge of treatment strategies, their proprietary chemogenomics library of a diverse set of compounds with known physicochemical properties, their screening expertise, and an array of molecular reagents.
If successful, this work could inform the development of therapies targeted to slow or stop neurodegeneration in ALS and, possibly, other neurodegenerative diseases.
Grantee: ALS – Kristi Wharton, Ph.D.
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Grant - Winter 2018 - ALS and DM – Lukasz Sznajder, MSc, Ph.D.
“Novel therapeutic approaches for the neurological and neuromuscular diseases caused by the expansion of repetitive elements in the human genome are being tested on a daily basis in many research laboratories and this activity will not stop until effective therapies for these diseases are available,” Lukasz Sznajder said.
Lukasz Sznajder, a postdoctoral associate at the University of Florida College of Medicine in Gainesville, Fla., was awarded an MDA development grant totaling $180,000 over three years to apply next-generation sequencing and other technologies to develop novel and disease-specific blood biomarkers for “repeat expansion diseases” (diseases that are caused by the abnormal expansion of particular stretches of DNA); These include ALS (amyotrophic lateral sclerosis) and frontotemporal dementia (FTD) caused by a mutation in C9ORF72 and type 2 myotonic dystrophy (DM2).
With colleagues, Sznajder is working to study a potentially novel mechanism whereby the expanded DNA sequences in DM2 and C9ORF72 ALS could alter the processing of RNA (the chemical step between DNA and protein production). The team plans to test whether these abnormalities could be detected not only in affected tissues such as the brain or muscle, but also in the blood — and whether they could be used as useful biomarkers.
If successful, Sznajder’s work could help point to new biomarkers for ALS and DM2 and open a new area for therapeutic intervention.
Grantee: ALS and DM – Lukasz Sznajder, MSc, Ph.D.
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Grant - Winter 2018 - ALS – Fatima Gasset-Rosa, Ph.D.
“I believe that understanding the initial event that provokes TDP-43 abnormalities and TDP-43 spread within the nervous system will guide directions for therapeutic development in ALS,” Fatima Gasset-Rosa said.
Fatima Gasset-Rosa, postdoctoral fellow at the Ludwig Institute for Cancer Research, University of California – San Diego in La Jolla, Calif., was awarded an MDA development grant totaling $180,000 over three years to study the role of abnormal TDP-43 protein in ALS (amyotrophic lateral sclerosis).
A common feature of the majority of ALS cases is the aggregation of TDP-43 protein in the tissues of the brain and spinal cord. Using neuronal cells and mouse models, Gasset-Rosa and colleagues are working to uncover the mechanisms that cause TDP-43 protein to assemble into these aggregates. In addition, they aim to determine whether the spread of these clumps of abnormal TDP-43 occurs anatomically — from cell to cell — to neighboring regions of the brain and spinal cord, leading to the spreading of disease and progression of ALS.
If successful, Gasset-Rosa’s work could help inform the development of drugs aimed at blocking the formation and propagation of TDP-43 aggregates in ALS.
Grantee: ALS – Fatima Gasset-Rosa, Ph.D.
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Grant - Summer 2017 - SBMA – Andrew Lieberman, M.D., Ph.D.
“There are no available disease-modifying treatments for SBMA,” Andrew Lieberman says. “Grants from the MDA provide critical support for translational studies in this area of unmet clinical need.”
Gerald Abrams Collegiate Professor of Pathology Andrew Lieberman, at University of Michigan Medical School in Ann Arbor, was awarded an MDA research grant totaling $300,000 over three years to test a modified antisense oligonucleotide (ASO) therapy to treat spinal-bulbar muscular atrophy (SBMA).
Working with colleagues at Ionis Pharmaceuticals, Lieberman will complete preclinical studies in a mouse model to establish the safety and efficacy of a new type of therapy to silence expression (activity) of the gene that is mutated in SBMA. They plan to deliver the drug under the skin and target skeletal muscle — in fact, the new drug has been specifically designed for efficient uptake by muscle.
The team hypothesizes that the enhanced targeting of muscle by the new drug will enable robust gene silencing at lower doses, thereby limiting off-target toxicity while concurrently enhancing activity in a variety of disease-relevant muscles.
The group plans to establish the extent to which the modified drug triggers enhanced gene silencing and prevents disease onset in SBMA mice, and will determine effects of the drug in symptomatic SBMA mice. These studies are expected to provide essential efficacy data in a preclinical model.
The work is part of an academic-industry partnership between Ionis Pharmaceuticals and the Lieberman laboratory. If successful, the work could de-risk further investment by Ionis and shed light on whether a similar muscle-targeting strategy could work for other muscle diseases as well.
Grantee: SBMA – Andrew Lieberman, M.D., Ph.D.
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Grant - Summer 2017 - Nemaline Myopathy – Jordan Blondelle, Ph.D.
“My focus is to better understand the role that Cullin-3-related protein degradation may play in the pathological mechanism leading to the development of nemaline myopathy,” Jordan Blondelle says. “It’s important because the underlying mechanisms of this life-threatening disease currently are poorly understood.”
Jordan Blondelle, postdoctoral researcher at the University of California San Diego in La Jolla, was awarded an MDA development grant totaling $180,000 over three years to increase understanding of the underlying mechanisms in nemaline myopathy.
Muscle mass maintenance is tightly regulated by a balance between muscle growth and atrophy, reflecting the balance between protein synthesis and degradation at the cellular level. Accumulation of misfolded proteins or premature degradation of proteins is often associated with diseases such as skeletal muscle myopathies.
The degradation of muscle proteins is accomplished mainly through a cellular “clean-up and disposal system” called the ubiquitin-proteasome system, or UPS. The Cullin family of proteins, a key component of the UPS system, incorporate into complexes after which they are able to bind and mark unwanted proteins for degradation. Recently, mutations in several binding partners of Cullin-3, a Cullin protein family member, were found in people with severe forms of nemaline myopathy. These findings suggest a specific and important function for Cullin-3 targeted protein degradation during muscle development and maintenance.
Using mutant mice in which Cullin-3 is depleted in muscles, Blondelle and colleagues determined that the protein is necessary for survival, and will now look at how the loss of Cullin-3 affects muscle development, structure and function.
The team expects to find new target proteins of the Cullin-3 complex that would be misregulated in the absence of Cullin-3 and responsible for the myopathy observed in mice. In addition, the team intends to decipher, for the first time, how protein degradation mediated by Cullin-3 is relevant for muscle physiology, and to provide insight into the pathological mechanisms leading to nemaline myopathy in people.
If successful, Blondelle’s work could inform the development of therapies for nemaline myopathy.
Grantee: Nemaline Myopathy – Jordan Blondelle, Ph.D.
Grant type: Development Grant
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Grant - Summer 2017 - DM – Auinash Kalsotra, Ph.D.
"I feel that the DM field is making impressive strides in deciphering the exact pathogenic mechanisms unleashed by the trinucleotide repeat expansion,” Auinash Kalsotra says. “This knowledge will undoubtedly lead to the development of new treatment modalities for this debilitating disease."
Auinash Kalsotra, assistant professor and Beckman Fellow at the University of Illinois in Urbana, was awarded an MDA research grant totaling $300,000 over three years to shed light on how defects develop in the heart in type 1 myotonic dystrophy (DM1).
While the mutation that underlies DM1 affects multiple tissues, cardiac defects are the second leading cause of death in individuals with DM1. However, the molecular mechanism(s) responsible for the cardiac pathogenesis remain poorly understood.
Kalsotra and colleagues have discovered that in DM1-diseased heart, the fetal non-muscle isoform of an RNA binding protein called RBFOX2 is significantly upregulated. By forcing the expression of the non-muscle isoform of RBFOX2 in adult mouse hearts, they have reproduced many of the cardiac dysfunctions observed in DM1, including arrhythmias and cardiac conduction defects.
Now, the team will determine how the balance between muscle and non-muscle isoforms for RBFOX2 is achieved during normal heart development. In addition, they will investigate how this regulation is disrupted in DM1 and why the selective expression of non-muscle RBFOX2 isoform triggers a cardiac disease phenotype.
These finding will offer important insight into how cardiac abnormalities develop in DM1, and may inform new approaches for cardiac care in individuals with DM1.
Grantee: DM – Auinash Kalsotra, Ph.D.
Grant type: Research Grant
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Grant - Summer 2017 - DM – Andrew Berglund, Ph.D.
“I think the myotonic dystrophy field has made great gains in understanding the mechanisms of this disease, and there a number of exciting therapeutic strategies underway,” Andrew Berglund says. “This includes clinical trials with antisense oligonucleotides that target the toxic RNA as well as other strategies that target other aspects of the disease.”
Andrew Berglund, professor of biochemistry and molecular biology at the University of Florida in Gainesville, received an MDA research grant totaling $300,000 over three years to develop a therapeutic strategy for both types 1 and 2 myotonic dystrophy (DM1, DM2).
It is thought that the genetic defect underlying DM causes a toxic RNA, which accumulates in the nucleus of the cell and causes protein dysfunction by trapping proteins important for normal cell function. (RNA is the chemical step between DNA and protein manufacturing.) Some therapeutic approaches aim at degrading these toxic RNAs, or prevent them from trapping important cellular proteins. Berglund’s approach is to prevent the toxic RNA from even being produced in the first place.
With colleagues, Berglund recently published proof-of-principle data supporting the approach they’ve developed, called IMPEDE (inhibition of microsatellite promoted expression of deleterious expansions), which showed that treatment with an FDA-approved drug called actinomycin D reduced toxic RNA production in DM1 cell and mouse models.
Now Berglund’s team is working to further develop this small-molecule approach. Small molecules have some advantages over other types of treatments — such as the ability to be given systemically and to get across the blood-brain-barrier.
If successful, this approach potentially could be used alone or in combination with other therapeutic strategies to treat myotonic dystrophy.
Grantee: DM – Andrew Berglund, Ph.D.
Grant type: Research Grant
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Grant - Summer 2017 - Mitochondrial Myopathy, DMD – Gino Cortopassi, Ph.D.
“We believe that this drug, already approved for use in humans, will cure mitochondrial disease in animals,” Gino Cortopassi says. “If it does, we would take the data directly to the FDA to support a clinical trial in patients with mitochondrial myopathy.”
Gino Cortopassi, professor of molecular biosciences at the University of California, Davis, was awarded an MDA research grant totaling $300,000 over three years to optimize dosing in an FDA-approved drug called dimethyl fumarate, or DMF, in animal models of mitochondrial myopathy and Duchenne muscular dystrophy (DMD).
Mitochondria are small organelles found in cells. They are considered the “powerhouse” of the cell and are necessary to sustain life and support growth. When mitochondrial function is disrupted, high energy-demanding tissues such as brain and muscles are severely affected.
With a grant from MDA in 2009, Cortopassi and colleagues determined that the drug DMF could improve mitochondrial function. Only recently, however, have they come to understand that DMF works by increasing the number and activity of mitochondria in muscle. Since DMF has been used safely in hundreds of thousands of individuals with multiple sclerosis and psoriasis, its path to approval in other diseases could be quick. But in order for the FDA to approve clinical trials in humans that could assess whether the drug is effective in mitochondrial myopathy or DMD, positive results in validated animal models of these diseases are necessary.
Now, Cortopassi and his team will work to optimize dosing and timing for maximum drug benefit, test the mechanism of the drug, and determine the functional muscle benefit in mitochondrial myopathy and DMD mouse models. The group intends to identify the maximum effective dose of DMF and determine whether it can improve function in the mice.
If successful, Cortopassi’s work could provide data to support an investigational new drug (IND) application to the FDA for a new therapy for mitochondrial myopathy and/or DMD.
https://doi.org/10.55762/pc.gr.76838
Grantee: Mitochondrial Myopathy, DMD – Gino Cortopassi, Ph.D.
Grant type: Research Grant
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Grant - Summer 2017 - FSHD – Angela Lek, Ph.D.
“Without the support of MDA, young scientists like myself will not have the means to focus and shine a spotlight on rare diseases such as FSHD and other muscular dystrophies,” Angela Lek says.
Angela Lek, a postdoctoral research fellow at Boston Children’s Hospital in Massachusetts, was awarded an MDA development grant totaling $180,000 over three years to use cutting-edge techniques and a novel approach to search for drug targets in facioscapulohumeral muscular dystrophy (FSHD).
Disease severity among FSHD patients varies widely, and differences may be attributable to genetic modifiers (genes that minimize or exacerbate symptoms). Such modifiers also may explain why some relatives of people who have FSHD and who have the same permissive genetics are not affected.
With colleagues, Lek will work to identify genetic modifiers that appear to allow some individuals to appear “resistant” to FSHD.
Using the latest in genome-editing technology, the team will perform genetic modifications that result in systematically switching on every gene, one by one, across the entire human genome. They hypothesize that one or more of these gene switches will result in reduction of FSHD-related cell toxicity, making it a modifier gene in FSHD that can potentially be used to ameliorate disease symptoms in patients.
Candidate modifier genes will be cross-referenced to genomic sequencing data derived from people with FSHD and their asymptomatic carrier relatives, as a possible explanation for their clinical variance. The team will then further validate these genes with functional rescue experiments in a zebrafish model of FSHD, and also measure their ability to change the molecular disease signature of FSHD patient cells.
Once validated, these target genes could serve as concrete targets for therapy development.
Grantee: FSHD – Angela Lek, Ph.D.
Grant type: Development Grant
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