“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.

“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.

“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.

“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.

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.

“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.

“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.

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.

“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.

“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.

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.

“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.

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.