Stanley Appel, MD, co-director of Houston Methodist Neurological Institute, chair of the Stanley H. Appel Department of Neurology and the Peggy and Gary Edwards Distinguished Chair in ALS at Houston Methodist Hospital, and professor of Neurology at Weill Cornell Medical College, was awarded an MDA human clinical trial grant totaling $558,800 over two-and-a-half years to expand the first-in-human study that demonstrated promising results leveraging patients’ own immune cells to treat amyotrophic lateral sclerosis (ALS). In ALS, muscle-controlling nerve cells called motor neurons are progressively lost, eventually causing muscles to become nonfunctional.

The award is part of a larger grant from The ALS Association, ALS Finding a Cure (ALSFAC), and MDA, which jointly awarded a clinical trial grant totaling more than $2.5 million over two-and-a-half years to leading investigators at the Houston Methodist Neurological Institute and Massachusetts General Hospital. The clinical trial grant is a collaborative study between the ALS team at Houston Methodist Hospital led by principal investigator Dr. Appel and the ALS team at Mass General Hospital led by Merit Cudkowicz, MD, chief of Neurology at Mass General Hospital and the Julieanne Dorn Professor of Neurology at Harvard Medical School.

Regulatory T-lymphocytes (Tregs) are a type of T-lymphocyte (a white blood cell that plays a central role in the immune response) that reduces immune system activation. Tregs are decreased in both numbers and function in the blood of people with ALS. Building on positive preclinical results showing that it was possible to restore Treg function outside the body, the first clinical trial in humans demonstrated that Tregs could be extracted from people living with ALS, expanded in vitro, and then safely infused back into the same patients, with three treated patients showing improved Treg suppressive function and slowed disease progression. The phase 2a clinical trial led by Dr. Appel will expand on the results of the first trial with participants receiving infusions of expanded regulatory (EPAR) T-cells followed by an ascending-dose, open-label extension trial.

"We are interested in both understanding how exercise affects skeletal muscle in FSHD and identifying the key cellular events contributing to those responses."

Adam Bittel, PT, DPT, PhD, a postdoctoral fellow at Children’s National Medical Center in Washington, DC, was awarded the 2019 SSSI-MDA Fellowship Award. The award, co-sponsored by Strength, Science & Stories of Inspiration (SSSI) and MDA, will provide a total of $40,000 over two years to support Dr. Bittel’s work investigating the cellular mechanisms underlying the effects of exercise in facioscapulohumeral muscular dystrophy (FSHD).

During his doctoral studies, Dr. Bittel explored how exercise influences multi-organ metabolism in metabolic syndromes as well as in Barth syndrome, a genetic disease affecting skeletal and cardiac muscle. While exercise is known to improve muscle health and metabolism in other forms of muscular dystrophy, there are very few studies assessing the effects of exercise in individuals with FSHD. Dr. Bittel is interested in understanding how exercise affects skeletal muscle in a mouse model of FSHD (the FLExDUX4 mouse) and in identifying important cellular events contributing to those responses.

"By emphasizing testing of FDA-approved compounds, the clinical trial pipeline can be sped up, reducing the wait time for any potential treatment."

Justin Cohen, PhD, a postdoctoral fellow at Yale University School of Medicine, was awarded an MDA development grant of $140,000 over two years to test FDA-approved drugs that target therapeutic pathways for facioscapulohumeral muscular dystrophy (FSHD). The award was made in conjunction with a grant from the Chris Carrino Foundation for FSHD. Since Dr. Cohen lives with FSHD himself, the award will provide for a lab technician who will work alongside Dr. Cohen to perform the benchwork for studies that he designs.

FSHD is caused by abnormal expression of double homeobox 4 protein (DUX4), which leads to the production of toxic proteins and muscle cell death. With this new funding, Dr. Cohen will identify biological pathways that contain therapeutic targets for FSHD and validate related genes among the pathways. He will then test drugs that target these pathways, with an emphasis on those that are already FDA-approved, for their ability to reduce both cell death caused by toxic DUX4 and biomarkers of FSHD — hopefully discovering one that could enter clinical trials for FSHD.

"We hope to identify a pre-clinical candidate that will treat DMD by boosting sarcospan levels. We also want to learn more about how our lead compounds target sarcospan in muscle cells so we can design better, more effective drugs."

Rachelle H. Crosbie, PhD, professor and chair of Integrative Biology and Physiology at the University of California, Los Angeles, was awarded MDA Venture Philanthropy (MVP) funding totaling $389,463 over two years to develop a small molecule drug that increases expression of sarcospan, a protein that may help to prevent the muscle damage that occurs in Duchenne muscular dystrophy (DMD). MVP funding is awarded to researchers developing therapeutics for neuromuscular diseases to help lower the barriers and bridge the high-risk stages of drug development.

DMD is caused by mutations in the dystrophin gene on the X chromosome that result in little or no production of dystrophin, a protein essential to keeping muscle cells intact. While funded by an MDA postdoctoral fellowship starting in 1996, Dr. Crosbie identified a protein called sarcospan that may improve the structural integrity of dystrophic muscle in DMD.

After setting up her own lab, Dr. Crosbie continued to work on sarcospan. Her lab found that increasing the amount of sarcospan can convey a protective effect on skeletal and cardiac muscle in mice with muscular dystrophy. Her team has recently identified a set of small molecules that increase the levels of sarcospan, and with support from the MVP award, her team will chemically optimize these lead compounds and test them in DMD mice and DMD human cells. If successful, this work may lead to the development of a novel drug that could slow the loss of function in limb muscles, respiratory muscles, and heart.

"Rational clinical trials in CMT with outcome measures that can measure effectiveness are in place and will hopefully lead to effective treatments within the next three to five years for many subtypes."

Michael Shy, PhD, professor of Neurology and Pediatrics at the University of Iowa, was awarded an MDA Clinical Research Network Grant (CRNG) totaling $423,413 over three years to further develop the Inherited Neuropathies Consortium (INC), a network of clinical investigators dedicated to evaluating therapies for patients with inherited peripheral neuropathies, collectively known as Charcot-Marie-Tooth disease (CMT).

In CMT peripheral nerves degenerate, typically resulting in muscle weakness and sensory loss in the hands, arms, feet, and legs. The disease is progressive; however, the severity of symptoms and rate of progression depend on the type of CMT.

Dr. Shy has a long history of MDA funding, including receiving awards to create the North American CMT Network and to establish the North American CMT Consortium. His last grant was awarded for the Inherited Neuropathies Consortium (INC), an international collection of centers devoted to developing treatments for and treating patients with CMT.

With this most recent funding, Dr. Shy will expand the INC’s natural history data to become “clinical-trial-ready” for common and rare forms of CMT; identify, characterize, and facilitate treatments for novel forms of CMT; train future investigators in the field; and share INC data with scientists, physicians, and patients in an easily accessible manner.

"The Myotonic Dystrophy Clinical Research Network is a natural extension of 30-plus years’ effort to understand the fundamental problems in myotonic dystrophy and then develop treatments to overcome the problems. MDA has supported a lot of the critical basic research that brought the field to this point where people can conceive and develop new treatments."

Charles Thornton, MD, professor of Neurology at the University of Rochester, was awarded an MDA clinical research network grant (CRNG) totaling $1,118,673 over three years to continue to lead the development of the Myotonic Dystrophy Clinical Research Network, which comprises six medical centers specializing in research and clinical care of myotonic dystrophy (DM) types 1 and 2. Dr. Thornton was previously awarded two other CRNGs totaling $918,000 each over the course of a combined six years.

Established in 2013 and supported by funding from MDA and other patient advocacy groups, the National Institutes of Health (NIH), and pharmaceutical company Biogen, the network’s aim is to gain a more detailed understanding of DM’s disease process and collect necessary clinical trial data to help determine the most appropriate outcome measures, biomarkers, and endpoints.

Since the network was formed, the six participating sites have developed standardized equipment and procedures for obtaining and analyzing needle muscle biopsies, quantifying measures of myotonia, and taking measurements of muscle strength and motor function. A group of coordinators and evaluators has been trained in all procedures, and strong relationships have been formed with patients and family members. The network completed initial studies of biomarkers and natural history, and it now aims to expand to larger cohorts, complete biomarker characterization, and gain a better understanding of the biological determinants of DM’s disease severity.

"In this project we will investigate the use of exosomes as a method to encapsulate or “hide” AAVs from the immune system — so-called “stealth” AAVs — as a new method to help to dramatically improve the way that gene therapy might be delivered to DMD and other patients."

Matthew Wood, PhD, professor of Neuroscience at the University of Oxford and director of both the Oxford Rare Disease Center and the MDUK Oxford Neuromuscular Center, was awarded an MDA research grant totaling $210,000 over two years to optimize the delivery of genetic therapies such as oligonucleotides to tissues for treating Duchenne muscular dystrophy (DMD).

DMD is a genetic disease caused by a mutation in the dystrophin gene on the X chromosome that results in little or no production of dystrophin, an essential protein for keeping muscle cells intact. In September 2016, Sarepta Therapeutics’ Exondys 51 was the first gene therapy approved to treat DMD (it is an exon-skipping drug). The delivery of these types of therapies into the right tissues remains challenging, however, and Dr. Wood’s team has addressed this by developing a range of gene-delivery technologies, including peptides and nanotechnologies.

In gene-replacement therapy, adeno-associated virus (AAV) vectors are used to deliver a normal copy of a missing or mutated gene to a patient’s cells. However, AAVs can cause an immune response, making it impossible to deliver the therapy more than once. With this funding, Dr. Wood will develop a nanotechnology that uses exosomes, naturally occurring nanoparticles that transport proteins and genetic material between cells, to deliver gene therapies to cells potentially without provoking an immune response. The aim is to be able to treat people with pre-existing immunity to AAV as well as be able to administer more than one dose, if needed, to treat DMD over the course of the disease.

"DM is caused by expression of dysfunctional, repetitive RNA in diseased tissues, where application of Locana’s core RNA-targeting technology has been shown to have potential for single-dose therapeutic benefit and could provide a long-lasting approach for patients."

Locana, a leading RNA-targeting gene therapy company based on the work of one of its founders Gene Yeo, PhD, MBA, professor of Cellular and Molecular Medicine at the University of California, San Diego, was awarded MDA Venture Philanthropy (MVP) funding totaling $550,000 over two years to advance Locana’s development program for myotonic dystrophy (DM), the most common form of adult-onset muscular dystrophy. MVP funding is awarded to researchers developing therapeutics for neuromuscular diseases to help lower the barriers and bridge the high-risk stages of drug development.

Myotonic dystrophy is a genetic neuromuscular disease that affects multiple muscles and systems, including skeletal muscle, cardiac muscle, the gastrointestinal tract, and the central nervous system. In both types of DM, DM1 and DM2, genetic mutations in the form of large repeat expansions of DNA lead to the development of clumps of RNA that become toxic to healthy cells. (RNA is the molecular step between DNA and protein.) 

Locana’s RNA-targeting platform technology aims to address a wide spectrum of human genetic diseases, including DM. Locana has advanced a powerful modular RNA targeting-effector approach that is distinct from DNA-targeting approaches (such as CRISPR/Cas9) and nucleic acid-based RNA targeting approaches (such as antisense oligonucleotides). Locana intends to build a portfolio of therapies that address the root cause of genetic diseases driven by dysfunctional RNA behavior.