Three Penn Medicine researchers awarded grants for neuromuscular disease research

The Muscular Dystrophy Association has awarded research grants totaling over $1,000,000 to three Penn Medicine researchers: James Shorter, PhD, associate professor of Biochemistry and Biophysics; Hansell Stedman, MD, associate professor of Surgery; and Lee Sweeney, PhD, director of the Center for Orphan Disease Research and Therapy.

The newly awarded funds will help support study in three diverse areas:

James Shorter, PhD: There are no effective therapies for amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. In ALS, cytoplasmic protein aggregates accumulate in degenerating motor neurons. In most ALS cases, these aggregates are comprised of the RNA-binding protein, TDP-43. In other cases, they are comprised of Cu/Zn superoxide dismutase 1 (SOD1) or another RNA-binding protein called FUS. "We will generate therapeutic disaggregases for ALS based on Hsp104, a protein from yeast. Hsp104 rescues aggregated proteins and restores their function. We hypothesize that hyperactivated Hsp104 variants can be generated with increased disaggregase activity against TDP-43, FUS and SOD1," says Shorter.

Hansell Stedman, MD: This new project addresses a critical problem in the development of effective therapy for Duchenne Muscular Dystrophy and other causally related muscle diseases. "The problem is the immune response to gene transfer in the inflammatory environment of dystrophic muscle," says Stedman. Recombinant gene transfer vectors based on the non-pathogenic adeno-associated viruses have shown great promise in mouse models of muscular dystrophy. Attempts to translate this approach to canine disease models and humans have failed, while providing evidence for powerful immune responses to vector-associated antigens. "We will identify targets for transient immunosuppression prior to vector administration, thereby improving the chances for safe and durable therapy for these devastating childhood-onset diseases," he adds. "Most of the experiments will use dystrophin-deficient mice to further unravel the complex modes of cell-to-cell communication that take place as muscles attempt self-repair after injury."

Lee Sweeney, PhD: The primary molecular deficiency in Duchenne Muscular Dystrophy (DMD) is the dystrophin protein, and the concomitant reduction in cell-surface glycoproteins. The lack of enough dystrophin makes muscle fibers more susceptible to necrosis, but is not well understood. One proposed mechanism involves abnormal calcium shuttling across the cell membrane, which may eventually lead to skeletal muscle weakness. Sweeney's lab will look at how to modulate the shuttling of calcium in mouse models of DMD.

This grant is part of $8.4 million awarded by MDA in 31 neuromuscular disease research projects. Many of the grants are multiyear awards to be distributed over several years.

"All of these grants were recommended for funding by the distinguished groups of neuromuscular disease researchers and clinicians voluntarily serving on the MDA Medical and Scientific Advisory Committees," said R. Rodney Howell, M.D., Chairman of the MDA Board of Directors.