Dr. Brown completed a B.A. in Biophysics (Amherst College, 1969), a D.Phil. in Neurophysiology (Oxford, 1973) and an M.D. (Harvard, 1975). After a neurology residency at the Massachusetts General Hospital/Harvard Medical School (1980), he joined the faculty at the Massachusetts General Hospital where he established the Day Neuromuscular Research Laboratory and co-directed the Neuromuscular Clinic. In 1998, he was awarded tenure as Professor of Neurology at Harvard Medical School. In 2008, he became the chair of neurology at UMass Medical School, where he holds the LaChance Family Chair of Neurology and serves as Director of the ALS Clinic and Director of Neurological Therapeutics.
Dr. Brown has a longstanding research interest in identifying gene defects that underlie ALS and related neuromuscular disorders. He was a lead member of the team that identified the first ALS gene (SOD1) and, with colleagues, has subsequently identified several other defective genes in ALS including alsin, dynactin, FUS/TLS, ErbB4 and profilin1. He has identified causative gene defects s in other disorders including limb girdle dystrophy type 2B (dysferlin), hereditary sensory neuropathy [serine palmitoyl-transferase], and hyperkalemic paralysis [skeletal muscle sodium channel]). His laboratory team has used insights from these investigations in genetics to generate cell and animal models of each of these disorders. These models have improved our understanding of pathological processes that trigger diseases like ALS and have assisted in therapy development. Most recently, he has initiated trials of ALS gene suppression therapy in non-human primates and now in humans. He has published more than 300 peer-reviewed reports and more than 70 reviews and chapters on these topics. He is a member of the National Academy of Medicine (formerly the Institute of Medicine) and is a past president of the American Neurological Association.
Toward Gene Suppression Therapy in ALS
Mutations in more than 40 genes are robustly associated with ALS and ALS-FTD. These define several primary categories of pathophysiology in ALS involving the biological properties of RNA, conformational stability of critical proteins, and axonal cytoskeletal dynamics. Secondarily, the mutant genes initiate downstream pathological processes in neurons (likely differing in different subcellular compartments) as well as neuroinflamation. These observations define multiple targets for therapy. When a specific ALS gene is identified, the most upstream therapies reduce the burden of the mutant RNA and proteins. Such therapies include (1) gene editing to correct the gene mutations; (2) reduction in the burden of the mutant RNA using antisense oligonucleotides, shRNA and microRNA, and small molecules that inhibit the SOD1 promoter; and (3) reduction in levels of the adverse mutant proteins, using intra- or extracellular antibodies. This presentation will review progress in the development of gene suppression therapies for SOD1, C9orf72 and FUS with a focus on recent pilot clinical studies.