ALS gene suppression: pilot studies
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.