Translating the ALS Genetic Revolution into Therapies: A Review

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing weakness, respiratory failure, and death within 3 to 5 years. Approximately, 10% of ALS cases have a genetic etiology (familial/fALS). The etiology of the remaining 90% of sporadic ALS (sALS) cases remains unknown. In this review, we provide an overview of approved and investigational therapies for fALS, as well as genetically informed therapeutic advances aimed at the larger sALS population.

Antisense oligonucleotides (ASOs) are a promising strategy to treat toxic gain-of-function mutations underlying most forms of fALS. We discuss the recent approval of tofersen for ALS caused by mutation in SOD1. We also discuss progress in the development of therapies for fALS associated with C9orf72 hexanucleotide repeat expansions (C9orf72) and fused in sarcoma (FUS) mutations. Finally, we will discuss the rationale and status of molecular therapies for sALS targeting mediators of TDP-43 pathogenesis: ataxin-2 (ATXN2) and stathmin-2 (STMN2).

Advances in understanding the genetics of ALS have propelled the development of promising gene therapies. Lessons learned from tofersen continue to inform clinical trial design for a growing pipeline of therapies directed towards other fALS subtypes and sALS.