N. Engl. J. Med. 383, 109–119 & 151–158 (2020)

Two studies show the potential of RNA-based gene-therapy approaches in the treatment of amyotrophic lateral sclerosis (ALS).

ALS is a neurodegenerative disease that in 10% of patients is caused by a mutation in the gene encoding superoxide dismutase 1 (SOD1), and targeting this gene is a therapeutic approach in development.

Mueller and colleagues use a microRNA directed against SOD1 (AAV-miR-SOD1) to target and reduce SOD1 expression in two patients with ALS. They find that the approach is safe and shows some clinical promise in one of the patients. In a phase 1/2 trial of 50 participants, the authors carry out intrathecal administration of an antisense oligonucleotide, tofersen, that mediates the degradation of SOD-1. The trial shows tofersen to be effective in reducing SOD-1 levels.