Recent Progress of Antisense Oligonucleotide Therapy for Superoxide-Dismutase-1-Mutated Amyotrophic Lateral Sclerosis: Focus on Tofersen

Abstract

Amyotrophic lateral sclerosis (ALS) is a refractory neurodegenerative disease characterized by the degeneration and loss of motor neurons, typically resulting in death within five years of onset. There have been few effective treatments, making the development of robust therapies an urgent challenge. Genetic mutations have been identified as contributors to ALS, with mutations in superoxide dismutase 1 (SOD1), which neutralizes the harmful reactive oxygen species superoxide, accounting for approximately 2% of all ALS cases. To counteract the toxic gain of function caused by SOD1 mutations, therapeutic strategies aimed at suppressing SOD1 gene expression have shown promise. Antisense oligonucleotide (ASO) is an artificially synthesized, short, single-stranded DNA/RNA molecule that binds to target RNA to alter gene expression, representing a next-generation therapeutic approach. In 2023, tofersen became the first ASO drug approved by the FDA for ALS. Administered intrathecally, tofersen specifically binds to SOD1 mRNA, inhibiting the production of toxic SOD1 protein, thereby improving biomarkers of ALS. The long-term efficacy and safety of tofersen require further validation, and the development of more optimized treatment protocols is essential. A series of studies and therapeutic developments related to SOD1 mutations have advanced the understanding of ALS pathophysiology and significantly contributed to treatment strategies for central nervous system disorders. This review focuses on an overview of SOD1 mutations and the development process of tofersen, aiming to deepen the understanding of advancements in ALS research and discuss future challenges and directions for ASO therapy.

Keywords: amyotrophic lateral sclerosis (ALS); antisense oligonucleotide (ASO); central nervous system (CNS); superoxide dismutase 1 (SOD1); tofersen.

Figure 1

Amino acid sequence of SOD1 and representative mutations known in ALS. Mutation data were extracted from the ALS online database (ALSoD, http://alsod.iop.kcl.ac.uk, accessed on 11 October 2024). Of the more than 200 known mutations, mutations reported in at least 5 individuals are listed here. Red letters indicate amino acids with high mutation frequency.

Figure 2

ASO (tofersen) mechanism of action. (A) In the absence of the SOD1 gene mutation, functional SOD1 protein is produced by normal transcription and translation. (B) In the presence of SOD1 gene mutation, toxic SOD1 protein is produced by its transcription and translation. (C) When tofersen, an ASO gapmer against the SOD1 gene, specifically binds to SOD1 mRNA, SOD1 mRNA is degraded by the activity of RNase H, inhibiting the production of toxic SOD1 protein.