SOD1-targeting therapies for neurodegenerative diseases : a review of current findings and future potential

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited effective treatments. Mutations in the SOD1 gene are causative in approximately 2% of ALS cases. As the first ALS-associated gene to be discovered, efforts in the development of therapies targeting SOD1 are advanced relative to other genetic causes of ALS. Two SOD1-targeting strategies: antisense oligonucleotides and microRNA, have been trialled in humans to date, with preliminary evidence of disease-modifying activity.

Areas covered: In this review, the following areas are discussed: 1) the pathophysiology of mutant SOD1-ALS, and the rationale for targeting the SOD1 gene; 2) the strategies that have been used to target mutant SOD1 in clinical and preclinical studies; 3) the role of misfolded wild-type SOD1 in sporadic ALS and other neurodegenerative diseases, and the potential for targeting SOD1 in these patients; 4) future avenues for research. A literature search of publications pertaining to SOD1-ALS and its treatment from 1992-present using the MEDLINE database form the basis for this review.

Expert opinion: Central nervous system SOD1 knockdown is achievable in SOD1-ALS patients with intrathecal antisense oligonucleotide therapy, and is both safe and well-tolerated: phase III study outcomes are awaited. Well-designed virus-based delivery strategies for RNA interference therapies targeting SOD1 show promise in animal models and may, with caution, provide an effective treatment strategy if these results can be recreated in future clinical studies.