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

ABSTRACT 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. Silencing of the SOD1 gene, has recently shown preliminary evidence of disease-modifying activity in SOD1-ALS patients. Areas covered: 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. A wide array of other SOD1-targeting strategies have shown considerable promise in preclinical studies.