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.

KEYWORDS:

• Antisense
• oligonucleotide
• rnai
• familial ALS
• tofersen
• immunotherapy
• superoxide dismutase
• gene therapy
• parkinson’s

Article highlights

• SOD1 was the first gene to be implicated in ALS: mutations in SOD1 are seen in 15-30% of familial, and 1.2-1.5% of sporadic ALS cases.

• Most SOD1-ALS is autosomal dominant and associated with a toxic gain-of-function of the SOD1 protein through misfolding, aggregation and disruption of many vital cellular processes: mice lacking SOD1 do not develop a neurodegenerative phenotype.

• SOD1 can be effectively knocked down at the mRNA level in humans and animal models using antisense oligonucleotides and RNA interference.

• Tofersen, now in phase III development, is an intrathecal antisense oligonucleotide: preliminary evidence suggests it is safe, well-tolerated and may have disease-modifying potential.

• Various non-antisense SOD1-targeting strategies have been trialled in humans and animals including small molecules, immunotherapy, and novel CRISPR-based approaches.

• Development of SOD1 targeting therapies is likely to be hampered by recruitment due to low point provenance of SOD1-ALS: there is some theoretical basis that targeting SOD1 may be beneficial in ALS without SOD1 mutation and Parkinson’s disease.

This box summarizes key points contained in the article.

Declaration of interest

JP Franklin is a sub-investigator for the Biogen Phase1/2 trial and the ongoing Phase 3 trial of Tofersen in SOD1 ALS. PJ Shaw is the European Chief Investigator for the Biogen Phase1/2 trial and the ongoing Phase 3 trial of Tofersen in SOD1 ALS. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

JP Franklin was supported by the MyName’5 Doddie Foundation. PJ Shaw was supported as an NIHR Senior Investigator (Ref: NF-SI-0617-10077), by the MND Association (AMBROSIA Ref: MNDA 972-797), the Medical Research Council (COEN award Ref: MR/S004920/1), the MyName’5 Doddie Foundation and by the NIHR Sheffield Biomedical Research Centre. M Azzouz was supported by JPND-MRC (MR/V000470/1), and ARUK award (ARUK-PG2018B-005).