Project Overview

Mutations in the SOD1 gene, leading to the misfolding and toxic aggregation of SOD1 protein, are the second leading cause of Familial Amyotrophic Lateral Sclerosis (FALS-SOD1) and emerging literature has detected misfolded SOD1 (mSOD1) in the cerebrospinal fluid (CSF) and post-mortem tissue of Sporadic ALS (SALS) patients. Based upon the recent paradigm shift in Alzheimer disease (i.e. another protein misfolding disorder with both familial and sporadic forms) such that impaired amyloid clearance is equally important for the pathogenesis as amyloid deposition, we hypothesize that impaired mSOD1 clearance has a similarly important role in the pathogenesis of ALS. The potential to specifically enhance the clearance of mSOD1 provides a rationale therapeutic strategy aimed to improve the quality of life for both FALS and SALS patients. In parallel to the pending global Phase 2 study by AL-S Pharma to evaluate the safety and tolerability of its lead anti-mSOD1 therapeutic antibody (AP-101) in FALS-SOD1 and SALS patients, the current proposal by Drs. Multhaup and Genge (world-renowned AD and ALS experts, respectively) seeks to discover robust mSOD1 biomarkers which are urgently needed to monitor the efficacy of mSOD1-targeted therapies such as AP-101. Therefore, this grant aims to: (i) characterize additional candidates from AL-S Pharma to identify capture/detection antibodies that specifically recognize different epitopes compared to AP-101 (to assess target engagement during the Phase 2 study), and (ii) develop leading-edge single molecule array (Simoa) immunoassays to quantify specific SOD1 intermediates (misfolded, truncated, and/or post-translationally modified) as novel biomarkers. The proposed project is significant because it will: (i) advance our fundamental understanding of mSOD1 clearance in ALS pathogenesis, and (ii) help discover novel AP-101-independent mSOD1 biomarkers to simplify the recruitment of FALS-SOD1 and SALS patients in future clinical trials.