RAG-17: A Novel siRNA Conjugate Demonstrating Efficacy in Late-Stage Treatment of SOD1G93AALS mice

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by rapid progression and high mortality. With genetic mutations, particularly in the SOD1 gene, playing a significant role in ALS pathogenesis, targeted therapies have become a primary focus. This study introduces RD-12500 (RAG-17), a novel siRNA-ACO (Accessory Oligonucleotide) conjugate designed to address the challenges of delivering duplex RNAs to the central nervous system (CNS). RD-12500 exhibits remarkable in vitro stability and target specificity with minimal immunostimulation. In vivo studies demonstrate its extensive CNS biodistribution, sustained accumulation post-intrathecal administration, and a robust dose-exposure-activity correlation. Notably, RD-12500 significantly reduces cerebrospinal fluid (CSF) SOD1 protein levels, indicating potent SOD1 mRNA and protein knockdown in cynomolgus monkeys. Most notably, our study breaks new ground by demonstrating the effectiveness of RD-12500 in late-stage treatment scenarios. In SOD1 G93A ALS mice, post-onset administration of RD-12500 significantly delayed disease progression, improved motor function, and extended survival, marking a significant advancement over other treatments which are typically initiated pre-symptomatically in the same model mice. These findings suggest RD-12500’s potential to provide therapeutic benefits not only to pre-symptomatic but also to post-symptomatic and late-stage SOD1-ALS patients.