Spinal Cord Proteomics of Antisense Oligonucleotide Drug Trial

ABSTRACT: C9orf72-linked amyotrophic lateral sclerosis (c9ALS) is driven by an intronic G4C2 repeat expansion, leading to the production of toxic RNA transcripts and dipeptide repeat proteins (DPRs). A clinical trial using the antisense oligonucleotide (ASO), BIIB078, to target these transcripts was discontinued after failing to meet secondary efficacy endpoints, despite a reduction in DPRs in cerebrospinal fluid (CSF). The extent of target engagement in the central nervous system (CNS) and the relevance of pharmacodynamic CSF biomarkers following BIIB078 treatment remain unclear. Post-mortem analysis of CNS tissue from six BIIB078-treated c9ALS patients revealed widespread intracellular BIIB078 distribution in the spinal cord and brain regions, persisting for over a year after the last dose. C9orf72 mRNA levels were inversely correlated with BIIB078 concentration, indicating partial target engagement. Despite reductions in CSF DPRs, these proteins and phosphorylated TDP-43 remained abundant in the brain and spinal cord, suggesting that CSF biomarkers may not fully reflect CNS target engagement. Additionally, sustained increases in inflammation biomarkers, including CCL26, GDF15, and other cytokines, were observed. Global proteomic analysis of spinal cord tissue revealed significant changes in c9ALS cases that were not normalized in BIIIB078 treated cases. Notably, proteome-wide correlations with BIIB078 concentration in the spinal cord identified hydrolytic nucleases, including RNASET2 and DNASE2, to be increased in BIIB078 treated cases. Thus, while BIIB078 demonstrated widespread and sustained distribution and partial target engagement, it did not significantly impact key proteomic and pathological features in the CNS of c9ALS patients. Consequently, ceasing strategies that target the G4C2 sense strand may be premature.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Spinal Cord

DISEASE(S): Amyotrophic Lateral Sclerosis

SUBMITTER: Eric Dammer  

LAB HEAD: Zachary McEachin

PROVIDER: PXD055796 | Pride | 2025-08-27

REPOSITORIES: Pride