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100 reviewsSUMMARYC9orf72-associated amyotrophic lateral sclerosis (c9ALS) is caused by an intronic G4C2 repeat expansion that leads to toxic RNA transcripts and dipeptide repeat proteins (DPRs). A clinical trial using theantisense oligonucleotide (ASO) BIIB078 to target these transcripts was discontinued after failing to provide clinical benefit. Here, we determine the extent of target engagement in the central nervous system(CNS) and elucidate pharmacodynamic cerebrospinal fluid (CSF) biomarkers following treatment. CSFfrom BIIB078-treated cases showed reduced DPRs and sustained increases in inflammatory biomarkers,including C-C motif chemokine ligand 26 (CCL26). BIIB078 was widely distributed in postmortem CNStissue; however, DPRs and phosphorylated TDP-43 remained abundant. Proteomic signatures inc9ALS spinal cord were not altered with treatment, although a distinct increase in RNase T2 abundancethat correlated with BIIB078 concentration was observed. Thus, despite widespread distribution,BIIB078 did not significantly impact key CNS pathologies, emphasizing the need to identify pharmacodynamic biomarkers that reflect disease-relevant neuropathological changes in response to ASOtherapies.
