Core Viewpoint - The article discusses the challenges and findings related to the ASO drug BIIB078, developed for treating C9orf72-associated ALS (c9ALS), highlighting its distribution in the central nervous system (CNS) and the lack of clinical benefits despite its presence [4][8]. Group 1: Drug Development and Mechanism - C9orf72-associated ALS is caused by the expansion of the G4C2 repeat sequence in the first intron of the C9orf72 gene, leading to toxic RNA transcripts and dipeptide repeat proteins (DPR) [7]. - BIIB078 is an ASO drug targeting an 18-base pair sequence in the C9orf72 gene, aiming to degrade the toxic G4C2 repeat transcripts [3]. - Preclinical studies indicated that BIIB078 could silence the G4C2 repeat transcripts and reduce the burden of toxic DPR proteins [3]. Group 2: Clinical Trial Outcomes - Clinical trials of BIIB078 in c9ALS patients failed to meet any secondary endpoints and did not demonstrate clinical benefits, leading to the termination of its development in March 2022 [3]. - Despite widespread distribution in the CNS, BIIB078 did not effectively reduce toxic proteins or pathological changes, nor did it improve clinical outcomes [8]. Group 3: Research Findings - A recent study published in Cell analyzed the effects of BIIB078 on c9ALS patients, revealing that while the drug achieved extensive CNS distribution, it did not significantly reduce toxic protein levels or alter disease pathology [4][5]. - The study found an increase in inflammatory biomarkers, indicating a persistent immune response, and an unexpected interaction with the RNase T2 enzyme [8][14]. - The research provides critical insights into the drug's distribution, efficacy, and inflammatory response, which could guide future clinical trial designs [5][13].

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