Antisense oligonucleotides for C9orf72-associated ALS: explaining the lack of success

Pamela Shaw, DBE, MBBS, MD, FRCP, FMedSci, FAAN, FANA, FAAAS, University of Sheffield, Sheffield, UK, explains the pathophysiology of C9orf72-mediated amyotrophic lateral sclerosis (ALS). The expanded GGGGCC hexanucleotide repeat in the non-coding region of the C9orf72 gene is the most common genetic cause of ALS. Despite being in the non-coding region, the expanded repeat can be translated in every reading frame to form five different dipeptide repeat proteins (DPRs). The result is three non-exclusive pathogenic mechanisms: loss of function of C9orf72 protein, and toxic gain of function from sense and antisense C9orf72 repeat RNA or from DPRs. Prof. Shaw suggests that recent investigational antisense oligonucleotides may have failed to show clinical benefit because they only targeted the sense strand, whereas there is some evidence to suggest that translation of the antisense strand can produce more toxic effects to motor neurons. This interview took place at the 18th Annual Congress on Controversies in Neurology (CONy 2024) in London, UK.

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