Huntington’s Disease (HD) is a genetically dominant trinucleotide repeat disorder resulting from CAG repeats within
the Huntingtin (HTT) gene exceeding a normal range (> 36 CAGs). Symptoms of the disease manifest in middle age
and include chorea, dystonia, and cognitive decline. Typical latency from diagnosis to death is 20 years. There are
currently no disease-modifying therapies available to HD patients. RNAi is a potentially curative therapy for HD. A
popular line of research employs siRNA or antisense oligonucleotides (ASO) to knock down mutant Huntingtin mRNA
(mHTT). Unfortunately, this modality requires repeated dosing, commonly exhibit off target effects (OTEs), and exert
renal and hepatic toxicity. In contrast, a single AAV-mediated short-hairpin RNA (shRNA) dose can last years with low
toxicity. In addition, we highlight research indicating that shRNA elicits fewer OTEs than siRNA when tested head-to-
head. Despite this promise, shRNA therapy has been held back by difficulties controlling expression (oversaturating
cells with toxic levels of RNA construct). In this review, we compare RNAi modalities for HD and propose novel methods
of optimizing shRNA expression and on-target fidelity.

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• RNAi mechanisms in Huntington’s disease therapy: siRNA versus shRNA