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Open Access 01-12-2017 | Review

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

Authors: Sebastian Aguiar, Bram van der Gaag, Francesco Albert Bosco Cortese

Published in: Translational Neurodegeneration | Issue 1/2017

Abstract

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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Title: RNAi mechanisms in Huntington’s disease therapy: siRNA versus shRNA
Authors: Sebastian Aguiar
Bram van der Gaag
Francesco Albert Bosco Cortese
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Translational Neurodegeneration / Issue 1/2017
Electronic ISSN: 2047-9158
DOI: https://doi.org/10.1186/s40035-017-0101-9

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

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Music therapy is a potential intervention for cognition of Alzheimer’s Disease: a mini-review

Identification of Ser465 as a novel PINK1 autophosphorylation site

Environmental insults: critical triggers for amyotrophic lateral sclerosis

Current understanding of the molecular mechanisms in Parkinson's disease: Targets for potential treatments

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