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. 2017 Oct;16(10):837-847.
doi: 10.1016/S1474-4422(17)30280-6. Epub 2017 Sep 12.

Therapies Targeting DNA and RNA in Huntington's Disease

Free PMC article

Therapies Targeting DNA and RNA in Huntington's Disease

Edward J Wild et al. Lancet Neurol. .
Free PMC article

Erratum in

  • Corrections.
    Lancet Neurol. 2017 Dec;16(12):954. doi: 10.1016/S1474-4422(17)30367-8. Epub 2017 Nov 14. Lancet Neurol. 2017. PMID: 29165252 No abstract available.


No disease-slowing treatment exists for Huntington's disease, but its monogenic inheritance makes it an appealing candidate for the development of therapies targeting processes close to its genetic cause. Huntington's disease is caused by CAG repeat expansions in the HTT gene, which encodes the huntingtin protein; development of therapies to target HTT transcription and the translation of its mRNA is therefore an area of intense investigation. Huntingtin-lowering strategies include antisense oligonucleotides and RNA interference targeting mRNA, and zinc finger transcriptional repressors and CRISPR-Cas9 methods aiming to reduce transcription by targeting DNA. An intrathecally delivered antisense oligonucleotide that aims to lower huntingtin is now well into its first human clinical trial, with other antisense oligonucleotides expected to enter trials in the next 1-2 years and virally delivered RNA interference and zinc finger transcriptional repressors in advanced testing in animal models. Recent advances in the design and delivery of therapies to target HTT RNA and DNA are expected to improve their efficacy, safety, tolerability, and duration of effect in future studies.

Conflict of interest statement

Declaration of interests

EJW has participated in scientific advisory boards with Hoffmann-La Roche Ltd, Ionis, Shire, Novartis and Wave Life Sciences and is an investigator on the HTTRx trial. SJT has participated in scientific advisory boards with Hoffmann-La Roche Ltd, Ionis, Shire, Teva Pharmaceuticals, GSK, Takeda Pharmaceuticals and Heptares Therapeutics, and is the global Principal Investigator on the HTTRx trial, for which she receives no personal salary or fees. All honoraria for these advisory boards were paid through UCL Consultants Ltd, a wholly owned subsidiary of UCL. Their host clinical institution, University College London Hospitals NHS Foundation Trust, receives funds as compensation for conducting clinical trials for Ionis Pharmaceuticals, Pfizer and Teva Pharmaceuticals.


Figure 1
Figure 1
The production of huntingtin protein, and targeted molecular therapies in development to reduce it. Yellow marks the pathogenic expanded CAG tract and its polyglutamine product. Therapeutic approaches are highlighted with pink boxes. Yellow boxes indicate the most widely accepted toxic species. Dotted arrows and grey boxes indicate proposed non-traditional mechanisms for the production of toxic species. The chief mechanisms of action of ASOs and RNAi compounds are shown at the bottom. The image of huntingtin protein is adapted from reference under a creative commons licence (CC-BY-4.0).
Figure 2
Figure 2
First, second and third generation ASOs and native DNA. Each generation may contain numerous variations around the altered characteristic. HTTRx combines a phosphorothioate backbone (1st generation) with 2’-O-MOE modification (2nd generation) and is considered a 2nd generation ASO overall.

Comment in

  • Sarah Tabrizi: timed to perfection.
    Burton A. Burton A. Lancet Neurol. 2018 Feb;17(2):117. doi: 10.1016/S1474-4422(17)30303-4. Epub 2017 Sep 12. Lancet Neurol. 2018. PMID: 28916420 No abstract available.

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