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Department of Medicine; RNA Therapeutics Institute; Program in Molecular Medicine

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Cell Biology | Immunity | Immunoprophylaxis and Therapy | Nervous System Diseases


Post-transcriptional gene silencing is a promising therapy for the monogenic, autosomal dominant, Huntington's disease (HD). However, wild-type huntingtin (HTT) has important cellular functions, so the ideal strategy would selectively lower mutant HTT while sparing wild-type. HD patients were genotyped for heterozygosity at three SNP sites, before phasing each SNP allele to wild-type or mutant HTT. Primary ex vivo myeloid cells were isolated from heterozygous patients and transfected with SNP-targeted siRNA, using glucan particles taken up by phagocytosis. Highly selective mRNA knockdown was achieved when targeting each allele of rs362331 in exon 50 of the HTT transcript; this selectivity was also present on protein studies. However, similar selectivity was not observed when targeting rs362273 or rs362307. Furthermore, HD myeloid cells are hyper-reactive compared to control. Allele-selective suppression of either wild-type or mutant HTT produced a significant, equivalent reduction in the cytokine response of HD myeloid cells to LPS, suggesting that wild-type HTT has a novel immune function. We demonstrate a sequential therapeutic process comprising genotyping and mutant HTT-linkage of SNPs, followed by personalised allele-selective suppression in a small patient cohort. We further show that allele-selectivity in ex vivo patient cells is highly SNP-dependent, with implications for clinical trial target selection.


Diseases of the nervous system, Huntington's disease, Innate immune cells

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Copyright © 2017, The Author(s)

DOI of Published Version



Sci Rep. 2017 Apr 24;7:46740. doi: 10.1038/srep46740. Link to article on publisher's site

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Scientific reports

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Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.