Department of Medicine; RNA Therapeutics Institute; Program in Molecular Medicine
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
Miller JR, Pfister EL, Liu W, Andre R, Trager U, Kennington LA, Lo K, Dijkstra S, Macdonald D, Ostroff GR, Aronin N, Tabrizi SJ. (2017). Allele-Selective Suppression of Mutant Huntingtin in Primary Human Blood Cells. Open Access Publications by UMass Chan Authors. https://doi.org/10.1038/srep46740. Retrieved from https://escholarship.umassmed.edu/oapubs/3135
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