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000120651 1001_ $$aMiller, James R C$$b0
000120651 245__ $$aAllele-Selective Suppression of Mutant Huntingtin in Primary Human Blood Cells.
000120651 260__ $$aLondon$$bNature Publishing Group$$c2017
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000120651 520__ $$aPost-transcriptional gene silencing is a promising therapy for the monogenic, autosomal dominant, Huntington's disease (HD). However, wild-type huntingtin (HTT) has important cellular functions, so the ideal strategy would selectively lower mutant HTT while sparing wild-type. HD patients were genotyped for heterozygosity at three SNP sites, before phasing each SNP allele to wild-type or mutant HTT. Primary ex vivo myeloid cells were isolated from heterozygous patients and transfected with SNP-targeted siRNA, using glucan particles taken up by phagocytosis. Highly selective mRNA knockdown was achieved when targeting each allele of rs362331 in exon 50 of the HTT transcript; this selectivity was also present on protein studies. However, similar selectivity was not observed when targeting rs362273 or rs362307. Furthermore, HD myeloid cells are hyper-reactive compared to control. Allele-selective suppression of either wild-type or mutant HTT produced a significant, equivalent reduction in the cytokine response of HD myeloid cells to LPS, suggesting that wild-type HTT has a novel immune function. We demonstrate a sequential therapeutic process comprising genotyping and mutant HTT-linkage of SNPs, followed by personalised allele-selective suppression in a small patient cohort. We further show that allele-selectivity in ex vivo patient cells is highly SNP-dependent, with implications for clinical trial target selection.
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000120651 7001_ $$aPfister, Edith L$$b1
000120651 7001_ $$aLiu, Wanzhao$$b2
000120651 7001_ $$aAndre, Ralph$$b3
000120651 7001_ $$0P:(DE-He78)4d320583e7adaedcb8374d787eb6bfe5$$aTräger, Ulrike$$b4$$udkfz
000120651 7001_ $$aKennington, Lori A$$b5
000120651 7001_ $$aLo, Kimberly$$b6
000120651 7001_ $$aDijkstra, Sipke$$b7
000120651 7001_ $$aMacdonald, Douglas$$b8
000120651 7001_ $$aOstroff, Gary$$b9
000120651 7001_ $$aAronin, Neil$$b10
000120651 7001_ $$aTabrizi, Sarah J$$b11
000120651 773__ $$0PERI:(DE-600)2615211-3$$a10.1038/srep46740$$gVol. 7, p. 46740 -$$p46740 -$$tScientific reports$$v7$$x2045-2322$$y2017
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