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| Home > Publications database > Allele-Selective Suppression of Mutant Huntingtin in Primary Human Blood Cells. > print |
| 001 | 120651 | ||
| 005 | 20240228145458.0 | ||
| 024 | 7 | _ | |a 10.1038/srep46740 |2 doi |
| 024 | 7 | _ | |a pmid:28436437 |2 pmid |
| 024 | 7 | _ | |a pmc:PMC5402279 |2 pmc |
| 024 | 7 | _ | |a altmetric:19549772 |2 altmetric |
| 037 | _ | _ | |a DKFZ-2017-01078 |
| 041 | _ | _ | |a eng |
| 082 | _ | _ | |a 000 |
| 100 | 1 | _ | |a Miller, James R C |b 0 |
| 245 | _ | _ | |a Allele-Selective Suppression of Mutant Huntingtin in Primary Human Blood Cells. |
| 260 | _ | _ | |a London |c 2017 |b Nature Publishing Group |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1510755625_10555 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a 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. |
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| 588 | _ | _ | |a Dataset connected to CrossRef, PubMed, |
| 700 | 1 | _ | |a Pfister, Edith L |b 1 |
| 700 | 1 | _ | |a Liu, Wanzhao |b 2 |
| 700 | 1 | _ | |a Andre, Ralph |b 3 |
| 700 | 1 | _ | |a Träger, Ulrike |0 P:(DE-He78)4d320583e7adaedcb8374d787eb6bfe5 |b 4 |u dkfz |
| 700 | 1 | _ | |a Kennington, Lori A |b 5 |
| 700 | 1 | _ | |a Lo, Kimberly |b 6 |
| 700 | 1 | _ | |a Dijkstra, Sipke |b 7 |
| 700 | 1 | _ | |a Macdonald, Douglas |b 8 |
| 700 | 1 | _ | |a Ostroff, Gary |b 9 |
| 700 | 1 | _ | |a Aronin, Neil |b 10 |
| 700 | 1 | _ | |a Tabrizi, Sarah J |b 11 |
| 773 | _ | _ | |a 10.1038/srep46740 |g Vol. 7, p. 46740 - |0 PERI:(DE-600)2615211-3 |p 46740 - |t Scientific reports |v 7 |y 2017 |x 2045-2322 |
| 909 | C | O | |o oai:inrepo02.dkfz.de:120651 |p VDB |
| 910 | 1 | _ | |a Deutsches Krebsforschungszentrum |0 I:(DE-588b)2036810-0 |k DKFZ |b 4 |6 P:(DE-He78)4d320583e7adaedcb8374d787eb6bfe5 |
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| 914 | 1 | _ | |y 2017 |
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