UMMS Affiliation
Department of Medicine; RNA Therapeutics Institute; Program in Molecular Medicine
Publication Date
2017-04-24
Document Type
Article
Disciplines
Cell Biology | Immunity | Immunoprophylaxis and Therapy | Nervous System Diseases
Abstract
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.
Keywords
Diseases of the nervous system, Huntington's disease, Innate immune cells
Rights and Permissions
Copyright © 2017, The Author(s)
DOI of Published Version
10.1038/srep46740
Source
Sci Rep. 2017 Apr 24;7:46740. doi: 10.1038/srep46740. Link to article on publisher's site
Journal/Book/Conference Title
Scientific reports
Related Resources
PubMed ID
28436437
Repository Citation
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 Articles. https://doi.org/10.1038/srep46740. Retrieved from https://escholarship.umassmed.edu/oapubs/3135
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Included in
Cell Biology Commons, Immunity Commons, Immunoprophylaxis and Therapy Commons, Nervous System Diseases Commons