A Comprehensive Haplotype-Targeting Strategy for Allele-Specific HTT Suppression in Huntington Disease.

Autor:	Kay C; Center for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC V5Z4H4, Canada., Collins JA; Center for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC V5Z4H4, Canada., Caron NS; Center for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC V5Z4H4, Canada., Agostinho LA; PPGNEURO, Universidade Federal do Estado do Rio de Janeiro (UNIRIO), Rio de Janeiro, RJ 20270-004, Brazil; Centro Universitário UNIFAMINAS, Muriaé, MG 36880-000, Brazil; Hospital do Câncer de Muriaé, Muriaé, MG 36880-000, Brazil., Findlay-Black H; Center for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC V5Z4H4, Canada., Casal L; Center for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC V5Z4H4, Canada., Sumathipala D; Human Genetics Unit, University of Colombo, Colombo 00800, Sri Lanka., Dissanayake VHW; Human Genetics Unit, University of Colombo, Colombo 00800, Sri Lanka., Cornejo-Olivas M; Neurogenetics Research Center, Instituto Nacional de Ciencias Neurologicas, Lima 15003, Peru; Center for Global Health, Universidad Peruana Cayetano Heredia, Lima 15102, Peru., Baine F; Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2001, South Africa; Division of Human Genetics, Department of Pathology, University of Cape Town, Observatory 7925, South Africa., Krause A; Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2001, South Africa., Greenberg JL; Division of Human Genetics, Department of Pathology, University of Cape Town, Observatory 7925, South Africa., Paiva CLA; PPGNEURO, Universidade Federal do Estado do Rio de Janeiro (UNIRIO), Rio de Janeiro, RJ 20270-004, Brazil., Squitieri F; Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo (FG), Italy., Hayden MR; Center for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC V5Z4H4, Canada. Electronic address: mrh@cmmt.ubc.ca.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2019 Dec 05; Vol. 105 (6), pp. 1112-1125. Date of Electronic Publication: 2019 Nov 07.
DOI:	10.1016/j.ajhg.2019.10.011
Abstrakt:	Huntington disease (HD) is a fatal neurodegenerative disorder caused by a gain-of-function mutation in HTT. Suppression of mutant HTT has emerged as a leading therapeutic strategy for HD, with allele-selective approaches targeting HTT SNPs now in clinical trials. Haplotypes associated with the HD mutation (A1, A2, A3a) represent panels of allele-specific gene silencing targets for efficient treatment of individuals with HD of Northern European and indigenous South American ancestry. Here we extend comprehensive haplotype analysis of the HD mutation to key populations of Southern European, South Asian, Middle Eastern, and admixed African ancestry. In each of these populations, the HD mutation occurs predominantly on the A2 HTT haplotype. Analysis of HD haplotypes across all affected population groups enables rational selection of candidate target SNPs for development of allele-selective gene silencing therapeutics worldwide. Targeting SNPs on the A1 and A2 haplotypes in parallel is essential to achieve treatment of the most HD-affected subjects in populations where HD is most prevalent. Current allele-specific approaches will leave a majority of individuals with HD untreated in populations where the HD mutation occurs most frequently on the A2 haplotype. We further demonstrate preclinical development of potent and selective ASOs targeting SNPs on the A2 HTT haplotype, representing an allele-specific treatment strategy for these individuals. On the basis of comprehensive haplotype analysis, we show the maximum proportion of HD-affected subjects that may be treated with three or four allele targets in different populations worldwide, informing current allele-specific HTT silencing strategies. (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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