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

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dc.contributor.author Kay, Chris
dc.contributor.author Collins, Jennifer A.
dc.contributor.author Caron, Nicholas S.
dc.contributor.author Agostinho, Luciana de Andrade
dc.contributor.author Findlay-Black, Hailey
dc.contributor.author Casal, Lorenzo
dc.contributor.author Sumathipala, Dulika
dc.contributor.author Dissanayake, Vajira H. W.
dc.contributor.author Cornejo-Olivas, Mario
dc.contributor.author Baine, Fiona
dc.contributor.author Krause, Amanda
dc.contributor.author Greenberg, Jacquie L.
dc.contributor.author Paiva, Carmen Lucia Antao
dc.contributor.author Squitieri, Ferdinando
dc.contributor.author Hayden, Michael R.
dc.date.accessioned 2019-12-06T21:02:55Z
dc.date.available 2019-12-06T21:02:55Z
dc.date.issued 2019
dc.identifier.uri https://hdl.handle.net/20.500.12866/7499
dc.description.abstract 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. en_US
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof urn:issn:1537-6605
dc.rights info:eu-repo/semantics/restrictedAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
dc.subject allele-specific en_US
dc.subject antisense en_US
dc.subject antisense oligonucleotides en_US
dc.subject gene silencing en_US
dc.subject haplogroups en_US
dc.subject haplotypes en_US
dc.subject Huntington disease en_US
dc.subject neurogenetics en_US
dc.subject population genetics en_US
dc.subject preclinical development en_US
dc.subject rare diseases en_US
dc.subject therapeutics en_US
dc.title A Comprehensive Haplotype Targeting Strategy for Allele-Specific HTT Suppression in Huntington Disease. en_US
dc.type info:eu-repo/semantics/article
dc.identifier.doi https://doi.org/10.1016/j.ajhg.2019.10.011
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.02.00 es_PE
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.01.02

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