A Comprehensive Haplotype Targeting Strategy for Allele-Specific HTT Suppression in Huntington Disease
| Autor: | Hailey Findlay-Black, Nicholas S. Caron, Fiona Baine, Jennifer A. Collins, Chris Kay, Dulika S. Sumathipala, Luciana de Andrade Agostinho, Jacquie Greenberg, Amanda Krause, Carmen Lucia Antão Paiva, Ferdinando Squitieri, Vajira H. W. Dissanayake, Lorenzo Casal, Mario Cornejo-Olivas, Michael R. Hayden |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
haplotypes antisense Population Population genetics Neurogenetics Single-nucleotide polymorphism 030105 genetics & heredity Biology Polymorphism Single Nucleotide Article Haplogroup 03 medical and health sciences gene silencing Ethnicity Genetics therapeutics Humans Gene Silencing Allele education neurogenetics Alleles Genetics (clinical) Huntingtin Protein education.field_of_study allele-specific Haplotype population genetics rare diseases Oligonucleotides Antisense Huntington disease Prognosis 3. Good health purl.org/pe-repo/ocde/ford#3.01.02 [https] Huntington Disease 030104 developmental biology Haplotypes Mutation Mutation (genetic algorithm) haplogroups antisense oligonucleotides Trinucleotide Repeat Expansion preclinical development |
| Zdroj: | Am J Hum Genet |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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