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A Comprehensive Haplotype-Targeting Strategy for Allele-Specific HTT Suppression in Huntington Disease
Chris Kay1, Jennifer A Collins1, Nicholas S Caron1
1Center for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC V5Z4H4, Canada.
Insights
Huntington disease (HD) gene silencing strategies must target specific HTT haplotypes like A1 and A2. This ensures broad treatment for most affected individuals worldwide, particularly those with the prevalent A2 haplotype.
Area of Science:
- Genetics
- Neurodegenerative Disorders
- Pharmacogenomics
Background:
- Huntington disease (HD) is a fatal neurodegenerative disorder caused by a mutation in the HTT gene.
- Allele-selective gene silencing targeting HTT single nucleotide polymorphisms (SNPs) is a promising therapeutic strategy for HD.
Purpose of the Study:
- To extend comprehensive haplotype analysis of the HD mutation to diverse global populations.
- To identify optimal allele-specific gene silencing targets for worldwide Huntington disease treatment.
Main Methods:
- Comprehensive haplotype analysis of the HD mutation across various ancestral populations.
- Preclinical development of allele-specific antisense oligonucleotides (ASOs) targeting A2 haplotype SNPs.
Main Results:
- The HD mutation predominantly occurs on the A2 HTT haplotype across Southern European, South Asian, Middle Eastern, and admixed African ancestries.
- Targeting both A1 and A2 haplotypes is crucial for treating the majority of HD patients globally.
- Developed potent and selective ASOs targeting A2 haplotype SNPs for preclinical use.
Conclusions:
- Comprehensive haplotype analysis guides the rational selection of SNPs for allele-selective HTT silencing therapeutics.
- Current strategies may leave many HD patients untreated; parallel targeting of A1 and A2 haplotypes is essential.
- This research informs global strategies for allele-specific HTT silencing to maximize treated HD subjects.
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.
