Investigational Assay for Haplotype Phasing of the Huntingtin Gene

Molecular Therapy. Methods & Clinical Development
Nenad SvrzikapaJaya Goyal

Abstract

Novel treatments for Huntington's disease (HD), a progressive neurodegenerative disorder, include selective targeting of the mutant allele of the huntingtin gene (mHTT) carrying the abnormally expanded disease-causing cytosine-adenine-guanine (CAG) repeat. WVE-120101 and WVE-120102 are investigational stereopure antisense oligonucleotides that enable selective suppression of mHTT by targeting single-nucleotide polymorphisms (SNPs) that are in haplotype phase with the CAG repeat expansion. Recently developed long-read sequencing technologies can capture CAG expansions and distant SNPs of interest and potentially facilitate haplotype-based identification of patients for clinical trials of oligonucleotide therapies. However, improved methods are needed to phase SNPs with CAG repeat expansions directly and reliably without need for familial genotype/haplotype data. Our haplotype phasing method uses single-molecule real-time sequencing and a custom algorithm to determine with confidence bases at SNPs on mutant alleles, even without familial data. Herein, we summarize this methodology and validate the approach using patient-derived samples with known phasing results. Comparison of experimentally measured CAG repeat lengths, heterozyg...Continue Reading

Citations

May 27, 2021·Acta Neuropathologica Communications·Sanjog R ChintalaphaniKishore R Kumar

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Datasets Mentioned

BETA
ND30259
GM02077f

Methods Mentioned

BETA
PCR
electrophoresis

Clinical Trials Mentioned

NCT03225833
NCT03225846

Software Mentioned

SHAPEIT4
WhatsHap
Bowtie
Q2 Solutions Genomics
Sequel
Q2

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