Use of RNA interference to reduce
huntingtin protein (htt) expression in affected brain regions may provide an effective treatment for
Huntington disease (HD), but it remains uncertain whether suppression of both wild-type and mutant alleles in a heterozygous patient will provide more benefit than harm. Previous research has shown suppression of just the mutant allele is achievable using
siRNA targeted to regions of HD
mRNA containing single nucleotide polymorphisms (SNPs). To determine whether more than a minority of patients may be eligible for an allele-specific
therapy, we genotyped
DNA from 327 unrelated European Caucasian HD patients at 26 SNP sites in the HD gene. Over 86% of the patients were found to be heterozygous for at least one SNP among those tested. Because the sites are genetically linked, one cannot use the heterozygosity rates of the individual SNPs to predict how many sites (and corresponding allele-specific
siRNA) would be needed to provide at least one treatment possibility for this percentage of patients. By computing all combinations, we found that a repertoire of allele-specific
siRNA corresponding to seven sites can provide at least one allele-specific
siRNA treatment option for 85.6% of our sample. Moreover, we provide evidence that allele-specific
siRNA targeting these sites are readily identifiable using a high throughput screening method, and that allele-specific
siRNA identified using this method indeed show selective suppression of endogenous mutant htt
protein in fibroblast cells from HD patients. Therefore, allele-specific
siRNA are not so rare as to be impractical to find and use therapeutically.