Genotyping and targeting of specific alleles is feasible in Huntington’s disease (HD). This could allow for personalized treatment and preservation of the wild-type (wt) huntingtin (HTT) protein in heterozygous patients.
Why this matters
In most patients, HD is caused by heterozygous mutations in the HTT gene. The mutant HTT (mHTT) allele is abnormally expanded due to cytosine-adenine-guanine (CAG) repeats, but patients retain one wtHTT allele.
The wtHTT protein may be important for normal brain and neuroprotective functions and may offer advantages if preserved by allele-specific therapy.
Two nonpathogenic single-nucleotide polymorphisms (SNP1 and SNP2) have been reported in 65–70% of HD patients with European ancestry.
Heterozygosity for mHTT and SNP1, SNP2, or both, would allow for allele-specific treatment.
Mapping the genetic suitability of patients for allele-specific treatment will help to demonstrate whether this is a feasible therapeutic option.