FREQUENCY OF SELECTED SINGLE NUCLEOTIDE POLYMORPHISMS IN PHASE WITH THE MUTANT AND WILD-TYPE HTT ALLELES IN HUNTINGTON DISEASE GENE EXPANSION CARRIERS

Research summary

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded cytosine-adenine-guanine (CAG) repeat in exon 1 on chromosome 4 of the huntingtin gene (HTT). This results in the production of a mutant huntingtin protein with an abnormally long CAG repeat leading to multiple downstream pathogenic effects and selective neuropathology. Those with greater than 39 CAG repeats are certain to develop the disease, while reduced penetrance is seen between 36 and 39 CAG repeats. Most individuals with HD are heterozygous for the CAG repeat, having one wild-type (wtHTT) and one abnormally expanded mutant HTT (mHTT) gene allele. Allele-selective targeting of the mHTT transcript offers a selective approach to HD treatment and has the potential advantage of keeping wtHTT expression intact. One approach is to target specific single nucleotide polymorphisms (SNPs) found on the mHTT allele. Although no single target SNP will allow treatment of all HD patients, in the future, the ultimate goal for the HD scientific community will be to have a panel of allele-specific antisense oligonucleotides (ASOs) that, in aggregate, will provide a therapeutic option for the majority of HD patients. Therefore, it is critical to better characterize the SNPs and their location, frequency, and geographical distribution in HD gene expansion carriers (HDGECs) to tailor future therapies and better design interventional studies. Globally, 600 participants (HDGECs) will be recruited and asked to provide demographic data, medical and medication history, and a blood sample for genotyping (including HTT gene sequencing to allow for phasing). The UK will look to recruit 15 participants at one site. The duration of the study for each individual is one day. The study is sponsored by F. Hoffmann- La Roche Research Summary; Version 1 dated 11 June 2024

Principal Investigator

Dr Richard Armstrong

Contact us

Email: dendron@ouh.nhs.uk

IRAS number

344821