Recipient organisationNIHR Cambridge Biomedical Research Centre
NIHR supportRecorded as supported by this research centre
PeriodMar 2025 — Sept 2025
In plain English
AI plain-English summary
A single blood sample and a day of questionnaires will determine which genetic variants travel alongside the mutant Huntington’s gene in 600 people worldwide, including 15 in the UK. Huntington’s disease is caused by a single mutated copy of the huntingtin gene. Treatments that selectively silence that mutant copy—while leaving the healthy copy intact—could slow or stop the disease without side effects from losing normal gene function. One promising strategy uses antisense oligonucleotides (ASOs) that target specific single nucleotide polymorphisms (SNPs) found only on the mutant allele. But no single SNP is present in all patients. This study maps which SNPs are linked to the mutant gene in different populations, so researchers can assemble a panel of ASOs that together cover the majority of patients. If successful, this work will provide the genetic data needed to design allele-selective therapies tailored to real-world patient populations. It will also help clinical trial planners recruit participants whose mutations match a given ASO, making future trials faster and more efficient. The research is fundamentally a genetic mapping exercise—it does not test any therapy itself—but without this map, allele-selective treatments cannot reach the patients who need them.
View original technical description
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 RocheResearch Summary; Version 1 dated 11 June 2024
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know