Despite its devastating impacts on patients and their families, there are currently limited treatments options, and no cure for Huntington’s disease
Researchers from the University of Cambridge and University of Surrey have identified early biomarkers of disease during examinations of Huntington’s disease sheep still at a pre-symptomatic stage of the disease.
Up until this point, the five-year-old sheep had displayed no signs of the illness, but the comprehensive study identified clear metabolic changes in the animals carrying the genetic variant. These new findings reveal that Huntington’s disease affects important metabolic processes in the body prior to the appearance of physical symptoms.
Huntington’s disease affects more than 6,700 people in the UK. It is an incurable neurodegenerative disease: patients typically die 10-25 years after diagnosis.
The disease is caused by a mutation in the huntingtin gene. Genetic information is coded in DNA that is made up of a repeated string of four molecules known as nucleotides, or bases – A, C, G and T. Changes in the genetic code of the hutingtin gene leads directly to disease. The gene contains a repeated string of CAG bases: in healthy individuals, the CAG repeat is around 20 CAGs long, but if the repeat has 36 or more CAGs, an individual will develop Huntington’s disease. The sheep model of Huntington’s disease, which carries a CAG repeat in the disease-causing range, has been developed to increase knowledge about the condition.
During this study, researchers took blood samples from the normal and Huntington’s disease animals every two hours over a 24-hour period and assessed their metabolic profiles using a targeted metabolomics approach established at the University of Surrey. Unlike previous research in this area, which was affected by to external environmental factors that impacted upon metabolic profiling, sheep in this study were monitored in a well-controlled setting, negating any outside influences.
Blood measurements found startling differences in the biochemistry of the sheep carrying the disease-causing variant, compared to the normal sheep. Significant changes were observed in 89 of the 130 metabolites measured in their blood, with increased levels of the amino acids, arginine and citrulline, and decreases in sphingolipids and fatty acids that are commonly found in brain and nervous tissue.
The alterations in these metabolites, which include key components of the urea cycle and nitric oxide pathways (both vital body processes), suggest that both of these processes are dysregulated in the early stages of Huntington’s disease, and that the illness affects the body long before physical symptoms appear.
The identification of these biomarkers may help to track disease in pre-symptomatic patients, and could help researchers develop strategies to remedy the biochemical abnormalities.
Professor Debra Skene from the University of Surrey said: “Metabolic profiling has revealed novel biomarkers that will be useful to monitor Huntington’s disease progression.
“Our research shows that this disease affects the body in a number of ways before the tell-tale signs of Huntington’s disease become visible.”
Professor Jenny Morton from the University of Cambridge said: “Despite its devastating impacts on patients and their families, there are currently limited treatments options, and no cure for Huntington’s disease. The development of objective and reliable biomarkers that can be rapidly measured from blood samples becomes immeasurably important once clinical trials for therapies begin.
“The more we learn about this devastating illness the better chance we have of finding a cure.”
The research was funded by the CHDI Foundation and the Biotechnology and Biological Sciences Research Council.