Targets and biomarkers in Huntington’s disease
HD is a devastating neurodegenerative disorder characterised by progressive loss of muscle coordination, cognitive decline and psychiatric problems. Slow advancement of the disease alongside the lack of stage-specific biomarkers have so far hampered HD clinical trials. Although the genetic basis of HD has been characterised, and involves a mutation in the Huntingtin gene (HTT), translation of this knowledge into therapeutic and diagnostic approaches has not been met with success. The limited information on HTT biology and on the cellular signalling pathways influenced by the HD mutation has hindered the identification of predictor molecules associated with disease progression. The scientific goal of the EU-funded Tamahud project was to discover therapeutically meaningful novel targets and biomarkers for HD. Project partners chose the method of RNA interference (RNAi) to perform high-throughput analysis of genes encoding pharmacologically tractable proteins. A number of candidate genes were identified whose expression inhibition offered protection against the HD mutation. Following stringent target validation, two target genes were selected for assay development and for generation of inhibitor drug-like compounds. State-of-the-art metabonomic analysis of the biomaterial, made available during the Tamahud project, is expected to verify the RNAi screen targets and identify further biomarkers predictive of disease onset and progression. The Tamahud project provided critical information on the molecular mechanisms associated with pathological consequences of the HD mutation. Coupled with the identified biomarkers, these findings have the potential to predict disease progression and form the basis for future intervention measures for HD.
