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Identification of early disease markers, novel pharmacologically tractable targets and small molecule phenotypic modulators in Huntington's Disease'

Final Report Summary - TAMAHUD (Identification of early disease markers, novel pharmacologically tractable targets and small molecule phenotypic modulators in Huntington's Disease)

There are no known ways of slowing or preventing the neurodegeneration, and clinical trials in man are hampered by the slow disease progression and the absence of suitable biomarkers of short-term progression. The genetics of HD is characterised by, and involves the expansion of a polyglutamine tract at the amino-terminus of the Huntingtin gene (HTT). However, the translation of this knowledge into therapeutic and diagnostic approaches is hampered by the limited knowledge of HTT biology, the paucity of information on how cellular signalling pathways interact with the HD mutation, and the lack of systematic and modern approaches aimed at identifying useful biopredictors of disease progression in individuals diagnosed with HD.

TAMAHUD addressed key areas of HD patient need, namely the discovery and development of therapeutically meaningful novel targets and biomarkers. The complementarity of the two objectives of TAMAHUD (target and lead discovery and biomarker discovery) was underscored by the need for therapeutically relevant lead compounds and for reliable means of assessing efficacy in both pre-clinical and clinical settings through the use of appropriate biomarkers. Ultimately, TAMAHUD aimed at delivering active lead molecules for further development and candidate biomarkers for clinical validation.

The two objectives (novel drug targets and biomarkers) were pursued in the two Work packages (WPs) in which TAMAHUD was organised. In WP1, High throughput-RNAi, focusing on genes encoding pharmacologically tractable proteins has been employed within a novel and robust HD cellular disease model to identify genes whose inhibition of expression is protective against the HD mutation. At the end of the first reporting period, a number of such targets have been identified that satisfy the criteria for progression to further target validation activities. Following these target validation activities, at least two targets are to be selected for assay development and primary screening activities, to identify drug-like compounds active on the target and efficacious against the HD mutation in cellular disease models. In parallel, in WP2, the biomaterial repository made available to the consortium from CAM is being investigated by TSL through state-of-the-art metabonomics approaches to identify biomarkers predictive of disease onset and progression.

The key unmet needs in HD are the lack of effective therapy currently available to patients, resulting from the limited understanding of the molecular mechanisms associated with the pathological consequences of the HD mutation, and the lack of easily accessible, rapid and predictive biomarkers for monitoring disease onset / progression in pre-clinical and clinical studies.

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