Project: Delineating the role of HTT Cis-Variants in the pathogenesis of Huntington disease
| Acronym | delCAA-HD (Reference Number: JPND2023-1822-096) |
| Project Topic | Huntington disease (HD) is a fatal neurodegenerative disorder without disease modifying therapies. It is well known that HD is always caused by an expanded CAG repeat in the huntingtin (HTT) gene leading to translation of a mutant HTT (mHTT) protein with an expanded polyglutamine stretch in the whole body. However, a number of clinical trials aiming to reduce levels of mHTT has so far failed. There is an inverse correlation between the length of the CAG repeat and the age of onset of typical motor symptoms in HD, that define the age of onset of the clinical HD today. Several large genetic studies including genome-wide and transcription-wide association studies have revealed important genetic modifiers of age-of-onset with cis-variants in HTT suggested to exert major effects. However, these variants have not been considered in the characterization of clinical cohorts of individuals with HD including in the development of or inclusion for clinical trials aiming to modify disease progression. Also, the impact of the genetic variants on the function of mHTT or on neuropathology is not known. Here we propose to fill an important and urgent gap in the knowledge of clinical genetics in HD. We will delineate the role of cis-variants in HTT identified in large -omics studies in the pathogenesis of HD (delCAA-HD) using a combination of clinical cohorts and novel animal and cellular models of HD. The clinical cohorts are composed of three different populations and the in-depth analyses of the cis-variants in HTT will lead to improved diagnostic assay accuracy, more accurate information for genetic counseling and enhanced sub-classification of HD that will facilitate further clinical trials. Proof-of-principle experiments of the functional and pathological effects of the genetic variants in HTT will be performed in novel immortalized and hPSC cellular models as well as in adeno-associated viral vector based animal models of HD in order to establish genetic-to-functional/pathological relationships. The delCAA-HD consortium is composed of five international leading research laboratories, each with recognized and complementary expertise in various aspects of HD, including pathogenesis, clinic, genetics, animal and hPSC models. This transnational collaboration will be crucial to successfully achieve the aims of this project. |
| Network | JPND |
| Call | Large scale analysis of OMICS data for drug-target finding in neurodegenerative diseases |