Grant: Team Grant: E-Rare Joint Transnational Call

Autosomal-recessive cerebellar ataxias (ARCAs) define a genetically heterogeneous group of rare degenerative disorders characterized by progressive cerebellar degeneration. Recent high-throughput sequencing techniques have allowed to identify an expanding number of novel rare ARCA genes, many identified by researchers from this consortium. However, the challenge is now to translate this genetic progress into preparing successful treatment trials. PREPARE will collate the complementary expertise from many ARCA centres and large supporting networks worldwide to facilitate the crucial translational steps from genetic fingerprinting to preclinical trials, FDA-conform outcome measures, and transnational trial-ready cohorts. To set this stage, it will establish a "translational pipeline" that will be applicable to several rare ARCAs alike. A shared prospective longitudinal registry will allow to aggregate ARCA cohorts of sufficient size and establish serial natural history data needed to launch treatment trials. Genetically still undefined ARCA patients will be screened by exome sequencing, thus maximizing the number of patients eligible for treatment trials and including definition of novel ARCA syndromes. To support causality of the novel genes and to identify pathway nodes susceptible to drug compounds, genetic fly models will be created. Trial outcome measures will be established by a stringent, FDA-conform international collaborative process, capturing the multisystemic complexity ARCA phenotypes and including extensive "„3-omics" biomarker screening. First preclinical trial protocols applicable to many ARCA types will be implemented in transgenic ARCA mice, including testing of drug compounds.