Hypomyelination with Brain stem and Spinal cord involvement and Leg spasticity (HBSL) is a leukodystrophy caused by defective cytoplasmic Aspartyl-tRNA synthetase (DARS). This enzyme is involved in building proteins, a fundamental biological process in bacteria and man alike. HBSL is caused by autosomal recessive mutations in the DARS gene and all point mutations identified result in neurological disease. HBSL is a potentially fatal spectrum disorder with no treatment and unclear etiology. In a pioneering effort our team at the University of New South Wales has generated the first mouse model of HBSL by introducing the same mutations causing HBSL in patients into the mouse Dars gene. Accurate animal models are the prerequisite to study the disease mechanisms and to develop and test treatments. Moreover, we have already identified that DARS expression in the brain of both mouse and man is enriched in neurons with far less expression in glia. This suggests that neurons might be the cells that a first line HBSL therapy should ideally target. In the first aim of this research proposal, we plan to engineer more mouse models that genetically mimic HBSL mutations and characterize them in order to model different forms of severity of HBSL. The second aim will be to develop a gene therapy platform for expression of a healthy copy of the DARS gene in mice. These experiments will help to identify the optimal route of delivery and the best timing for intervention. In the third aim we will perform a proof-of-concept gene therapy in the most relevant mouse model using optimized paramemters for DARS gene therapy identified in the previous aims. This project will yield an accurate animal model of HBSL that will be instrumental for preclinical testing of gene therapy or other treatment avenues. We propose that this study will generate data with high clinical relevance as our preclinical endpoints and gene therapy platform could easily be adapted for the treatment of other leukodystrophies caused by abnormal protein translation.

Project financed by ELA up to: 97 575 €