Category: HBSL

The leukodystrophy Hypomyelination with Brain stem and Spinal cord involvement and Leg spasticity, or short HBSL, is a devastating neurological condition caused by mutations of the DARS1 gene. DARS1 encodes an enzyme indispensably involved in protein synthesis in all cells and organisms. In most cases, HBSL has an early childhood onset and progressive disease course. Symptoms include motor impairments, hypomyelination, spasticity, ataxia, seizures, inability to walk unsupported, intellectual disability, and premature death. As with most leukodystrophies, no curative treatments exist. In a pioneering effort, our team at UNSW Sydney has created a set of accurate mouse disease models capturing the clinical spectrum of HBSL. We have further developed optimised viral gene therapy vectors with the ability to replace the mutated, malfunctioning DARS1 gene with a healthy and functional copy. This project brings together these two key innovative approaches to establish the effectiveness and safety of the HBSL gene therapy across the spectrum of disease severities. Our aim is to establish the proof-of-therapeutic-concept for a genetic treatment of HBSL, with the potential to halt and reverse neurological deficits arising from DARS1 deficiency. The project will further identify translation ready gene delivery vectors with the propensity for the human central nervous system to accelerate the development of an HBSL gene therapy pathway towards clinical studies. Our optimised HBSL gene therapy platform – paired with the identification of novel vectors for human gene delivery – will also advance our capabilities for the development of gene therapies for other forms of leukodystrophy, with broad extension for the treatment of genetic brain diseases in general.

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 €

In Hypomyelination with Brain stem and Spinal cord involvement and Leg spasticity (HBSL), the rate and degree of spread of symptoms throughout the body are linked to survival outcome. However, the cause for the pathology in HBSL is unknown. Using mini 3D brain oligodendrocytes generated from HBSL patient skin cells, we will study how interactions between oligodendrocytes and their support cells (neurons, astrocytes, and microglia) might lead to the development of disease over time. We will apply the cutting-edge technology of spatial transcriptomics to generate “cell-to-cell network maps” to inform whether we can manipulate cell networks to prevent demyelination. Finally, this research project aims to test nutraceutical supplementation as a therapeutic potential to ameliorate and or reverse established HBSL pathology.

Project financed by ELA up to: 65 846 €