Leukodystrophies are a major source of handicap at all ages, but children are affected most. The team studies leukodystrophies since 1987. Initially their research was focused on describing new leukodystrophies and finding the underlying gene defects. Much of their research efforts have focused on the new leukodystrophy vanishing white matter (VWM), also called childhood ataxia with CNS hypomyelination (CACH). The disease may occur at all ages, but mainly affects young children (2-6 years). Children with VWM experience progressive neurological handicap and die early, usually a few years after diagnosis. There is no cure for VWM, but patients benefit from treatments that prevent fever and head trauma, as these events trigger a fast worsening of the disease.

Several years ago, the team founds that the gene defect for VWM lies in an enzyme complex that is crucial for protein synthesis. Since then, they study how the disease works (disease mechanisms), most of all to find openings for treatment. The group founds that cells in the white matter of the brain do not develop into mature cells that can execute their normal function of myelination and white matter repair properly. The problem with maturing in functional cells can well explain the severe white matter damage that is observed in patients. Their recent studies have demonstrated that a basic stress pathway is abnormally activated in VWM white matter cells. They have evidence that abnormal activation of this stress pathway may contribute to disease.

In the proposed study they will test the effects of three FDA-approved inhibitors of this stress pathway in representative disease models. The proposed work has the potential to open up new treatment options fast. Their vision on treatment of VWM is that effective cure of this complex disease is not achieved with any single therapeutic modality. The team believes that the treatment should target the disease at multiple levels, including reduction of stress pathways, reduction of the toxicity of the diseased white matter, provision of patient derived cured/healthy white matter cells (stem cell transplantation) and possibly gene therapy.

Project financed by ELA up to: 99 762 €