Leukodystrophies are a major source of handicap at all ages, but children are affected most. We have studied leukodystrophies since 1987. Initially, our research focused on describing new leukodystrophies and finding the underlying gene defects. Much of our subsequent research efforts concerned the new leukodystrophy vanishing white matter (VWM), also called childhood ataxia with CNS hypomyelination (CACH). The disease occurs at all ages, but mainly starts in young children (2-6 years). Children with VWM experience progressive neurological handicap that prevent fever and head trauma, as these events trigger a fast worsening of the disease.

Several years ago we found that the gene defect for VWM lies in an enzyme complex that is crucial for protein synthesis. Since then we have studied how the disease works (disease mechanisms), most of all to find openings for potential treatment. We found 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 into functional cells can well explain the severe white matter damage that we observe in patients. Our recent studies have demonstrated that a basic stress pathway is abnormally activated in VWM white matter cells. We have evidence that abnormal activation of this stress pathway causes the disease. In the proposed study we will target and inhibit an important and toxic component of this stress pathway with antisense oligonucleotides and test the effects in a representative disease model. The proposed work has the potential to open up new treatment options relatively fast.

Our vision on treatment of VWM is that effective treatment of this complex disease is most likely not achieved with any single therapeutic modality. We think 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 healthy white matter cells and possibly gene therapy.

Project financed by ELA up to: 50 000 €