iNSC-WMD

Childhood white matter (WM) disorders (CWMDs) constitute a large group of rare disorders. The “leukodystrophies” are the genetically determined progressive CWMDs. We focus on the relatively prevalent leukodystrophy “Vanishing White Matter” (VWM), caused by recessive mutations in any of the 5 genes encoding translation initiation factor eIF2B (EIF2B1-5). VWM patients show increasing handicap and early death. Neuropathologic findings indicate a selective disruption of glia in the brain WM. There is no treatment. Currently cell replacement therapies have realistic therapeutic prospects. Experimental studies in animals have shown that cell transplants can improve brain function. The first FDA-approved clinical trials for CWMDs have shown acceptable safety outcome after 1 year. Our aim is to investigate the prospects of cell replacement therapies for patients with VWM. We will generate induced neural stem cells (iNSCs) from VWM patient fibroblasts. To correct the EIF2B gene defect, iNSCs will be genetically repaired by the CRISPR/Cas9 genome editing technology. Subsequently, genetically-corrected iNSCs will be differentiated into glial precursor cells. Efficacy and safety of transplantation of the iNSC-derived cells will be tested in VWM mouse models. We recently developed 2 VWM mouse models, which show progressive neurological dysfunction and WM abnormalities closely resembling human VWM. If a cell therapy approach will prove beneficial in VWM mice, this will become an important new strategy in treating numerous different WMDs associated with severe handicap in patients.