Patient-Derived Glial Precursor Cell Therapy for Vanishing White Matter Disease (iNSC-WMD)

Childhood white matter disorders (CWMDs) constitute a large group of rare disorders. The so-called leukodystrophies represent the genetically determined progressive CWMDs. Within this research project we focus on the relatively prevalent leukodystrophy Vanishing White Matter (VWM), caused by recessive mutations in any of the five genes encoding translation initiation factor eIF2B (EIF2B1-5). VWM patients show increasing handicap and early death. Neuropathological findings indicate a selective disruption of glia in the brain white matter. There is no treatment available yet and cell replacement therapies have realistic therapeutic prospects. Experimental studies in animals have shown that cell transplants can improve brain function. The first Food and Drug Administration-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 suffering from VWM. We will generate induced neural stem cells (iNSCs) from VWM patient fibroblasts. To correct the eIF2B gene defect, iNSCs will be genetically repaired employing 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 white matter 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. This research project will be conducted by a consortium of internationally recognized researchers from Austria (Prof. Frank Edenhofer, Leopold-Franzens Universität Innsbruck), Switzerland (Prof. Gerald Schwank, Eidgenössische Technische Hochschule Zürich), coordinated by Prof. Marjo Van der Knaap (University Medical Center Amsterdam, Netherlands).

This research project aims at developing a novel cellular therapy to treat patients suffering from a particular form of leukodystrophy by combining stem cell and gene therapy strategies. Leukodystrophies are a group of disorders characterized by the degeneration of the white matter in the brain, caused by imperfect growth or development of the myelin sheath that covers nerve fibers. Patients show decreased motor function, muscle rigidity, and usually die early during childhood. There is no treatment available yet. Cell replacement therapies have realistic therapeutic prospects, however, transplantable functional cells are scarce. Within this research project we generated for the first time patient-specific induced neural stem cells (iNSCs) that can be expanded in the cell culture dish in a virtually unlimited manner. Subsequently, we plan to correct the gene defect that results in the deleterious effects by genetic manipulation employing the CRISPR/Cas9 genome editing technology. Genetically corrected iNSCs will be differentiated into glial precursor cells that have the potential to remyelinate axons in vitro and in vivo. Functionality and safety of iNSC-derived cells will be tested in animals that carry mutations modeling the disease. If a cell therapy approach will prove beneficial in this preclinical setting, our approach will become an important new strategy in treating numerous different leukodystrophies associated with severe handicap in patients.