Cell replacement therapies for Pediatric Leukoencephalopathic disorders

Currently cell replacement therapies have realistic therapeutic prospects. Numerous experimental studies in animals performed over the last two decades have shown that neuronal and glial cell transplants can improve function of the central neural system. In models of myelin disease, glial precursor cells (GPCs) isolated from fetal or adult tissue successively integrated and ameliorated the demyelinated regions. Hence treatment of leukodystrophic disorders, like Leukoencephalopathy with Vanishing White Matter (VWM), is particularly amenable to cell based strategies.

Embryonic stem (ES) cells, derived from the inner cell mass of the blastocyst, are self-renewing, pluripotent and can be manipulated in vitro to induce different cell types. For these properties, human ES cells would be an attractive tool in treating patients with various diseases and injuries. However, use of human embryos has ethical dilemmas. In addition, it is difficult to generate patient-specific ES cells. One way to get around these issues is to reprogram somatic cells to a pluripotent state, so called induced-pluripotent stem (iPS) cells.

Takahashi and Yamanaka (2006) were the first to show that incorporation of the four genes Oct3/4, Sox2, Klf4 and c-Myc in the nucleus of mouse fibroblasts could induce pluripotency. Afterwards the Yamanaka group also reported the successful reprogramming of human somatic cells into iPS cells. iPS cells have the morphology and growth properties of ES cells, express ES cell marker genes and have the ability to differentiate into all tissue types of the body.

If this approach would work in the human nervous system, cell transplantation therapy would become an important new strategy in treating severe neurological disorders. To evaluate the prospects of iPS-derived transplant therapies for patients with VWM, we have the following aims 1) to reprogram fibroblasts of VWM patient into iPS cells, 2) to repair the genetic defect, 3) to differentiate repaired iPS cells into GPCs, and 4) to transplant iPS-derived GPCs into a mouse models for VWM.