Pluripotent stem cells, including human embryonic stem cells and induced pluripotent stem cells, have generated much excitement about their prospects for use in
cell transplantation therapies. This is largely attributable to their virtually unlimited growth potential, their ability to be precisely genetically altered in culture, and their utility for forming differentiated cell populations with potential clinical applications.
Lysosomal storage diseases such as
Sanfilippo syndrome (
MPS-IIIA) represent ideal candidate diseases for the evaluation of cell
therapies in the central nervous system (CNS). These diseases exhibit widespread pathology yet result from a single gene deficiency, in the case of
Sanfilippo syndrome the lysosomal
enzyme sulfamidase. The aim of this study was to investigate mouse embryonic stem (ES) cell-derived glial precursor cells as a vehicle for
sulfamidase delivery in the
MPS-IIIA mouse brain. In this study we have created a mouse ES cell line genetically modified to stably express and secrete high levels of human
sulfamidase and a protocol for the in vitro derivation of large numbers glial precursors from ES cells. Differentiation of
sulfamidase-expressing ES cells resulted in cell populations with sustained secretion of high levels of
sulfamidase, comprised primarily of glial precursor cells with minor contaminants of other neural cell phenotypes but not residual pluripotent cells. CNS implantation studies demonstrated that ES cell-derived glial precursor cells formed using this differentiation method were able to engraft and survive for at least 12 weeks following implantation. The percentage of engraftment was quantified in different regions of the brain in 2-, 4-, and 8-week-old normal and
MPS-IIIA mice. No
teratomas were observed in any of the cell-transplanted animals. The results of this study support the further investigation of
sulfamidase-expressing glial precursor cells as a vehicle for delivery of deficient
enzyme into the CNS of
MPS-IIIA mice.