Arylsulfatase A Overexpressing Human iPSC-derived Neural Cells Reduce CNS Sulfatide Storage in a Mouse Model of Metachromatic Leukodystrophy.

摘要: Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disorder resulting from a functional deficiency of arylsulfatase A (ARSA), enzyme that catalyzes desulfation 3-O-sulfogalactosylceramide (sulfatide). Lack active ARSA leads to the accumulation sulfatide in oligodendrocytes, Schwann cells and some neurons triggers progressive demyelination, neuropathological hallmark MLD. Several therapeutic approaches have been explored, including replacement, autologous hematopoietic stem cell-based gene therapy, intracerebral therapy or delivery into central nervous system (CNS). However, long-term treatment blood-brain-barrier protected CNS remains challenging. Here we used MLD patient-derived induced pluripotent (iPSCs) generate self-renewing neuroepithelial astroglial progenitors for replacement. Following transplantation ARSA-overexpressing precursors ARSA-deficient mice observed significant reduction up distance 300 µm grafted cells. Our data indicate neural generated via reprogramming patients can be engineered ameliorate may thus serve as vehicle continuous supply MLD-affected brain tissue.