title: Arylsulfatase A Overexpressing Human iPSC-derived Neural Cells Reduce CNS Sulfatide Storage in a Mouse Model of Metachromatic Leukodystrophy.
abstract: Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disorder resulting from a functional deficiency of arylsulfatase A (ARSA), an enzyme that catalyzes desulfation of 3-O-sulfogalactosylceramide (sulfatide). Lack of active ARSA leads to the accumulation of sulfatide in oligodendrocytes, Schwann cells and some neurons and triggers progressive demyelination, the neuropathological hallmark of MLD. Several therapeutic approaches have been explored, including enzyme replacement, autologous hematopoietic stem cell-based gene therapy, intracerebral gene therapy or cell-based gene delivery into the central nervous system (CNS). However, long-term treatment of the blood-brain-barrier protected CNS remains challenging. Here we used MLD patient-derived induced pluripotent stem cells (iPSCs) to generate long-term self-renewing neuroepithelial stem cells and astroglial progenitors for cell-based ARSA replacement. Following transplantation of ARSA-overexpressing precursors into ARSA-deficient mice we observed a significant reduction of sulfatide storage up to a distance of 300 µm from grafted cells. Our data indicate that neural precursors generated via reprogramming from MLD patients can be engineered to ameliorate sulfatide accumulation and may thus serve as autologous cell-based vehicle for continuous ARSA supply in MLD-affected brain tissue.
authors.affiliation: Institute of Reconstructive Neurobiology, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Doerr
authors.affiliation: Institute of Biochemistry and Molecular Biology, University of Bonn, Bonn, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Böckenhoff
authors.affiliation: Institute of Reconstructive Neurobiology, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ewald
authors.affiliation: Institute of Reconstructive Neurobiology, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Ladewig
authors.affiliation: Institute of Biochemistry and Molecular Biology, University of Bonn, Bonn, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Eckhardt
authors.affiliation: Institute of Biochemistry and Molecular Biology, University of Bonn, Bonn, Germany.
authors.forename: Volkmar
authors.initials: V
authors.lastname: Gieselmann
authors.affiliation: Institute of Biochemistry and Molecular Biology, University of Bonn, Bonn, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Matzner
authors.affiliation: Institute of Reconstructive Neurobiology, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Brüstle
authors.affiliation: Institute of Reconstructive Neurobiology, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Koch
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002454:Cell Differentiation; D002470:Cell Survival / Q000235:genetics; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D002490:Central Nervous System / Q000378:metabolism*; D002553:Cerebroside-Sulfatase / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency; D004195:Disease Models, Animal; D015870:Gene Expression; D023061:Gene Order; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics; D007966:Leukodystrophy, Metachromatic / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D013433:Sulfoglycosphingolipids / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D013433:Sulfoglycosphingolipids; D002553:Cerebroside-Sulfatase