Oligodendroglial progenitor cell therapy limits central neurological deficits in mice with metachromatic leukodystrophy.
This work describes the first successful oligodendrocyte-based cell therapy for presymptomatic arylsulfatase A (ARSA) null neonate mice, a murine model for human metachromatic leukodystrophy (MLD). We found that oligodendrocyte progenitors (OLPs) engrafted and survived into adulthood when transplanted in the neonatal MLD brain. Transplanted cells integrated nondisruptively, did not produce tumors, and survived as proteolipid protein- and MBP-positive postmitotic myelinating oligodendrocytes (OLs) intermingled with endogenous MLD OLs within the adult MLD white matter. Transplanted MLD mice had reduced sulfatide accumulation in the CNS, increased brain ARSA activity, and full prevention of the electrophysiological and motor deficits that characterize untreated MLD mice. Our results provide direct evidence that healthy OLPs can tolerate the neurotoxic accumulation of sulfatides that evolves during the postnatal development of the MLD brain and contribute to OL cell replacement to limit the accumulation of sulfatides and the evolution of CNS defects in this lysosomal storage disease mouse model.
Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy. givogri.maria@hsr.it
Maria I
MI
Givogri
Francesca
F
Galbiati
Stefania
S
Fasano
Stefano
S
Amadio
Laura
L
Perani
Daniela
D
Superchi
Pablo
P
Morana
Ubaldo
U
Del Carro
Sergio
S
Marchesini
Riccardo
R
Brambilla
Lawrence
L
Wrabetz
Ernesto
E
Bongarzone
D000818:Animals; D000831:Animals, Newborn; D016380:Brain Tissue Transplantation / Q000379:methods* / Q000639:trends; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D002553:Cerebroside-Sulfatase / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006085:Graft Survival / Q000502:physiology; D007966:Leukodystrophy, Metachromatic / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D004676:Myelin Basic Protein / Q000378:metabolism; D018991:Myelin Proteolipid Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism / Q000637:transplantation*; D033581:Stem Cell Transplantation / Q000379:methods* / Q000639:trends; D013433:Sulfoglycosphingolipids / Q000378:metabolism; D016896:Treatment Outcome
D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D013433:Sulfoglycosphingolipids; D002553:Cerebroside-Sulfatase