title: Correction of metachromatic leukodystrophy in the mouse model by transplantation of genetically modified hematopoietic stem cells.
abstract: Gene-based delivery can establish a sustained supply of therapeutic proteins within the nervous system. For diseases characterized by extensive CNS and peripheral nervous system (PNS) involvement, widespread distribution of the exogenous gene may be required, a challenge to in vivo gene transfer strategies. Here, using lentiviral vectors (LVs), we efficiently transduced hematopoietic stem cells (HSCs) ex vivo and evaluated the potential of their progeny to target therapeutic genes to the CNS and PNS of transplanted mice and correct a neurodegenerative disorder, metachromatic leukodystrophy (MLD). We proved extensive repopulation of CNS microglia and PNS endoneurial macrophages by transgene-expressing cells. Intriguingly, recruitment of these HSC-derived cells was faster and more robust in MLD mice. By transplanting HSCs transduced with the arylsulfatase A gene, we fully reconstituted enzyme activity in the hematopoietic system of MLD mice and prevented the development of motor conduction impairment, learning and coordination deficits, and neuropathological abnormalities typical of the disease. Remarkably, ex vivo gene therapy had a significantly higher therapeutic impact than WT HSC transplantation, indicating a critical role for enzyme overexpression in the HSC progeny. These results indicate that transplantation of LV-transduced autologous HSCs represents a potentially efficacious therapeutic strategy for MLD and possibly other neurodegenerative disorders.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scienctific Institute, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Biffi
authors.forename: Michele
authors.initials: M
authors.lastname: De Palma
authors.forename: Angelo
authors.initials: A
authors.lastname: Quattrini
authors.forename: Ubaldo
authors.initials: U
authors.lastname: Del Carro
authors.forename: Stefano
authors.initials: S
authors.lastname: Amadio
authors.forename: Ilaria
authors.initials: I
authors.lastname: Visigalli
authors.forename: Maria
authors.initials: M
authors.lastname: Sessa
authors.forename: Stefania
authors.initials: S
authors.lastname: Fasano
authors.forename: Riccardo
authors.initials: R
authors.lastname: Brambilla
authors.forename: Sergio
authors.initials: S
authors.lastname: Marchesini
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D004195:Disease Models, Animal; D015316:Genetic Therapy; D018380:Hematopoietic Stem Cell Transplantation; D016086:Lentivirus / Q000235:genetics; D007966:Leukodystrophy, Metachromatic / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D009420:Nervous System / Q000166:cytology