title: Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy.
abstract: Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disease caused by arylsulfatase A (ARSA) deficiency. Patients with MLD exhibit progressive motor and cognitive impairment and die within a few years of symptom onset. We used a lentiviral vector to transfer a functional ARSA gene into hematopoietic stem cells (HSCs) from three presymptomatic patients who showed genetic, biochemical, and neurophysiological evidence of late infantile MLD. After reinfusion of the gene-corrected HSCs, the patients showed extensive and stable ARSA gene replacement, which led to high enzyme expression throughout hematopoietic lineages and in cerebrospinal fluid. Analyses of vector integrations revealed no evidence of aberrant clonal behavior. The disease did not manifest or progress in the three patients 7 to 21 months beyond the predicted age of symptom onset. These findings indicate that extensive genetic engineering of human hematopoiesis can be achieved with lentiviral vectors and that this approach may offer therapeutic benefit for MLD patients.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy. biffi.alessandra@hsr.it
authors.forename: Alessandra
authors.initials: A
authors.lastname: Biffi
authors.forename: Eugenio
authors.initials: E
authors.lastname: Montini
authors.forename: Laura
authors.initials: L
authors.lastname: Lorioli
authors.forename: Martina
authors.initials: M
authors.lastname: Cesani
authors.forename: Francesca
authors.initials: F
authors.lastname: Fumagalli
authors.forename: Tiziana
authors.initials: T
authors.lastname: Plati
authors.forename: Cristina
authors.initials: C
authors.lastname: Baldoli
authors.forename: Sabata
authors.initials: S
authors.lastname: Martino
authors.forename: Andrea
authors.initials: A
authors.lastname: Calabria
authors.forename: Sabrina
authors.initials: S
authors.lastname: Canale
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Benedicenti
authors.forename: Giuliana
authors.initials: G
authors.lastname: Vallanti
authors.forename: Luca
authors.initials: L
authors.lastname: Biasco
authors.forename: Simone
authors.initials: S
authors.lastname: Leo
authors.forename: Nabil
authors.initials: N
authors.lastname: Kabbara
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zanetti
authors.forename: William B
authors.initials: WB
authors.lastname: Rizzo
authors.forename: Nalini A L
authors.initials: NA
authors.lastname: Mehta
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Cicalese
authors.forename: Miriam
authors.initials: M
authors.lastname: Casiraghi
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Boelens
authors.forename: Ubaldo
authors.initials: U
authors.lastname: Del Carro
authors.forename: David J
authors.initials: DJ
authors.lastname: Dow
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmidt
authors.forename: Andrea
authors.initials: A
authors.lastname: Assanelli
authors.forename: Victor
authors.initials: V
authors.lastname: Neduva
authors.forename: Clelia
authors.initials: C
authors.lastname: Di Serio
authors.forename: Elia
authors.initials: E
authors.lastname: Stupka
authors.forename: Jason
authors.initials: J
authors.lastname: Gardner
authors.forename: Christof
authors.initials: C
authors.lastname: von Kalle
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
authors.forename: Attilio
authors.initials: A
authors.lastname: Rovelli
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
authors.forename: Maria
authors.initials: M
authors.lastname: Sessa
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
mesh_terms: D001921:Brain / Q000473:pathology; D002553:Cerebroside-Sulfatase / Q000235:genetics*; D004249:DNA Damage; D005500:Follow-Up Studies; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000633:toxicity; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D016086:Lentivirus; D007966:Leukodystrophy, Metachromatic / Q000473:pathology / Q000628:therapy*; D008279:Magnetic Resonance Imaging; D014161:Transduction, Genetic; D016896:Treatment Outcome; D016662:Virus Integration
chemical_list: D002553:Cerebroside-Sulfatase