Publication Date:
2013-07-13
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Biffi, Alessandra -- Montini, Eugenio -- Lorioli, Laura -- Cesani, Martina -- Fumagalli, Francesca -- Plati, Tiziana -- Baldoli, Cristina -- Martino, Sabata -- Calabria, Andrea -- Canale, Sabrina -- Benedicenti, Fabrizio -- Vallanti, Giuliana -- Biasco, Luca -- Leo, Simone -- Kabbara, Nabil -- Zanetti, Gianluigi -- Rizzo, William B -- Mehta, Nalini A L -- Cicalese, Maria Pia -- Casiraghi, Miriam -- Boelens, Jaap J -- Del Carro, Ubaldo -- Dow, David J -- Schmidt, Manfred -- Assanelli, Andrea -- Neduva, Victor -- Di Serio, Clelia -- Stupka, Elia -- Gardner, Jason -- von Kalle, Christof -- Bordignon, Claudio -- Ciceri, Fabio -- Rovelli, Attilio -- Roncarolo, Maria Grazia -- Aiuti, Alessandro -- Sessa, Maria -- Naldini, Luigi -- TGT11B02/Telethon/Italy -- TGT11D02/Telethon/Italy -- New York, N.Y. -- Science. 2013 Aug 23;341(6148):1233158. doi: 10.1126/science.1233158. Epub 2013 Jul 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy. biffi.alessandra@hsr.it〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23845948" target="_blank"〉PubMed〈/a〉
Keywords:
Brain/pathology
;
Cerebroside-Sulfatase/*genetics
;
DNA Damage
;
Follow-Up Studies
;
Genetic Engineering
;
Genetic Therapy/*methods
;
Genetic Vectors/toxicity
;
*Hematopoietic Stem Cell Transplantation
;
Hematopoietic Stem Cells/*metabolism
;
Humans
;
Lentivirus
;
Leukodystrophy, Metachromatic/pathology/*therapy
;
Magnetic Resonance Imaging
;
Transduction, Genetic
;
Treatment Outcome
;
Virus Integration
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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