Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy

Alessandra Biffi, Eugenio Montini, Laura Lorioli, Martina Cesani, Francesca Fumagalli, Tiziana Plati, Cristina Baldoli, Sabata Martino, Andrea Calabria, Sabrina Canale, Fabrizio Benedicenti, Giuliana Vallanti, Luca Biasco, Simone Leo, Nabil Kabbara, Gianluigi Zanetti, William B Rizzo, Nalini A L Mehta, Maria Pia Cicalese, Miriam CasiraghiJaap J. Boelens, Ubaldo Del Carro, David J. Dow, Manfred Schmidt, Andrea Assanelli, Victor Neduva, Clelia Di Serio, Elia Stupka, Jason Gardner, Christof Von Kalle, Claudio Bordignon, Fabio Ciceri, Attilio Rovelli, Maria Grazia Roncarolo, Alessandro Aiuti, Maria Sessa, Luigi Naldini

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number1233158
JournalScience
Volume341
Issue number6148
DOIs
StatePublished - Jan 1 2013

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Metachromatic Leukodystrophy
Cell- and Tissue-Based Therapy
Hematopoietic Stem Cells
Genetic Therapy
Cerebroside-Sulfatase
Genes
Lysosomal Storage Diseases
Genetic Engineering
Hematopoiesis
Age of Onset
Cerebrospinal Fluid
Molecular Biology
Enzymes

ASJC Scopus subject areas

  • General

Cite this

Biffi, A., Montini, E., Lorioli, L., Cesani, M., Fumagalli, F., Plati, T., ... Naldini, L. (2013). Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science, 341(6148), [1233158]. https://doi.org/10.1126/science.1233158

Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. / 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.

In: Science, Vol. 341, No. 6148, 1233158, 01.01.2013.

Research output: Contribution to journalArticle

Biffi, A, Montini, E, Lorioli, L, Cesani, M, Fumagalli, F, Plati, T, Baldoli, C, Martino, S, Calabria, A, Canale, S, Benedicenti, F, Vallanti, G, Biasco, L, Leo, S, Kabbara, N, Zanetti, G, Rizzo, WB, Mehta, NAL, Cicalese, MP, Casiraghi, M, Boelens, JJ, Del Carro, U, Dow, DJ, Schmidt, M, Assanelli, A, Neduva, V, Di Serio, C, Stupka, E, Gardner, J, Von Kalle, C, Bordignon, C, Ciceri, F, Rovelli, A, Roncarolo, MG, Aiuti, A, Sessa, M & Naldini, L 2013, 'Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy', Science, vol. 341, no. 6148, 1233158. https://doi.org/10.1126/science.1233158
Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013 Jan 1;341(6148). 1233158. https://doi.org/10.1126/science.1233158
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. / Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. In: Science. 2013 ; Vol. 341, No. 6148.
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AU - Ciceri, Fabio

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