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 Casiraghi; Jaap 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

doi:10.1126/science.1233158

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

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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 language	English (US)
Article number	1233158
Journal	Science
Volume	341
Issue number	6148
DOIs	https://doi.org/10.1126/science.1233158
State	Published - 2013

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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, W. B., Mehta, N. A. L., Cicalese, M. P., ... Naldini, L. (2013). Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science, 341(6148), [1233158]. https://doi.org/10.1126/science.1233158

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

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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.",

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

year = "2013",

doi = "10.1126/science.1233158",

language = "English (US)",

volume = "341",

journal = "Science",

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T1 - Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy

AU - Biffi, Alessandra

AU - Montini, Eugenio

AU - Lorioli, Laura

AU - Cesani, Martina

AU - Fumagalli, Francesca

AU - Plati, Tiziana

AU - Baldoli, Cristina

AU - Martino, Sabata

AU - Calabria, Andrea

AU - Canale, Sabrina

AU - Benedicenti, Fabrizio

AU - Vallanti, Giuliana

AU - Biasco, Luca

AU - Leo, Simone

AU - Kabbara, Nabil

AU - Zanetti, Gianluigi

AU - Rizzo, William B.

AU - Mehta, Nalini A.L.

AU - Cicalese, Maria Pia

AU - Casiraghi, Miriam

AU - Boelens, Jaap J.

AU - Del Carro, Ubaldo

AU - Dow, David J.

AU - Schmidt, Manfred

AU - Assanelli, Andrea

AU - Neduva, Victor

AU - Di Serio, Clelia

AU - Stupka, Elia

AU - Gardner, Jason

AU - Von Kalle, Christof

AU - Bordignon, Claudio

AU - Ciceri, Fabio

AU - Rovelli, Attilio

AU - Roncarolo, Maria Grazia

AU - Aiuti, Alessandro

AU - Sessa, Maria

AU - Naldini, Luigi

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

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SN - 0036-8075

VL - 341

JO - Science

JF - Science

IS - 6148

M1 - 1233158

ER -

Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy

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