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: 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
• Journal: Science (New York, N.Y.) (Science) Vol. 341 Issue 6148 Pg. 1233158 (Aug 23 2013) ISSN: 1095-9203 [Electronic] United States
• PMID: 23845948 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cerebroside-Sulfatase

Topics

• 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