Journal Article

Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy

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

2013

Overview

Few disciplines in contemporary clinical research have experienced the high expectations directed at the gene therapy field. However, gene therapy has been challenging to translate to the clinic, often because the therapeutic gene is expressed at insufficient levels in the patient or because the gene delivery vector integrates near protooncogenes, which can cause leukemia (see the Perspective by Verma ). Biffi et al. ( 1233158 , published online 11 July) and Aiuti et al. ( 1233151 ; published online 11 July) report progress on both fronts in gene therapy trials of three patients with metachromatic leukodystrophy (MLD), a neurodegenerative disorder, and three patients with Wiskott-Aldrich syndrome (WAS), an immunodeficiency disorder. Optimized lentiviral vectors were used to introduce functional MLD or WAS genes into the patients' hematopoietic stem cells (HSCs) ex vivo, and the transduced cells were then infused back into the patients, who were then monitored for up to 2 years. In both trials, the patients showed stable engraftment of the transduced HSC and high expression levels of functional MLD or WAS genes. Encouragingly, there was no evidence of lentiviral vector integration near proto-oncogenes, and the gene therapy treatment halted disease progression in most patients. A longer follow-up period will be needed to further validate efficacy and safety. Lentivirus-mediated gene therapy produces encouraging results in three children with a rare lysosomal storage disease. [Also see Perspective by Verma ] 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.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Anatomy / Animal diseases / Bone marrow / Brain / Brain - pathology / Cerebroside-Sulfatase - genetics / Cognitive ability / Demyelinating diseases / disease course / DNA Damage / Evidence / Follow-Up Studies / Gene therapy / gene transfer / Genetic Engineering / Genetic Therapy - methods / Genetic Vectors - toxicity / Genetics / Genotoxicity / Hematopoietic Stem Cell Transplantation / Hematopoietic stem cells / Hematopoietic Stem Cells - metabolism / Humans / Image contrast / immunosuppression / Lentivirus / Leukemia / Leukodystrophy, Metachromatic - pathology / Leukodystrophy, Metachromatic - therapy / Magnetic Resonance Imaging / Medical treatment / Metachromatic leukodystrophy / Nervous system diseases / Neurodegenerative diseases / Patients / proto-oncogenes / RESEARCH ARTICLE SUMMARY / Stem cells / Transduction, Genetic / Treatment Outcome / Verma / Virus Integration