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Blood, 1 November 2006, Vol. 108, No. 9, pp. 2979-2988. Prepublished online as a Blood First Edition Paper on July 11, 2006; DOI 10.1182/blood-2006-05-023507. This Article Full Text Full Text (PDF) Supplemental Tables All Versions of this Article: blood-2006-05-023507v1 108/9/2979    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mortellaro, A. Articles by Aiuti, A. Search for Related Content PubMed PubMed Citation Articles by Mortellaro, A. Articles by Aiuti, A. Related Collections Immunobiology Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Ex vivo gene therapy with lentiviral vectors rescues adenosine deaminase (ADA)–deficient mice and corrects their immune and metabolic defects Alessandra Mortellaro, Raisa Jofra Hernandez, Matteo M. Guerrini, Filippo Carlucci, Antonella Tabucchi, Maurilio Ponzoni, Francesca Sanvito, Claudio Doglioni, Clelia Di Serio, Luca Biasco, Antonia Follenzi, Luigi Naldini, Claudio Bordignon, Maria Grazia Roncarolo, and Alessandro Aiuti From the San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy; Department of Medicina Interna, Scienze Endocrino Metaboliche e Biochimica, University of Siena, Italy; Pathology Unit, Department of Oncology, San Raffaele H Scientific Institute, Milan, Italy; University Statistics Centre for Biomedical Sciences, Università Vita-Salute San Raffaele, Milan, Italy; and Università Vita-Salute San Raffaele, Milan, Italy. Adenosine deaminase (ADA) deficiency is caused by a purine metabolic dysfunction, leading to severe combined immunodeficiency (SCID) and multiple organ damage. To investigate the efficacy of ex vivo gene therapy with self-inactivating lentiviral vectors (LVs) in correcting this complex phenotype, we used an ADA–/– mouse model characterized by early postnatal lethality. LV-mediated ADA gene transfer into bone marrow cells combined with low-dose irradiation rescued mice from lethality and restored their growth, as did transplantation of wild-type bone marrow. Mixed chimerism with multilineage engraftment of transduced cells was detected in the long term in animals that underwent transplantation. ADA activity was normalized in lymphocytes and partially corrected in red blood cells (RBCs), resulting in full metabolic detoxification and prevention of severe pulmonary insufficiency. Moreover, gene therapy restored normal lymphoid differentiation and immune functions, including antigen-specific antibody production. Similar degrees of detoxification and immune reconstitution were obtained in mice treated early after birth or after 1 month of enzyme-replacement therapy, mimicking 2 potential applications for ADA-SCID. Overall, this study demonstrates the efficacy of LV gene transfer in correcting both the immunological and metabolic phenotypes of ADA-SCID and supports the future clinical use of this approach. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. B. Gaspar, A. Aiuti, F. Porta, F. Candotti, M. S. Hershfield, and L. D. Notarangelo How I treat ADA deficiency Blood, October 22, 2009; 114(17): 3524 - 3532. [Abstract] [Full Text] [PDF] B. Cassani, E. Montini, G. Maruggi, A. Ambrosi, M. Mirolo, S. Selleri, E. Biral, I. Frugnoli, V. Hernandez-Trujillo, C. Di Serio, et al. Integration of retroviral vectors induces minor changes in the transcriptional activity of T cells from ADA-SCID patients treated with gene therapy Blood, October 22, 2009; 114(17): 3546 - 3556. [Abstract] [Full Text] [PDF] A. V. Sauer, E. Mrak, R. Jofra Hernandez, E. Zacchi, F. Cavani, M. Casiraghi, E. Grunebaum, C. M. Roifman, M. C. Cervi, A. Ambrosi, et al. ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency Blood, October 8, 2009; 114(15): 3216 - 3226. [Abstract] [Full Text] [PDF] D. A. Carbonaro, X. Jin, D. Cotoi, T. Mi, X.-J. Yu, D. C. Skelton, F. Dorey, R. E. Kellems, M. R. Blackburn, and D. B. Kohn Neonatal bone marrow transplantation of ADA-deficient SCID mice results in immunologic reconstitution despite low levels of engraftment and an absence of selective donor T lymphoid expansion Blood, June 15, 2008; 111(12): 5745 - 5754. [Abstract] [Full Text] [PDF] M. K. Johansson, T. J. de Vries, T. Schoenmaker, M. Ehinger, A. C. M. Brun, A. Fasth, S. Karlsson, V. Everts, and J. Richter Hematopoietic stem cell-targeted neonatal gene therapy reverses lethally progressive osteopetrosis in oc/oc mice Blood, June 15, 2007; 109(12): 5178 - 5185. [Abstract] [Full Text] [PDF]

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