title: Ex vivo gene therapy with lentiviral vectors rescues adenosine deaminase (ADA)-deficient mice and corrects their immune and metabolic defects.
abstract: 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.
authors.affiliation: Via Olgettina 58, 20132, Milan, Italy. alessandro.aiuti@hsr.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mortellaro
authors.forename: Raisa Jofra
authors.initials: RJ
authors.lastname: Hernandez
authors.forename: Matteo M
authors.initials: MM
authors.lastname: Guerrini
authors.forename: Filippo
authors.initials: F
authors.lastname: Carlucci
authors.forename: Antonella
authors.initials: A
authors.lastname: Tabucchi
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanvito
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.forename: Clelia
authors.initials: C
authors.lastname: Di Serio
authors.forename: Luca
authors.initials: L
authors.lastname: Biasco
authors.forename: Antonia
authors.initials: A
authors.lastname: Follenzi
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
mesh_terms: D000243:Adenosine Deaminase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology*; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007694:Killer Cells, Natural / Q000276:immunology; D016086:Lentivirus / Q000235:genetics*; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013154:Spleen / Q000276:immunology
chemical_list: D000243:Adenosine Deaminase