title: In vivo transduction by intravenous injection of a lentiviral vector expressing human ADA into neonatal ADA gene knockout mice: a novel form of enzyme replacement therapy for ADA deficiency.
abstract: Using a mouse model of adenosine deaminase-deficient severe combined immune deficiency syndrome (ADA-deficient SCID), we have developed a noninvasive method of gene transfer for the sustained systemic expression of human ADA as enzyme replacement therapy. The method of delivery is a human immunodeficiency virus 1-based lentiviral vector given systemically by intravenous injection on day 1 to 2 of life. In this article we characterize the biodistribution of the integrated vector, the expression levels of ADA enzyme activity in various tissues, as well as the efficacy of systemic ADA expression to correct the ADA-deficient phenotype in this mouse model. The long-term expression of enzymatically active ADA achieved by this method, primarily from transduction of liver and lung, restored immunologic function and significantly extended survival. These studies illustrate the potential for sustained in vivo production of enzymatically active ADA, as an alternative to therapy by frequent injection of exogenous ADA protein.
authors.affiliation: Division of Research Immunology/B.M.T., Childrens Hospital Los Angeles, California 90027, USA.
authors.forename: Denise A
authors.initials: DA
authors.lastname: Carbonaro
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Jin
authors.forename: Denise
authors.initials: D
authors.lastname: Petersen
authors.forename: Xingchao
authors.initials: X
authors.lastname: Wang
authors.forename: Fred
authors.initials: F
authors.lastname: Dorey
authors.forename: Ki Soo
authors.initials: KS
authors.lastname: Kil
authors.forename: Melissa
authors.initials: M
authors.lastname: Aldrich
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Kellems
authors.forename: Donald B
authors.initials: DB
authors.lastname: Kohn
mesh_terms: D000243:Adenosine Deaminase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005854:Germ Cells / Q000502:physiology; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016511:Severe Combined Immunodeficiency / Q000276:immunology / Q000628:therapy*; D014018:Tissue Distribution; D014161:Transduction, Genetic
chemical_list: D000243:Adenosine Deaminase