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.
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.
Carbonaro
Denise A
DA
Division of Research Immunology/B.M.T., Childrens Hospital Los Angeles, California 90027, USA.
Jin
Xiangyang
X
Petersen
Denise
D
Wang
Xingchao
X
Dorey
Fred
F
Kil
Ki Soo
KS
Aldrich
Melissa
M
Blackburn
Michael R
MR
Kellems
Rodney E
RE
Kohn
Donald B
DB
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
D000243:Adenosine Deaminase