Gene therapy for human α1-antitrypsin deficiency in an animal model using SV40-derived vectors

Background & Aims: In most genetic diseases, the goal of gene therapy is to deliver a particular transgene; however, sometimes a deleterious gene product must be eliminated. Because of the promise of recombinant simian virus 40 (rSV40) vectors, we tested their ability to deliver a transgene and to target a transcript for destruction by direct administration of the vectors to the liver of an animal model for human alpha(1)-antitrypsin (alpha-AT) deficiency. Methods: Therapy of human alpha(1)-AT deficiency requires stable transduction of resting hepatocytes, both to deliver wild-type (xi-AT and to inhibit production of mutant alpha(1)-AT. Transgenic mice carrying the mutant human alpha(1)-AT PiZ allele were treated through an indwelling portal vein catheter with a simian virus 40 (SV40)-derived vector carrying a ribozyme designed to target the human transcript. Results: Treated transgenic mice showed marked decreases of human alpha(1)-AT messenger RNA and the protein in the liver, and serum levels of human oil-AT were decreased to 50% +/- 5% of pretreatment values 3-16 weeks after transduction. Moreover, when normal mice were treated with an SV40-derived vector containing a modified human alpha(1)-AT complementary DNA engineered to be resistant to cleavage by the alpha(1)-AT ribozyme, they expressed human alpha(1)-AT messenger RNA and protein in their livers and serum levels of human alpha(1)-AT remained >1 mug/mL for 1 year. Conclusions: These results represent the initial steps toward a novel approach to the gene therapy of alpha(1)-AT deficiency.