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 α 1-antitrypsin (α 1-AT) deficiency. Methods:Therapy of human α 1-AT deficiency requires stable transduction of resting hepatocytes, both to deliver wild-type α 1-AT and to inhibit production of mutant α 1-AT. Transgenic mice carrying the mutant human α 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 α 1-AT messenger RNA and the protein in the liver, and serum levels of human α 1-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 α 1-AT complementary DNA engineered to be resistant to cleavage by the α 1-AT ribozyme, they expressed human α 1-AT messenger RNA and protein in their livers and serum levels of human α 1-AT remained >1 μg/mL for 1 year. Conclusions:These results represent the initial steps toward a novel approach to the gene therapy of α 1-AT deficiency.
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