Gene therapy for human alpha1-antitrypsin deficiency in an animal model using SV40-derived vectors.
OBJECTIVE
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 alpha1-antitrypsin (alpha1-AT) deficiency.


METHODS
Therapy of human alpha1-AT deficiency requires stable transduction of resting hepatocytes, both to deliver wild-type alpha1-AT and to inhibit production of mutant alpha1-AT. Transgenic mice carrying the mutant human alpha1-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 alpha1-AT messenger RNA and the protein in the liver, and serum levels of human alpha1-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 alpha1-AT complementary DNA engineered to be resistant to cleavage by the alpha1-AT ribozyme, they expressed human alpha1-AT messenger RNA and protein in their livers and serum levels of human alpha1-AT remained >1 microg/mL for 1 year.


CONCLUSIONS
These results represent the initial steps toward a novel approach to the gene therapy of alpha1-AT deficiency.
Duan
Yu-You
YY
Transplant Research Institute, University of California, Davis Medical Center, Sacramento 95817, USA.
Wu
Jian
J
Zhu
Jian-Liang
JL
Liu
Shu-Ling
SL
Ozaki
Iwata
I
Strayer
David S
DS
Zern
Mark A
MA
D000818:Animals; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D016337:RNA, Catalytic / Q000235:genetics*; D013539:Simian virus 40 / Q000235:genetics*; D014161:Transduction, Genetic; D000515:alpha 1-Antitrypsin / Q000235:genetics*; D019896:alpha 1-Antitrypsin Deficiency / Q000628:therapy*
D016337:RNA, Catalytic; D000515:alpha 1-Antitrypsin