Gene therapy for human α 1-antitrypsin deficiency in an animal model using SV40-Derived vectors

YuYou Duan, Jian Wu, Jian Liang Zhu, Shu Ling Liu, Iwata Ozaki, David S. Strayer, Mark A Zern

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1222-1232
Number of pages11
JournalGastroenterology
Volume127
Issue number4
DOIs
StatePublished - Oct 2004

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Simian virus 40
Genetic Therapy
Animal Models
Catalytic RNA
Transgenes
Transgenic Mice
Liver
Messenger RNA
Inborn Genetic Diseases
Portal Vein
Serum
Hepatocytes
Proteins
Catheters
Complementary DNA
Alleles

ASJC Scopus subject areas

  • Gastroenterology

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Gene therapy for human α 1-antitrypsin deficiency in an animal model using SV40-Derived vectors. / Duan, YuYou; Wu, Jian; Zhu, Jian Liang; Liu, Shu Ling; Ozaki, Iwata; Strayer, David S.; Zern, Mark A.

In: Gastroenterology, Vol. 127, No. 4, 10.2004, p. 1222-1232.

Research output: Contribution to journalArticle

Duan, YuYou ; Wu, Jian ; Zhu, Jian Liang ; Liu, Shu Ling ; Ozaki, Iwata ; Strayer, David S. ; Zern, Mark A. / Gene therapy for human α 1-antitrypsin deficiency in an animal model using SV40-Derived vectors. In: Gastroenterology. 2004 ; Vol. 127, No. 4. pp. 1222-1232.
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