The effect of age on hepatic gene transfer with self-inactivating lentiviral vectors in vivo.
It is known that cellular proliferation, by either compensatory regeneration or direct hyperplasia, can augment lentiviral vector transduction into hepatocytes in vivo. For this reason, the present study was designed to determine if adolescent mice (312 weeks of age), which still have relatively proliferating livers, would have differential transduction compared to older (7 weeks of age) mice. Self-inactivating lentiviral vectors containing the human alpha(1)-antitrypsin (hAAT) promoter driving the expression of either the bacterial lacZ gene or the hAAT cDNA were generated for these studies. We found that adolescent mice given lentiviral vectors expressing lacZ (50 micro g p24/mouse) via intravenous administration had a significantly higher level of hepatocyte transduction as measured by X-gal staining of liver sections compared to the 7-week-old mice. In addition, serum hAAT levels were nearly 40-fold higher in 312-week-old mice administered lentiviral vectors expressing hAAT (50 micro g p24/mouse) compared to the 7-week-old mice. Moreover, the incorporation of a matrix attachment region from immunoglobulin kappa significantly increased transduction of hepatocytes in vivo. Although there was a small reduction in the circulating levels of hAAT, likely due to an immune response against the transgene product, gene expression was sustained for the duration of the study (30 weeks in total). In conclusion, the present study strongly demonstrates that lentiviral vector transduction efficiency and transgene expression were significantly enhanced in adolescent compared to older mice.
Park
Frank
F
Department of Medicine and Department of Pharmacology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA. fpark@lsuhsc.edu
Ohashi
Kazuo
K
Kay
Mark A
MA
D000375:Aging / Q000502:physiology*; D000818:Animals; D001835:Body Weight; D002455:Cell Division; D045744:Cell Line, Tumor; D005697:Galactosides / Q000235:genetics; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D006801:Humans; D007211:Indoles; D007275:Injections, Intravenous; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D009928:Organ Specificity; D011401:Promoter Regions, Genetic / Q000235:genetics; D013997:Time Factors; D014161:Transduction, Genetic; D019076:Transgenes / Q000235:genetics*; D000515:alpha 1-Antitrypsin / Q000235:genetics
D005697:Galactosides; D007211:Indoles; D000515:alpha 1-Antitrypsin; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside