The effect of age on hepatic gene transfer with self-inactivating lentiviral vectors in vivo

Frank Park, Kazuo Ohashi, Mark A. Kay

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

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 (3 1/2 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 α1,-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 μg 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 3 1/2-week-old mice administered lentiviral vectors expressing hAAT (50 μg p24/mouse) compared to the 7-week-old mice. Moreover, the incorporation of a matrix attachment region from immunoglobulin κ 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.

Original languageEnglish (US)
Pages (from-to)314-323
Number of pages10
JournalMolecular Therapy
Volume8
Issue number2
DOIs
StatePublished - Aug 1 2003

Fingerprint

Liver
Genes
Hepatocytes
Transgenes
Matrix Attachment Regions
Bacterial Genes
Lac Operon
Intravenous Administration
Hyperplasia
Immunoglobulins
Regeneration
Complementary DNA
Cell Proliferation
Staining and Labeling
Gene Expression
Serum

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

The effect of age on hepatic gene transfer with self-inactivating lentiviral vectors in vivo. / Park, Frank; Ohashi, Kazuo; Kay, Mark A.

In: Molecular Therapy, Vol. 8, No. 2, 01.08.2003, p. 314-323.

Research output: Contribution to journalArticle

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