Efficient transduction of liver and muscle after in utero injection of lentiviral vectors with different pseudotypes

Tippi C. MacKenzie, Gary P. Kobinger, Neeltje A. Kootstra, Antoneta Radu, Miguel Sena-Esteves, Sarah Bouchard, James M. Wilson, Inder M. Verma, Alan W. Flake

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

Abstract

In this study we investigate the efficacy of lentiviral vectors of different pseudotypes for gene transfer to tissues of the preimmune fetus. BALB/c fetuses at 14-15 days' gestation received lentiviral vectors carrying the transgene lacZ under the control of the human cytomegalovirus (CMV) promoter by intramuscular (i.m.) or intrahepatic (i.h.) injection. We pseudotyped the lentiviral vectors with vesicular stomatitis virus (VSV-G), with Mokola virus, or with Ebola virus envelope glycoproteins. We harvested the pups at time points between 5 days and 9 months following injection and performed a detailed histologic assessment. The efficiency and distribution of transduction after in utero administration was highly dependent upon the route of administration and the pseudotype of vector used. Biodistribution studies showed widespread distribution of vector sequences in multiple tissues, albeit at very low levels, and transduced cells were found in significant numbers only in liver, heart, and muscle. Overall, VSV-G was the most efficient in transducing hepatocytes, whereas Mokola and Ebola were more efficient in transducing myocytes. Transduction of cardiomyocytes was observed after both i.m. and i.h. injection of all three vectors. Our findings of long-term transduction of skeletal myocytes and cardiomyocytes after in utero administration suggest a novel strategy for the treatment of congenital muscular dystrophies.

Original languageEnglish (US)
Pages (from-to)349-358
Number of pages10
JournalMolecular Therapy
Volume6
Issue number3
DOIs
StatePublished - Sep 1 2002
Externally publishedYes

Keywords

  • CMV promoter
  • Ebola
  • Fetal therapy
  • Lentivirus
  • Liver transduction
  • Mokola
  • Muscle transduction
  • Pseudotyping
  • VSV-G

ASJC Scopus subject areas

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

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