Development of recombinant adeno-associated virus and adenovirus cocktail system for efficient hTERTC27 polypeptide-mediated cancer gene therapy.

Abstract

The low in vivo transduction efficiency of recombinant adeno-associated virus (rAAV) and the undesirably strong immunogenicity of adenovirus (rAdv) have limited their clinical utilization in cancer gene therapy. We have previously demonstrated that intratumoral injection of rAAV expressing a C-terminal polypeptide of human telomerase reverse transcriptase (rAAV-hTERTC27) effectively inhibits the growth of glioblastoma xenografts in nude mice. To further improve its efficacy, we combined rAAV-hTERTC27 with rAdv and investigated the efficiency of the cocktail vectors in vivo. At a nontherapeutic dose (1 x 10(8) plaque-forming units (PFUs)), rAdv-null and rAdv-hTERTC27 were equipotent in enhancing the therapeutic efficacy of rAAV-hTERTC27 (1.5 x 10(11) v.g.), and complete tumor regression was achieved in 25% of the treated animals. Importantly, the combination of rAAV-hTERTC27 and a therapeutic dose (2.5 x 10(9) PFU) of rAdv-hTERTC27 significantly augmented the therapeutic effects and led to a 38% complete tumor regression rate. In vivo optical imaging also showed that rAAV-luc/rAdv-luc cocktail vectors could synergistically enhance the early transient and latent sustained expression of luciferase, as compared to rAdv-luc and rAAV-luc alone. These findings suggest that the combination of rAAV-hTERTC27 and a therapeutic dose of rAdv-hTERTC27 is potentially a promising treatment for glioblastoma, and the rAAV/rAdv cocktail vector system warrants further development for cancer gene therapy.

• Authors: Y Gao, S S M Ng, D H W Chau, H Yao, C Yang, K Man, P T Huang, C Huang, J J Huang, H-F Kung, M C Lin
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 15 Issue 11 Pg. 723-32 (Nov 2008) ISSN: 1476-5500 [Electronic] England
• PMID: 18535618 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• Luciferases
• TERT protein, human
• Telomerase

Topics

• Adenoviridae (genetics)
• Animals
• DNA Primers (genetics)
• Dependovirus (genetics)
• Gene Transfer Techniques
• Genetic Therapy (methods)
• Genetic Vectors (genetics)
• Glioblastoma (genetics, therapy)
• Humans
• Luciferases
• Mice
• Mice, Nude
• Reverse Transcriptase Polymerase Chain Reaction
• Telomerase (genetics)
• Transduction, Genetic (methods)