In vivo reprogramming of hTERT by trans-splicing ribozyme to target tumor cells.

Published

Journal Article

We have developed and validated a new tumor-targeting gene therapy strategy based upon the targeting and replacement of human telomerase reverse transcriptase (hTERT) RNA, using a trans-splicing ribozyme. By constructing novel adenoviral vectors harboring the hTERT-targeting trans-splicing ribozymes with the downstream reporter gene (Ad-Ribo-LacZ) or suicide gene (Ad-Ribo-HSVtk) driven by the cytomegalovirus (CMV) promoter, we demonstrated that this viral system selectively marks tumor cells expressing hTERT or sensitizes tumor cells to prodrug treatments. We confirmed that Ad-Ribo-LacZ successfully and selectively delivered a ribozyme that performed a highly specific trans-splicing reaction into hTERT-expressing cancer cells, both in vitro and in a peritoneal carcinomatosis nude mouse model. We also determined that the hTERT-specific expression of the suicide gene in the Ad-Ribo-HSVtk, and treatment with the corresponding prodrug, reduced tumor progression with almost the same efficacy as the strong constitutive CMV promoter-driven adenovirus, both in cancer cell lines and in nude mouse HT-29 xenografts. These observations provide the basis for a novel approach to cancer gene therapy, and demonstrate that trans-splicing ribozymes can be employed as targeting anti-cancer agents which recognize cancer-specific transcripts and reprogram them, thereby combating cancerous cells.

Full Text

Duke Authors

Cited Authors

  • Hong, S-H; Jeong, J-S; Lee, Y-J; Jung, H-I; Cho, K-S; Kim, C-M; Kwon, B-S; Sullenger, BA; Lee, S-W; Kim, I-H

Published Date

  • January 2008

Published In

Volume / Issue

  • 16 / 1

Start / End Page

  • 74 - 80

PubMed ID

  • 17700543

Pubmed Central ID

  • 17700543

Electronic International Standard Serial Number (EISSN)

  • 1525-0024

Digital Object Identifier (DOI)

  • 10.1038/sj.mt.6300282

Language

  • eng

Conference Location

  • United States