In vivo reprogramming of hTERT by trans-splicing ribozyme to target tumor cells.
Journal Article (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
Electronic International Standard Serial Number (EISSN)
- 1525-0024
Digital Object Identifier (DOI)
- 10.1038/sj.mt.6300282
Language
- eng
Conference Location
- United States