Human telomerase reverse transcriptase promoter-driven oncolytic adenovirus with E1B-19 kDa and E1B-55 kDa gene deletions

Joshua Doloff, David J. Waxman, Youssef Jounaidi

Research output: Contribution to journalArticle

Abstract

We constructed an oncolytic adenovirus, Adeno-hTERT-E1A, with deletions of the viral E1B, E3A, and E3B regions and insertion of a human telomerase reverse transcriptase (hTERT) promoter-driven early viral 1A (E1A) cassette that confers high transcriptional activity in multiple human tumor cell lines. The oncolytic potential of Adeno-hTERT-E1A was characterized in comparison with that of the E1B-55kDa- and E3B-region-deleted oncolytic adenovirus ONYX-015. Tumor cells infected with Adeno-hTERT-E1A expressed dramatically higher levels of E1A oncoprotein, underwent enhanced lysis, and displayed an earlier and higher apoptotic index than cells infected with ONYX-015. Despite the increase in virus-induced apoptotic death, Adeno-hTERT-E1A replicated and produced functional progeny leading to viral spread, but with reduced efficiency compared with ONYX-015, in particular in A549 cells. Virus-induced E1A expression, host cell apoptosis, viral hexon protein production, and DNA synthesis were markedly reduced in primary human hepatocytes after infection with Adeno-hTERT-E1A as compared with ONYX-015. The strong oncolytic activity of Adeno-hTERT-E1A in tumor cell culture translated into superior antitumor activity in vivo in an MDA-MB-231 solid tumor xenograft model. Adeno-hTERT-E1A thus has strong therapeutic potential and an improved safety profile compared with ONYX-015, which may lead to reduced toxicity in the clinic.

Original languageEnglish (US)
Pages (from-to)1383-1399
Number of pages17
JournalHuman gene therapy
Volume19
Issue number12
DOIs
StatePublished - Dec 1 2008

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Gene Deletion
Adenoviridae
Viruses
Neoplasms
human TERT protein
Oncogene Proteins
Viral Proteins
Tumor Cell Line
Heterografts
Hepatocytes
Cell Culture Techniques
ONYX015
Apoptosis
Safety
DNA
Infection

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Human telomerase reverse transcriptase promoter-driven oncolytic adenovirus with E1B-19 kDa and E1B-55 kDa gene deletions. / Doloff, Joshua; Waxman, David J.; Jounaidi, Youssef.

In: Human gene therapy, Vol. 19, No. 12, 01.12.2008, p. 1383-1399.

Research output: Contribution to journalArticle

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