Theranostics 2016; 6(3):357-368. doi:10.7150/thno.13621

Research Paper

Image-aided Suicide Gene Therapy Utilizing Multifunctional hTERT-targeting Adenovirus for Clinical Translation in Hepatocellular Carcinoma

Yun-Hee Kim 1,2, Kyung Tae Kim 1, Sang-Jin Lee 1,2, Seung-Hee Hong 3, Ju Young Moon 1, Eun Kyung Yoon1,4, Sukyoung Kim1, Eun Ok Kim1, Se Hun Kang 1, Seok Ki Kim 1, Sun Il Choi1,4, Sung Ho Goh 1, Daehong Kim1, Seong-Wook Lee 5, Mi Ha Ju6, Jin Sook Jeong 6✉, In-Hoo Kim 1,2✉

1. Research Institute and hospital, National Cancer Center, Goyang 410-769, Republic of Korea
2. Graduate School of Cancer Science & Policy, National Cancer Center, Goyang 410-769, Republic of Korea
3. Division of Food Science and Culinary Arts, Food and Nutrition Major, Shinhan University, Uijeonbu 480-857, Republic of Korea
4. Department of Life Science, Ewha Womans University, Seoul 120-750, Republic of Korea
5. Department of Molecular Biology, Institute of Nanosensor and Biotechnology, Dankook University, Youngin 448-701, Republic of Korea
6. Department of Pathology, Dong-A University College of Medicine, Busan 602-714, Republic of Korea

Abstract

Trans-splicing ribozyme enables to sense and reprogram target RNA into therapeutic transgene and thereby becomes a good sensing device for detection of cancer cells, judging from transgene expression. Previously we proposed PEPCK-Rz-HSVtk (PRT), hTERT targeting trans-splicing ribozyme (Rz) driven by liver-specific promoter phosphoenolpyruvate carboxykinase (PEPCK) with downstream suicide gene, herpes simplex virus thymidine kinase (HSVtk) for hepatocellular carcinoma (HCC) gene therapy. Here, we describe success of a re-engineered adenoviral vector harboring PRT in obtaining greater antitumor activity with less off-target effect for clinical application as a theranostics. We introduced liver-selective apolipoprotein E (ApoE) enhancer to the distal region of PRT unit to augment activity and liver selectivity of PEPCK promoter, and achieved better transduction into liver cancer cells by replacement of serotype 35 fiber knob on additional E4orf1-4 deletion of E1&E3-deleted serotype 5 back bone. We demonstrated that our refined adenovirus harboring PEPCK/ApoE-Rz-HSVtk (Ad-PRT-E) achieved great anti-tumor efficacy and improved ability to specifically target HCC without damaging normal hepatocytes. We also showed noninvasive imaging modalities were successfully employed to monitor both how well a therapeutic gene (HSVtk) was expressed inside tumor and how effectively a gene therapy took an action in terms of tumor growth. Collectively, this study suggests that the advanced therapeutic adenoviruses Ad-PRT-E and its image-aided evaluation system may lead to the powerful strategy for successful clinical translation and the development of clinical protocols for HCC therapy.

Keywords: trans-splicing ribozyme, in vivo imaging, cancer gene therapy, hepatocellular carcinoma

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How to cite this article:
Kim YH, Kim KT, Lee SJ, Hong SH, Moon JY, Yoon EK, Kim S, Kim EO, Kang SH, Kim SK, Choi SI, Goh SH, Kim D, Lee SW, Ju MH, Jeong JS, Kim IH. Image-aided Suicide Gene Therapy Utilizing Multifunctional hTERT-targeting Adenovirus for Clinical Translation in Hepatocellular Carcinoma. Theranostics 2016; 6(3):357-368. doi:10.7150/thno.13621. Available from http://www.thno.org/v06p0357.htm