title: Image-aided Suicide Gene Therapy Utilizing Multifunctional hTERT-targeting Adenovirus for Clinical Translation in Hepatocellular Carcinoma.
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.
authors.affiliation: 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.
authors.forename: Yun-Hee
authors.initials: YH
authors.lastname: Kim
authors.affiliation: 1. Research Institute and hospital, National Cancer Center, Goyang 410-769, Republic of Korea.
authors.forename: Kyung Tae
authors.initials: KT
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Sang-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: 3. Division of Food Science and Culinary Arts, Food and Nutrition Major, Shinhan University, Uijeonbu 480-857, Republic of Korea.
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Hong
authors.affiliation: 1. Research Institute and hospital, National Cancer Center, Goyang 410-769, Republic of Korea.
authors.forename: Ju Young
authors.initials: JY
authors.lastname: Moon
authors.affiliation: 1. Research Institute and hospital, National Cancer Center, Goyang 410-769, Republic of Korea; 4. Department of Life Science, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Yoon
authors.affiliation: 1. Research Institute and hospital, National Cancer Center, Goyang 410-769, Republic of Korea.
authors.forename: Sukyoung
authors.initials: S
authors.lastname: Kim
authors.affiliation: 1. Research Institute and hospital, National Cancer Center, Goyang 410-769, Republic of Korea.
authors.forename: Eun Ok
authors.initials: EO
authors.lastname: Kim
authors.affiliation: 1. Research Institute and hospital, National Cancer Center, Goyang 410-769, Republic of Korea.
authors.forename: Se Hun
authors.initials: SH
authors.lastname: Kang
authors.affiliation: 1. Research Institute and hospital, National Cancer Center, Goyang 410-769, Republic of Korea.
authors.forename: Seok Ki
authors.initials: SK
authors.lastname: Kim
authors.affiliation: 1. Research Institute and hospital, National Cancer Center, Goyang 410-769, Republic of Korea; 4. Department of Life Science, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Sun Il
authors.initials: SI
authors.lastname: Choi
authors.affiliation: 1. Research Institute and hospital, National Cancer Center, Goyang 410-769, Republic of Korea.
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Goh
authors.affiliation: 1. Research Institute and hospital, National Cancer Center, Goyang 410-769, Republic of Korea.
authors.forename: Daehong
authors.initials: D
authors.lastname: Kim
authors.affiliation: 5. Department of Molecular Biology, Institute of Nanosensor and Biotechnology, Dankook University, Youngin 448-701, Republic of Korea.
authors.forename: Seong-Wook
authors.initials: SW
authors.lastname: Lee
authors.affiliation: 6. Department of Pathology, Dong-A University College of Medicine, Busan 602-714, Republic of Korea.
authors.forename: Mi Ha
authors.initials: MH
authors.lastname: Ju
authors.affiliation: 6. Department of Pathology, Dong-A University College of Medicine, Busan 602-714, Republic of Korea.
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Jeong
authors.affiliation: 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.
authors.forename: In-Hoo
authors.initials: IH
authors.lastname: Kim
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis* / Q000628:therapy*; D003952:Diagnostic Imaging / Q000379:methods; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D008807:Mice, Inbred BALB C; D014161:Transduction, Genetic; D016896:Treatment Outcome
keywords: cancer gene therapy; hepatocellular carcinoma; in vivo imaging; trans-splicing ribozyme