Non-viral gene delivery of the oncotoxic protein NS1 for treatment of hepatocellular carcinoma

Dominik Witzigmann; Philip Grossen; Cristina Quintavalle; Manuela Lanzafame; Susanne H Schenk; Xue-Ting Tran; Bernhard Englinger; Patrick Hauswirth; David Grünig; Sushilla van Schoonhoven; Stephan Krähenbühl; Luigi M Terracciano; Walter Berger; Salvatore Piscuoglio; Luca Quagliata; Jean Rommelaere; Jürg P F Nüesch; Jörg Huwyler

doi:10.1016/j.jconrel.2021.04.023

Non-viral gene delivery of the oncotoxic protein NS1 for treatment of hepatocellular carcinoma

J Control Release. 2021 Jun 10:334:138-152. doi: 10.1016/j.jconrel.2021.04.023. Epub 2021 Apr 22.

Authors

Dominik Witzigmann¹, Philip Grossen², Cristina Quintavalle³, Manuela Lanzafame³, Susanne H Schenk², Xue-Ting Tran², Bernhard Englinger⁴, Patrick Hauswirth², David Grünig⁵, Sushilla van Schoonhoven⁴, Stephan Krähenbühl⁵, Luigi M Terracciano³, Walter Berger⁴, Salvatore Piscuoglio⁶, Luca Quagliata³, Jean Rommelaere⁷, Jürg P F Nüesch⁷, Jörg Huwyler⁸

Affiliations

¹ Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland; Department of Biochemistry and Molecular Biology, University of British Columbia, Health Sciences Mall, V6T 1Z3 Vancouver, British Columbia, Canada.
² Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland.
³ Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, 4003 Basel, Switzerland.
⁴ Applied and Experimental Oncology, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
⁵ Division of Clinical Pharmacology and Toxicology, University Hospital of Basel, 4031 Basel, Switzerland.
⁶ Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, 4003 Basel, Switzerland; Visceral Surgery laboratory, Clarunis, Department of Biomedicine, 4031 Basel, Switzerland.
⁷ Infection, Inflammation and Cancer Program, Division of Tumor Virology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁸ Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland. Electronic address: joerg.huwyler@unibas.ch.

PMID: 33894304
DOI: 10.1016/j.jconrel.2021.04.023

Abstract

Hepatocellular carcinoma (HCC) is related to increasing incidence rates and poor clinical outcomes due to lack of efficient treatment options and emerging resistance mechanisms. The aim of the present study is to exploit a non-viral gene therapy enabling the expression of the parvovirus-derived oncotoxic protein NS1 in HCC. This anticancer protein interacts with different cellular kinases mediating a multimodal host-cell death. Lipoplexes (LPX) designed to deliver a DNA expression plasmid encoding NS1 are characterized using a comprehensive set of in vitro assays. The mechanisms of cell death induction are assessed and phosphoinositide-dependent kinase 1 (PDK1) is identified as a potential predictive biomarker for a NS1-LPX-based gene therapy. In an HCC xenograft mouse model, NS1-LPX therapeutic approach results in a significant reduction in tumor growth and extended survival. Data provide convincing evidence for future studies using a targeted NS1 gene therapy for PDK1 overexpressing HCC.

Keywords: Gene therapy; Hepatocellular carcinoma; Nanoparticles; Oncotoxic protein; Parvovirus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Hepatocellular* / therapy
Genetic Therapy
Liver Neoplasms* / therapy
Mice
Plasmids
Proteins

Substances

Proteins