Inducible Caspase9-mediated suicide gene for MSC-based cancer gene therapy

• Type of Material: Article
• Authors: Filippo Rossignoli, University-Hospital of Modena and Reggio Emilia; Giulia Grisendi, University-Hospital of Modena and Reggio Emilia; Carlotta Spano, University-Hospital of Modena and Reggio Emilia; Giulia Golinelli, University-Hospital of Modena and Reggio Emilia; Alessandra Recchia, University of Modena and Reggio Emilia; Giulia Rovesti, University-Hospital of Modena and Reggio Emilia; Giulia Orsi, University-Hospital of Modena and Reggio Emilia; Elena Veronesi, University-Hospital of Modena and Reggio Emilia; Edwin Horwitz, Emory University; Massimo Dominici, University-Hospital of Modena and Reggio Emilia
• Language: English
• Date: 2019-02-01
• Publisher: Springer Nature [academic journals on nature.com]: Hybrid Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2018, Nature America, Inc., part of Springer Nature.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41417-018-0034-1
• Title of Journal or Parent Work: Cancer Gene Therapy
• ISSN: 0929-1903
• Volume: 26
• Issue: 1-2
• Start Page: 11
• End Page: 16
• Grant/Funding Information: This work was supported in parts by Associazione Italiana Ricerca Cancro (AIRC) IG 2012 Grant #12755 (MD, CS, GG); AIRC IG 2015 Grant #17326 (MD, CS, FR, GG); and the Associazione Sostegno Ematologia e Oncologia Pediatrica (ASEOP) (MD).
• Keywords: Life Sciences & Biomedicine; Science & Technology; Medicine, Research & Experimental; IMPROVE; Biotechnology & Applied Microbiology; APOPTOSIS; Oncology; T-CELLS; Genetics & Heredity; STROMAL CELLS; Research & Experimental Medicine; SAFETY SWITCH; MESENCHYMAL STEM-CELLS
• Research Categories: Health Sciences, Oncology; Biology, Genetics

Abstract

Cellular therapies based on mesenchymal stromal/stem cells (MSC) are promising strategies in regenerative medicine and oncology. Despite encouraging results, there is still some level of concerns on inoculating MSC in cancer patients. To face this issue, one possibility resides in engineering MSC by incorporating a suicide gene in order to control their fate once infused. Strategies based on Herpes Simplex Virus Thymidine Kinase (HSV-TK) and the Cytosine Deaminase genes have been developed and more recently a novel suicide gene, namely, iCasp9, has been proposed. This approach is based on a variant of human Caspase9 that binds with high affinity to a synthetic, bioinert small molecule (AP20187) leading to cell death. Based on this technology so far marginally applied to MSC, we tested the suitability of iCasp9 suicide strategy in MSC to further increase their safety. MSC have been transfected by a lentiviral vector carrying iCasp9 gene and then tested for viability after AP20187 treatment in comparison with mock-transfected cells. Moreover, accounting our anti-tumor approaches based on MSC expressing potent anti-cancer ligand TNF-Related Apoptosis-Inducing Ligand (TRAIL), we generated adipose MSC co-expressing iCasp9 and TRAIL successfully targeting an aggressive sarcoma type. These data show that anti-cancer and suicide mechanisms can coexist without affecting cells performance and hampering the tumoricidal activity mediated by TRAIL. In conclusion, this study originally indicates the suitability of combining a MSC-based anti-cancer gene approach with iCasp9 demonstrating efficiency and specificity.