Gene Therapy for Human Lung Adenocarcinoma Using a Suicide Gene Driven by a Lung-Specific Promoter Delivered by JC Virus-Like Particles

Abstract

Lung adenocarcinoma, the most commonly diagnosed type of lung cancer, has a poor prognosis even with combined surgery, chemotherapy, or molecular targeted therapies. Most patients are diagnosed with an in-operable advanced or metastatic disease, both pointing to the necessity of developing effective therapies for lung adenocarcinoma. Surfactant protein B (SP-B) has been found to be overexpressed in lung adenocarcinoma. In addition, it has also been demonstrated that human lung adenocarcinoma cells are susceptible to the JC polyomavirus (JCPyV) infection. Therefore, we designed that the JCPyV virus-like particle (VLP) packaged with an SP-B promoter–driven thymidine kinase suicide gene (pSPB-tk) for possible gene therapy of human lung adenocarcinoma. Plasmids expressing the GFP (pSPB-gfp) or thymidine kinase gene (pSPB-tk) under the control of the human SP-B promoter were constructed. The promoter’s tissue specificity was tested by transfection of pSPB-gfp into A549, CH27, and H460 human lung carcinoma cells and non-lung cells. The JCPyV VLP’s gene transfer efficiency and the selective cytotoxicity of pSPB-tk combined with ganciclovir (GCV) were tested in vitro and in a xenograft mouse model. In the current study, we found that SP-B promoter–driven GFP was specifically expressed in human lung adenocarcinoma (A549) and large cell carcinoma (H460) cells. JCPyV VLPs were able to deliver a GFP reporter gene into A549 cells for expression. Selective cytotoxicity was observed in A549 but not non-lung cells that were transfected with pSPB-tk or infected with pSPB-tk–carrying JCPyV VLPs. In mice injected with pSPB-tk–carrying JCPyV VLPs through the tail vein and treated with ganciclovir (GCV), a potent 80% inhibition of growth of human lung adenocarcinoma nodules resulted. The JCPyV VLPs combined with the use of SP-B promoter demonstrates effectiveness as a potential gene therapy against human lung adenocarcinoma.

In vivo and in vitro effects of hyperplasia suppressor gene on the proliferation and apoptosis of lung adenocarcinoma A549 cells

“…People suffering from lung adenocarcinoma usually have a poor prognosis or can also develop a resistant disease easily. Hence, there is an urgent need for advanced and valid therapeutic options [ 7 ]. The current therapeutic approaches for lung cancers include surgical removal of the tumor and adjacent lymph nodes, radio, and chemotherapy, but with limited efficacy [ 8 , 9 ].…”

Extracellular vesicles enhance the targeted delivery of immunogenic oncolytic adenovirus and paclitaxel in immunocompetent mice

“…The use of EVs as delivery system of OVs [39,63] or anti-neoplastic drugs [37,64] is a promising therapeutic strategy for primary and metastatic cancers. Nevertheless, the EVs biodistribution profile [65] and the potential side-effects associated with the systemic administration of OVs encapsulated in EVs are still poorly characterized. We have previously developed a strategy to encapsulate in EVs anti-cancer agents, including OVs and PTX together, showing, for the first time, that these formulations can be administered systemically: we reported a selective cancer cell tropism along with inhibition of cancer cell growth in nude mice, thus exploiting their potential use of these novel therapeutic concept also for the treatment of metastatic cancers [39].…”

Virus-like particle vaccines: immunology and formulation for clinical translation

“…Retention of the ability to deliver DNA/RNA requires conservation of intracellular processing pathways utilized by the parent virus for replication, or the induction of an alternative method of nucleic acid translocation. John Cunningham virus (JCV) VLP is a polyomavirus VLP that has received significant attention over its ability to facilitate gene delivery and genetic manipulation [77,94,95]. JCV is internalized by clathrin-dependent endocytosis upon binding to an undefined plethora of receptors and molecules known to include the serotonin receptor and sialic acid [96,97].…”