A major interest of my research is to study the biology of brain tumors, especially malignant gliomas and to seek an effective treatment using gene therapy techniques. Our previous work showed that genetically engineered herpes simplex virus(HSV-1) can selectively and effectively destroy gliomas in immunocompetent animal models, suggesting that the HSV-1 virus is potentially useful as a vector for the treatment of gliomas in human.
Our research in the recent years showed that infection with defective HSV-1 virus in the brain may not cause any long term toxicity. Furthermore, infection with defective HSV-1 virus may not reactivate the latently infected wild-type virus, which was one of the major concerns in using HSV-1 as a gene therapy agent since the majority of patients have been previously infected with the wild-type HSV-1 and reactivation of latent HSV-1 could be a potential risk of fetal encephalitis. The conclusion from our study is one of the major facts that convinced FDA for approving the first clinical trial using HSV-1 viral vector for the treatment of gliomas.
We have also investigated the immune response of the brain and glioma cells to HSV-1 infection. Our studies indicate that while a general immune response can be stimulated by the HSV-1 infection in the brain, the virus is able to block the presentation of major histocompatibility complex (MHC) molecules on infected glioma cells, which prevents the infected cells from the attack of the host immune system. We also found that interferon gamma can partially block the HSV-1 induced inhibition in cell surface expression of MHC. Therefore, deletion of a viral gene that is responsible for the inhibitory effect will enable the infected tumor cells to be recognized by immune cells for destruction.
Our study in glioma cell death caused by chemotherapy may involve two mechanisims depending on drug dosages. A low, clinical dosage induces a slow necrotic cell death while a high dosage results in a rapid, apoptotic cell death due to expression of bax. Most recently, a HSV viral vector carrying bax gene has been constructed. This viral vector effectively induces apoptosis in human glioma cells in vitro. This viral vector will be further tested in various animal tumor models. Our ultimate goal is to develop viral vectors carrying various therapeutic genes that can specifically destroy different malignant tumors, especially gliomas and prostate cancer.
Jia W, McDermott M, Tufaro G, Goldie J: Thymidine kinase defective herpes virus type-I selectively destroy gliomas in immunocompetent rats. J Natl Cancer Inst 86, 16:1209-1215, 1994.
Wang Q, Guo J and Jia W: Intracerebral recombinant HSV-1 vector does not reactivate latent HSV-1. Gene Therapy 4:1300-1304, 1997.
Yang DC, Song J, Bacchetti S, Rennie P. and Jia W: Herpes Simplex Virus Type-1 infection upregulates cellular promoters and telomerase activity in both tumor and non-tumor human cells. Gene Therapy 10(17):1494-502, 2003.
Jia W, Yan H, Bu B, Li G: Rh2, A compound extracted from Ginseng, hypersensitizes multidrug resistant tumor cells to chemotherapy. Can J Physiol Pharma 82:431-437, 2004.
Zhou Q and Jia W: Viral vectors for cancer gene therapy: Viral dissemination and tumor targeting (review). Current Gene Therapy, 2004 (in print).