Adeno-associated virus for cancer gene therapy.

Gene therapy for cancer offers novel treatment paradigms that will eventually lead to the destruction of tumor cells in patients with solid and hematopoietic malignancies. Major cancer gene therapy approaches that directly target tumor cells include chemosensitization, cytokine gene transfer, inactivation of proto-oncogene expression, replacement of defective tumor suppressor genes, and transduction of oncolytic viruses. A vast majority of these approaches have been attempted using adenoviral vectors and to a lesser extent, retroviral vectors. AAV-based vectors are recently emerging nonpathogenic vectors with potential for cancer gene therapy. AAV belongs to the group of human Parvovirus with a single-stranded DNA genome. The identification of AAV as a viral entity was reported 3 decades ago (1). For a replicative life cycle, AAV requires the presence of helper viruses and, hence, is also known as dependovirus. The helper functions are normally provided by adenovirus, herpesvirus, or vaccinia virus (2–4). In the absence of a helper virus, AAV integrates into host genome and establishes a latent cycle. When a latently infected cell encounters superinfection by any of the helper viruses, the integrated AAV genome rescues itself and undergoes a productive lytic cycle. Although a plethora of studies on the biology of AAV has been published in the past 3 decades, a realization of the potential of AAV as a gene-transfer vector began about 15 years ago (5, 6). Since then, a number of studies have shown significant progress in both the application of AAV-based vectors in gene therapy for a variety of diseases and the technology of high-titer, contamination-free rAAV production. Over the last few years, several in vivo studies using rAAV have shown efficacious results in the treatment of multiple diseases in animal models and in human clinical trials (7–17). Furthermore, rAAV does not encode any wt viral genes and, hence, is less immunogenic compared with other commonly used viral vectors (18, 19). Interestingly, wtAAV has also been identified as possessing antioncogenic properties (20–21). Although rAAV vectors are relatively less studied in cancer gene therapy, those reported thus far indicate their potential in cancer gene therapy targeting the tumor cells. In addition, although most of the above-mentioned strategies target tumor cells directly for increasing therapeutic benefit, targeting normal cells that regulate key events conducive to tumor growth is becoming a promising alternative in cancer therapy. For direct targeting of tumor cells, although a vector need not possess characteristics of long-term expression or the ability to integrate into the host genome, these features may be beneficial in strategies aimed at targeting normal cells, such as tumor endothelium, that exert a sustained control over tumor growth. In this regard, AAV remains a promising vector for cancer gene therapy. We describe here the biology and potential of rAAV as applied to direct and indirect cancer gene therapy approaches.