Mini-reviewAdeno-associated virus-mediated cancer gene therapy: Current status
Introduction
Cancer is still one of the most devastating diseases in the world. According to the Centers for Disease Control and Prevention (CDC), cancer incidence in the U.S.A. was 7,178,172 from 2006 to 2010, with mortality reaching 2,830,559 (http://www.cdc.gov/cancer/dcpc/data/). The existing therapeutic approaches, such as surgery, thermotherapy, chemotherapy, and radiotherapy, often have severe side effects, such as cytotoxicity to normal cells and strong host immune responses. Most critically, some cancers barely respond to these therapies [1], [2] and so alternative therapeutic approaches are needed. Gene therapy is one such attempt.
Gene therapy consists of three basic steps: (i) constructing a gene-carrying vector, (ii) transferring genes into target cancer cells with the vector, and (iii) expressing gene products to kill cancer cells. Constructing an effective vector for carrying therapeutic genes is essential for successful gene therapy. Gene-carrying vectors can be divided into two categories: non-viral vectors and viral vectors. Non-viral vectors, such as naked plasmids, microbubbles, nanoparticles, liposomes, and polymers, are safe, low-cost, and offer large insert size of genes; however, in vivo gene transfection and expression is inefficient and transient, despite low immunogenicity [3]. Viral vectors, such as adenoviral vectors, retroviral vectors, and lentiviral vectors, provide effective gene transduction and expression; however, they have several disadvantages, including high immunorejection, possible tumorigenicity, uncertain insertional mutagenesis, and limited constructive sizes for gene insertion. These disadvantages have prevented translation into clinical practice. Thus, it is imperative that gene-carrying vectors have (1) high transferring ability, (2) low immunorejection, and (3) long-term gene expression [4]. Adeno-associated virus (AAV) gene-carrying vectors meet these requirements.
AAVs for cancer gene therapy are superior to other gene vectors, with relatively low host immune response, weak toxicity, and long-term gene expression. AAVs have been successfully used to deliver and transfer a variety of therapeutic genes to cancer cells, including suicide genes, anti-angiogenic genes, and immune-related genes, to inhibit tumor initiation, growth, and metastasis. Herein, we review the development and recent advances of AAV-mediated cancer gene therapy, aiming to provide up-to-date information on the clinical application of AAV-based gene therapy.
Section snippets
Biology of AAVs
The adeno-associated virus, first discovered in the 1960s [5], is replication-deficient and belongs to the family of Parvoviridae. As the best known representative of all the AAVs, AAV2 contains a single stranded DNA genome comprising inverted terminal repeats (ITRs) and two open reading frames encoding replication and capsid proteins. The structure of AAV2 has been determined to 3-Å resolution (Fig. 1) [7]. Recently Gao et al. have obtained more than 120 novel primate AAVs [8]. The diverse
Advances of AAV vectors
The AAV based gene delivery systems are more attractive compared to other vectors. More benefits were discovered using AAV vectors such as more safety due to the lack of pathogenicity, more varied host and cell-type tropisms, long-term gene expression, ability to transfect both dividing and nondividing cells, absence of enormous immune response. Furthermore, the discovery of more novel AAV serotypes will further extend the scope of application of an AAV based gene delivery system.
However
Development of AAV-mediated gene therapy
A variety of preclinical experiments involving AAV-based gene therapies have been carried out. In 1984, a study reported the first construction of AAVs as vectors for gene transfer to eukaryotic cells [31], while the urgency of curing cystic fibrosis (CF) motivated the development of in vivo AAV-based gene therapy technology. By utilizing AAV vectors, scientists successfully transduced a therapeutic gene, cystic fibrosis transmembrane regulator (CFTR), into the airways of rabbits and monkeys.
AAV-mediated suicide gene therapy
Suicide gene therapy, also called gene-directed enzyme prodrug therapy (GDEPT) or molecular chemotherapy, is currently the most promising strategy for genetic treatment of different cancers. GDEPT relies on the intratumor delivery of a transgene encoding an enzyme, which then activates a systemically-delivered prodrug that inhibits DNA polymerase and blocks DNA replication in tumor cells. Among the candidate genes, the herpes simplex virus thymidine kinase gene/ganciclovir prodrug (HSV-tk/GCV)
Clinical trials of AAV-mediated gene therapy
Clinical applications of AAV-mediated gene therapies show great promise in the treatment of some life-threatening diseases, including hemophilia B, Leber congenital amaurosis, Parkinson's disease, and different cancers. Hemophilia B is an X-linked disorder. A clinical trial of AAV-mediated human factor IX (FIX) gene therapy was carried out in the first group of three patients in 2000, and FIX expression was detected in the muscles and circulating systems of the three subjects [112].
Concluding remarks
Compared to other vectors, AAV offers several advantages, including low pathogenicity, limited immunogenicity, efficient gene transfer, and long-lasting gene expression. Tremendous efforts have led to the great development of AAV-mediated gene therapy in different cancers. Although obstacles remain, promising preclinical and clinical results have opened new avenues for the efficient management of malignancy using AAV-integrated gene therapy technology.
Conflict of interest
All authors declare that there are no conflicts of interest.
Acknowledgments
This study was supported by National Basic Research Program of China (973 Program, 2014CB744505), US National Institutes of Health grant (R01EB012467), Natural Science Foundation of China (81401504, 81430040), Program for National Science and Technology Major Project of China (2013ZX10002004-001-005), Medical Science and Technology Project of Zhejiang Province (201461368), Qianjiang Talent Program of Zhejiang Province in China (2012R10027), Scientific Research Foundation of the Health Bureau of
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