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Oncolytic viruses: a novel form of immunotherapy

Prestwich, Robin J; Harrington, Kevin J; Pandha, Hardev S; Vile, Richard G; Melcher, Alan A; Errington, Fiona
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/2008 EN
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46.71%
Oncolytic viruses are novel anticancer agents, currently under investigation in Phase I–III clinical trials. Until recently, most studies have focused on the direct antitumor properties of these viruses, although there is now an increasing body of evidence that the host immune response may be critical to the efficacy of oncolytic virotherapy. This may be mediated via innate immune effectors, adaptive antiviral immune responses eliminating infected cells or adaptive antitumor immune responses. This report summarizes preclinical and clinical evidence for the importance of immune interactions, which may be finely balanced between viral and tumor elimination. On this basis, oncolytic viruses represent a promising novel immunotherapy strategy, which may be optimally combined with existing therapeutic modalities.

The Case of Oncolytic Viruses Versus the Immune System: Waiting on the Judgment of Solomon

Prestwich, Robin J.; Errington, Fiona; Diaz, Rosa M.; Pandha, Hardev S.; Harrington, Kevin J.; Melcher, Alan A.; Vile, Richard G.
Fonte: Mary Ann Liebert, Inc. Publicador: Mary Ann Liebert, Inc.
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.59%
The three-way interaction between oncolytic viruses, the tumor microenvironment, and the immune system is critical to the outcome of antitumor therapy. Classically, the immune system is thought to limit the efficacy of therapy, leading to viral clearance. However, preclinical and clinical data suggest that in some cases virotherapy may in fact act as cancer immunotherapy. In this review we discuss the ability of oncolytic viruses to alter the immunogenic milieu of the tumor microenvironment, and the role of innate and adaptive immunity in both restricting and augmenting therapy. Strategies to improve virotherapy by immunomodulation, including suppression or enhancement of the innate and adaptive responses, are discussed.

Cell Carriers for Oncolytic Viruses: Fed Ex for Cancer Therapy

Willmon, Candice; Harrington, Kevin; Kottke, Timothy; Prestwich, Robin; Melcher, Alan; Vile, Richard
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.67%
Oncolytic viruses delivered directly into the circulation face many hazards that impede their localization to, and infection of, metastatic tumors. Such barriers to systemic delivery could be overcome if couriers, which confer both protection, and tumor localization, to their viral cargoes, could be found. Several preclincal studies have shown that viruses can be loaded into, or onto, different types of cells without losing the biological activity of either virus or cell carrier. Importantly, such loading can significantly protect the viruses from immune-mediated virus-neutralizing activities, including antiviral antibody. Moreover, an impressive portfolio of cellular vehicles, which have some degree of tropism for tumor cells themselves, or for the biological properties associated with the tumor stroma, is already available. Therefore, it will soon be possible to initiate clinical protocols to test the hypopthesis that cell-mediated delivery can permit efficient shipping of oncolytic viruses from the loading bay (the production laboratory) directly to the tumor in immune-competent patients with metastatic disease.

Targeting Cancer-initiating Cells With Oncolytic Viruses

Cripe, Timothy P; Wang, Pin-Yi; Marcato, Paola; Mahller, Yonatan Y; Lee, Patrick WK
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.67%
Recent studies in a variety of leukemias and solid tumors indicate that there is significant heterogeneity with respect to tumor-forming ability within a given population of tumor cells, suggesting that only a subpopulation of cells is responsible for tumorigenesis. These cells have been commonly referred to as cancer stem cells (CSCs) or cancer-initiating cells (CICs). CICs have been shown to be relatively resistant to conventional anticancer therapies and are thus thought to be responsible for disease relapse. As such, they represent a potentially critical therapeutic target. Oncolytic viruses are in clinical trials for cancer and kill cells through mechanisms different from conventional therapeutics. Because these viruses are not susceptible to the same pathways of drug or radiation resistance, it is important to learn whether CICs are susceptible to oncolytic virus infection. Here we review the available data regarding the ability of several different oncolytic virus types to target CICs for destruction.

Oncolytic Viruses for Cancer Therapy: Overcoming the Obstacles

Wong, Han Hsi; Lemoine, Nicholas R.; Wang, Yaohe
Fonte: Molecular Diversity Preservation International (MDPI) Publicador: Molecular Diversity Preservation International (MDPI)
Tipo: Artigo de Revista Científica
Publicado em 11/01/2010 EN
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46.77%
Targeted therapy of cancer using oncolytic viruses has generated much interest over the past few years in the light of the limited efficacy and side effects of standard cancer therapeutics for advanced disease. In 2006, the world witnessed the first government-approved oncolytic virus for the treatment of head and neck cancer. It has been known for many years that viruses have the ability to replicate in and lyse cancer cells. Although encouraging results have been demonstrated in vitro and in animal models, most oncolytic viruses have failed to impress in the clinical setting. The explanation is multifactorial, determined by the complex interactions between the tumor and its microenvironment, the virus, and the host immune response. This review focuses on discussion of the obstacles that oncolytic virotherapy faces and recent advances made to overcome them, with particular reference to adenoviruses.

Oncolytic Viruses: Do They Have a Role in Anti-Cancer Therapy?

Prestwich, Robin J; Errington, Fiona; Harrington, Kevin J.; Pandha, Hardev S.; Selby, Peter; Melcher, Alan
Fonte: Libertas Academica Publicador: Libertas Academica
Tipo: Artigo de Revista Científica
Publicado em 09/02/2008 EN
Relevância na Pesquisa
46.86%
Oncolytic viruses are replication competent, tumor selective and lyse cancer cells. Their potential for anti-cancer therapy is based upon the concept that selective intratumoral replication will produce a potent anti-tumor effect and possibly bystander or remote cell killing, whilst minimizing normal tissue toxicity. Viruses may be naturally oncolytic or be engineered for oncolytic activity, and possess a host of different mechanisms to provide tumor selectivity. Clinical use of live replicating viruses is associated with a unique set of safety issues. Clinical experience has so far provided evidence of limited efficacy and a favourable toxicity profile. The interaction with the host immune system is complex. An anti-viral immune response may limit efficacy by rapidly clearing the virus. However, virally-induced cell lysis releases tumor associated antigens in a ‘dangerous’ context, and limited evidence suggests that this can lead to the generation of a specific anti-tumor immune response. Combination therapy with chemotherapy or radiotherapy represents a promising avenue for ongoing translation of oncolytic viruses into clinical practice. Obstacles to therapy include highly effective non-specific host mechanisms to clear virus following systemic delivery...

Ex Vivo Infection of Live Tissue with Oncolytic Viruses

Diallo, Jean-Simon; Roy, Dominic; Abdelbary, Hesham; De Silva, Naomi; Bell, John C.
Fonte: MyJove Corporation Publicador: MyJove Corporation
Tipo: Artigo de Revista Científica
Publicado em 25/06/2011 EN
Relevância na Pesquisa
46.76%
Oncolytic Viruses (OVs) are novel therapeutics that selectively replicate in and kill tumor cells1. Several clinical trials evaluating the effectiveness of a variety of oncolytic platforms including HSV, Reovirus, and Vaccinia OVs as treatment for cancer are currently underway2-5. One key characteristic of oncolytic viruses is that they can be genetically modified to express reporter transgenes which makes it possible to visualize the infection of tissues by microscopy or bio-luminescence imaging6,7. This offers a unique advantage since it is possible to infect tissues from patients ex vivo prior to therapy in order to ascertain the likelihood of successful oncolytic virotherapy8. To this end, it is critical to appropriately sample tissue to compensate for tissue heterogeneity and assess tissue viability, particularly prior to infection9. It is also important to follow viral replication using reporter transgenes if expressed by the oncolytic platform as well as by direct titration of tissues following homogenization in order to discriminate between abortive and productive infection. The object of this protocol is to address these issues and herein describes 1. The sampling and preparation of tumor tissue for cell culture 2. The assessment of tissue viability using the metabolic dye alamar blue 3. Ex vivo infection of cultured tissues with vaccinia virus expressing either GFP or firefly luciferase 4. Detection of transgene expression by fluorescence microscopy or using an In Vivo Imaging System (IVIS) 5. Quantification of virus by plaque assay. This comprehensive method presents several advantages including ease of tissue processing...

Oncolytic Viruses: The Power of Directed Evolution

Bauzon, Maxine; Hermiston, Terry W.
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.77%
Attempts at developing oncolytic viruses have been primarily based on rational design. However, this approach has been met with limited success. An alternative approach employs directed evolution as a means of producing highly selective and potent anticancer viruses. In this method, diverse viruses are grown under conditions that maximize diversity and then passaged under conditions meant to mimic those encountered in the human cancer microenvironment. Viruses which evolve to thrive under this selective pressure are isolated and tested to identify those with increased potency (i.e., ability to replicate and spread) and/or an increased therapeutic window (i.e., differentiated replication and spread on tumor versus normal cells), both of which have potential value but the latter of which defines an oncolytic virus. Using ColoAd1, an oncolytic virus derived by this approach as a prototype, we highlight the benefits of directed evolution, discuss methods to “arm” these novel viruses, and introduce techniques for their genetic modulation and control.

Systemic Delivery of Oncolytic Viruses: Hopes and Hurdles

Ferguson, Mark S.; Lemoine, Nicholas R.; Wang, Yaohe
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.8%
Despite recent advances in both surgery and chemoradiotherapy, mortality rates for advanced cancer remain high. There is a pressing need for novel therapeutic strategies; one option is systemic oncolytic viral therapy. Intravenous administration affords the opportunity to treat both the primary tumour and any metastatic deposits simultaneously. Data from clinical trials have shown that oncolytic viruses can be systemically delivered safely with limited toxicity but the results are equivocal in terms of efficacy, particularly when delivered with adjuvant chemotherapy. A key reason for this is the rapid clearance of the viruses from the circulation before they reach their targets. This phenomenon is mainly mediated through neutralising antibodies, complement activation, antiviral cytokines, and tissue-resident macrophages, as well as nonspecific uptake by other tissues such as the lung, liver and spleen, and suboptimal viral escape from the vascular compartment. A range of methods have been reported in the literature, which are designed to overcome these hurdles in preclinical models. In this paper, the potential advantages of, and obstacles to, successful systemic delivery of oncolytic viruses are discussed. The next stage of development will be the commencement of clinical trials combining these novel approaches for overcoming the barriers with systemically delivered oncolytic viruses.

Oncolytic viruses & their specific targeting to tumour cells

Singh, Prafull K.; Doley, Juwar; Kumar, G. Ravi; Sahoo, A.P.; Tiwari, Ashok K.
Fonte: Medknow Publications & Media Pvt Ltd Publicador: Medknow Publications & Media Pvt Ltd
Tipo: Artigo de Revista Científica
Publicado em /10/2012 EN
Relevância na Pesquisa
46.71%
Cancer is one of the major causes of death worldwide. In spite of achieving significant successes in medical sciences in the past few decades, the number of deaths due to cancer remains unchecked. The conventional chemotherapy and radiotherapy have limited therapeutic index and a plethora of treatment related side effects. This situation has provided an impetus for search of novel therapeutic strategies that can selectively destroy the tumour cells, leaving the normal cells unharmed. Viral oncotherapy is such a promising treatment modality that offers unique opportunity for tumour targeting. Numerous viruses with inherent anti-cancer activity have been identified and are in different phases of clinical trials. In the era of modern biotechnology and with better understanding of cancer biology and virology, it has become feasible to engineer the oncolytic viruses (OVs) to increase their tumour selectivity and enhance their oncolytic activity. In this review, the mechanisms by which oncolytic viruses kill the tumour cells have been discussed as also the development made in virotherapy for cancer treatment with emphasis on their tumour specific targeting.

Trial watch: Oncolytic viruses for cancer therapy

Vacchelli, Erika; Eggermont, Alexander; Sautès-Fridman, Catherine; Galon, Jérôme; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo
Fonte: Landes Bioscience Publicador: Landes Bioscience
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.94%
Oncolytic virotherapy is emerging as a promising approach for the treatment of several neoplasms. The term “oncolytic viruses” is generally employed to indicate naturally occurring or genetically engineered attenuated viral particles that cause the demise of malignant cells while sparing their non-transformed counterparts. From a conceptual standpoint, oncolytic viruses differ from so-called “oncotropic viruses” in that only the former are able to kill cancer cells, even though both display a preferential tropism for malignant tissues. Of note, such a specificity can originate at several different steps of the viral cycle, including the entry of virions (transductional specificity) as well as their intracellular survival and replication (post-transcriptional and transcriptional specificity). During the past two decades, a large array of replication-competent and replication-incompetent oncolytic viruses has been developed and engineered to express gene products that would specifically promote the death of infected (cancer) cells. However, contrarily to long-standing beliefs, the antineoplastic activity of oncolytic viruses is not a mere consequence of the cytopathic effect, i.e., the lethal outcome of an intense, productive viral infection...

Amalgamating Oncolytic Viruses to Enhance Their Safety, Consolidate Their Killing Mechanisms, and Accelerate Their Spread

Ayala-Breton, Camilo; Suksanpaisan, Lukkana; Mader, Emily K; Russell, Stephen J; Peng, Kah-Whye
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.76%
Oncolytic viruses are structurally and biologically diverse, spreading through tumors and killing them by various mechanisms and with different kinetics. Here, we created a hybrid vesicular stomatitis/measles virus (VSV/MV) that harnesses the safety of oncolytic MV, the speed of VSV, and the tumor killing mechanisms of both viruses. Oncolytic MV targets CD46 and kills by forcing infected cells to fuse with uninfected neighbors, but propagates slowly. VSV spreads rapidly, directly lysing tumor cells, but is neurotoxic and loses oncolytic potency when neuroattenuated by conventional approaches. The hybrid VSV/MV lacks neurotoxicity, replicates rapidly with VSV kinetics, and selectively targets CD46 on tumor cells. Its in vivo performance in a myeloma xenograft model was substantially superior to either MV or widely used recombinant oncolytic VSV-M51.

Trial Watch:: Oncolytic viruses for cancer therapy

Pol, Jonathan; Bloy, Norma; Obrist, Florine; Eggermont, Alexander; Galon, Jérôme; Cremer, Isabelle; Erbs, Philippe; Limacher, Jean-Marc; Preville, Xavier; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo
Fonte: Landes Bioscience Publicador: Landes Bioscience
Tipo: Artigo de Revista Científica
Publicado em 01/06/2014 EN
Relevância na Pesquisa
46.89%
Oncolytic viruses are natural or genetically modified viral species that selectively infect and kill neoplastic cells. Such an innate or exogenously conferred specificity has generated considerable interest around the possibility to employ oncolytic viruses as highly targeted agents that would mediate cancer cell-autonomous anticancer effects. Accumulating evidence, however, suggests that the therapeutic potential of oncolytic virotherapy is not a simple consequence of the cytopathic effect, but strongly relies on the induction of an endogenous immune response against transformed cells. In line with this notion, superior anticancer effects are being observed when oncolytic viruses are engineered to express (or co-administered with) immunostimulatory molecules. Although multiple studies have shown that oncolytic viruses are well tolerated by cancer patients, the full-blown therapeutic potential of oncolytic virotherapy, especially when implemented in the absence of immunostimulatory interventions, remains unclear. Here, we cover the latest advances in this active area of translational investigation, summarizing high-impact studies that have been published during the last 12 months and discussing clinical trials that have been initiated in the same period to assess the therapeutic potential of oncolytic virotherapy in oncological indications.

Oncolytic Viruses as Anticancer Vaccines

Woller, Norman; Gürlevik, Engin; Ureche, Cristina-Ileana; Schumacher, Anja; Kühnel, Florian
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
Publicado em 21/07/2014 EN
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46.76%
Oncolytic virotherapy has shown impressive results in preclinical studies and first promising therapeutic outcomes in clinical trials as well. Since viruses are known for a long time as excellent vaccination agents, oncolytic viruses are now designed as novel anticancer agents combining the aspect of lysis-dependent cytoreductive activity with concomitant induction of antitumoral immune responses. Antitumoral immune activation by oncolytic virus infection of tumor tissue comprises both, immediate effects of innate immunity and also adaptive responses for long lasting antitumoral activity, which is regarded as the most prominent challenge in clinical oncology. To date, the complex effects of a viral tumor infection on the tumor microenvironment and the consequences for the tumor-infiltrating immune cell compartment are poorly understood. However, there is more and more evidence that a tumor infection by an oncolytic virus opens up a number of options for further immunomodulating interventions such as systemic chemotherapy, generic immunostimulating strategies, dendritic cell-based vaccines, and antigenic libraries to further support clinical efficacy of oncolytic virotherapy.

Oncolytic Viruses in Head and Neck Cancer: A New Ray of Hope in the Management Protocol

Shilpa, PS; Kaul, R; Bhat, S; Sultana, N; Pandeshwar, P
Fonte: Medknow Publications & Media Pvt Ltd Publicador: Medknow Publications & Media Pvt Ltd
Tipo: Artigo de Revista Científica
Publicado em //2014 EN
Relevância na Pesquisa
46.64%
This paper intends to highlight the different types of oncolytic viruses (OVs), mechanism of tumor specificity, its safety, and various obstacles in the design of treatment and combination therapy utilizing oncotherapy. Search was conducted using the internet-based search engines and scholarly bibliographic databases with key words such as OVs, head and neck cancer, viruses, oral squamous cell carcinoma, and gene therapy. Revolutionary technologies in the field of cancer treatment have gone through a series changes leading to the development of innovative therapeutic strategies. Oncolytic virotherapy is one such therapeutic approach that has awaited phase III clinical trial validation. OVs are self-replicating, tumor selective and lyse cancer cells following viral infection. By modifying the viral genome, it is possible to direct their toxicity toward cancer cells. Viruses that are used for treatment of head and neck cancer are either naturally occurring or genetically modified. OVs are tumor selective and potential anticancer agents. Virotherapy may become the standard of care and part of combination therapy in the management of head and neck cancer in the future.

Oncolytic Viruses to Treat Ovarian Cancer Patients – a Review of Results From Clinical Trials

Hartkopf, A. D.; Fehm, T.; Wallwiener, M.; Lauer, U.
Fonte: Georg Thieme Verlag KG Publicador: Georg Thieme Verlag KG
Tipo: Artigo de Revista Científica
Publicado em /02/2012 EN
Relevância na Pesquisa
46.75%
Oncolytic viruses are replication competent “live” viruses. They infect tumor cells, replicate highly selective inside and thereby destroy them. Because of the enormous advances in the field of genetic engineering and biotechnology during the last decade, virotherapy is increasingly used within clinical trials and proved to be safe and effective. In particular, treatment of ovarian cancer patients is one main focus of research. On the one hand, this is due to the poor prognosis of this dismal entity, resulting in the urgent need for novel therapeutics. On the other hand, as ovarian cancer typically spreads within the peritoneal cavity, intraperitoneal administration of oncolytic viruses is feasible. This paper provides an overview of promising results from clinical trials to treat ovarian cancer patients with oncolytic viruses.

Immune cells: more than simple carriers for systemic delivery of oncolytic viruses

Eisenstein, Samuel; Chen, Shu-Hsia; Pan, Ping-Ying
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.76%
Oncolytic virotherapy on its own has numerous drawbacks, including an inability of the virus to actively target tumor cells and systemic toxicities at the high doses necessary to effectively treat tumors. Addition of immune cell-based carriers of oncolytic viruses holds promise as a technique in which oncolytic virus can be delivered directly to tumors in smaller and less toxic doses. Interestingly, the cell carriers themselves have also demonstrated antitumor effects, which can be augmented further by tailoring the appropriate oncolytic virus to the appropriate cell type. This review discusses the multiple factors that go into devising an effective, cell-based delivery system for oncolytic viruses.

The viral tropism of two distinct oncolytic viruses, reovirus and myxoma virus, is modulated by cellular tumor suppressor gene status

Kim, M; Williamson, CT; Prudhomme, J; Bebb, DG; Riabowol, K; Lee, PWK; Lees-Miller, SP; Mori, Y; Rahman, MM; McFadden, G; Johnston, RN
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.75%
Replication-competent oncolytic viruses hold great potential for the clinical treatment of many cancers. Importantly, many oncolytic virus candidates, such as reovirus and myxoma virus, preferentially infect cancer cells bearing abnormal cellular signaling pathways. Reovirus and myxoma virus are highly responsive to activated Ras and Akt signaling pathways, respectively, for their specificity for viral oncolysis. However, considering the complexity of cancer cell populations, it is possible that other tumor-specific signaling pathways may also contribute to viral discrimination between normal versus cancer cells. Because carcinogenesis is a multistep process involving the accumulation of both oncogene activations and the inactivation of tumor suppressor genes, we speculated that not only oncogenes but also tumor suppressor genes may have an important role in determining the tropism of these viruses for cancer cells. It has been previously shown that many cellular tumor suppressor genes, such as p53, ATM and Rb, are important for maintaining genomic stability; dysfunction of these tumor suppressors may disrupt intact cellular antiviral activity due to the accumulation of genomic instability or due to interference with apoptotic signaling. Therefore...

Oncolytic herpes simplex virus-based strategies: toward a breakthrough in glioblastoma therapy

Ning, Jianfang; Wakimoto, Hiroaki
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
46.67%
Oncolytic viruses (OV) are a class of antitumor agents that selectively kill tumor cells while sparing normal cells. Oncolytic herpes simplex virus (oHSV) has been investigated in clinical trials for patients with the malignant brain tumor glioblastoma for more than a decade. These clinical studies have shown the safety of oHSV administration to the human brain, however, therapeutic efficacy of oHSV as a single treatment remains unsatisfactory. Factors that could hamper the anti-glioblastoma efficacy of oHSV include: attenuated potency of oHSV due to deletion or mutation of viral genes involved in virulence, restricting viral replication and spread within the tumor; suboptimal oHSV delivery associated with intratumoral injection; virus infection-induced inflammatory and cellular immune responses which could inhibit oHSV replication and promote its clearance; lack of effective incorporation of oHSV into standard-of-care, and poor knowledge about the ability of oHSV to target glioblastoma stem cells (GSCs). In an attempt to address these issues, recent research efforts have been directed at: (1) design of new engineered viruses to enhance potency, (2) better understanding of the role of the cellular immunity elicited by oHSV infection of tumors...

Updates on current advances in gene therapy

Tani,Jowy; Faustine,B; Sufian,Jomiany Tani
Fonte: West Indian Medical Journal Publicador: West Indian Medical Journal
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/03/2011 EN
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46.69%
Gene therapy is the attempt to treat diseases by means of genetic manipulation. Numerous challenges remain to be overcome before it becomes available as a safe and effective treatment option. Retroviruses and adenoviruses are among the most commonly used viral vectors in trials. The retrovirus introduces the gene it carries into the target cell genome while the adenovirus introduces the gene into the target cell nucleus without incorporating it into the target cell genome. Other viral vectors such as adenoassociated viruses, pseudotyped viruses and herpes simplex viruses, are also gaining popularity. Proposed nonviral methods for gene transfer include physical methods and the employment of chemical vectors (lipoplexes, polyplexes and inorganic nanoparticles). Recent studies have investigated potential applications of gene therapy in correcting genetic diseases, treating malignant disorders and for treatment of other diseases. Trials on gene therapy for SCID and Leber's congenital amaurosis have achieved considerable success, but the widely publicized adverse reaction in Xlinked SCID patient receiving gene therapy raised concerns for safety profile of gene therapy. For that, several methods of improving safety and efficacy of gene therapy have been proposed. At present...