Current Gene Therapy - Volume 8, Issue 2, 2008

Gene therapy involves the transfer of genetic information to a target cell to facilitate the production of therapeutic proteins and is now a realistic prospect as a cancer treatment. Gene transfer may be achieved through the use of both viral and non-viral delivery methods and the role of this method in the gene therapy of cancer has been demonstrated. Viruses represent an attractive vehicle for cancer gene therapy due to their high efficiency of gene delivery. Many viruses can mediate long term gene expression, while some are also capable of infecting both dividing and non-dividing cells. Given the broadly differing capabilities of various viral vectors, it is imperative that the functionality of the virus meets the requirements of the specific treatment. A number of immunogene therapy strategies have been undertaken, utilising a range of viral vectors, and studies carried out in animal models and patients have demonstrated the therapeutic potential of viral vectors to carry genes to cancer cells and induce anti-tumour immune responses. This review critically discusses the advances in the viral vector mediated delivery of immunostimulatory molecules directly to tumour cells, the use of viral vectors to modify tumour cells, the creation of whole cell vaccines and the direct delivery of tumour antigens in animal models and clinical trials, specifically in the context of the suitability of vector types for specific strategies.

The status of adipose tissue changes rapidly. From a simple filler tissue, it successively acquires the status of metabolic active tissue, endocrine tissue, plastic tissue, and finally that of a large reservoir of cells suitable for cell therapy and regenerative medicine. All throughout this story, our knowledge has been largely dependent on genetic tools and gene transfer. Now, the time has come where gene transfer in adipose derived cells can be envisioned, not only for understanding the role or importance of one gene, but also to engineer adipose derived cells for the purpose of therapy by delivering secreted products. In this paper, after a brief overview of adipose tissues, a large part will be devoted to the use of virusbased gene transfer in transducing adipose tissue and cells which reside therein. We also critically review the use of adipose “specific” promoters and the applications already described in the literature.

It has been hypothesized that cancers originate from a small population of cells with stem cell-like characteristics, including self-renewal and pluripotency. Such tumor-initiating cells, also referred to as cancer stem cells, are thought to account for relapses following seemingly successful treatments, because their slow turnover and capacity for expelling anti-tumor drugs leaves them untouched by conventional treatment regimens. Targeting of cancer stem cells might be key for improving survival and producing cures in patients with metastatic tumors. Viruses enter cells though infection and might therefore not be sensitive to stem cell resistance mechanisms. During the last decades, oncolytic adenoviruses have been shown to effectively kill cancer cells, by seizing control of their DNA replication machinery and utilizing it for the production of new virions, ultimately resulting in the rupture of the cell. Human safety data in cancer trials has been excellent even when the dose of administered adenovirus has been high. Future approaches include additional modifications of the adenoviral genome that prime them to attack cancer stem cells specifically, utilizing linage-specific cell surface markers, dysfunctional stem cell signaling pathways or up-regulated oncogenic genes. However, already existing oncolytic adenoviruses have displayed potential to efficiently kill not only differentiated cancer cells, but also tumor-initiating stem cells. Here, we review the current literature that supports the existence of cancer stem cells and discuss the potential of virotherapy for killing tumor-initiating cells.

Recombinants based on poxviruses have been used extensively as gene delivery systems to study many biological functions of foreign genes and as vaccines against many pathogens, particularly in the veterinary field. Based on safety record, efficient expression and ability to trigger specific immune responses, two of the most promising poxvirus vectors for human use are the attenuated modified vaccinia virus Ankara (MVA) and the Copenhagen derived NYVAC strains. Because of the scientific and clinical interest in these two vectors, here we review their biological characteristics, with emphasis on virus-host cell interactions, viral immunomodulators, gene expression profiling, virus distribution in animals, and application as vaccines against different pathogens and tumors.

Male infertility has been considered a major contributory factor to infertility. The causes of spermatogenetic failure found in most cases of male infertility remain largely idiopathic. Unfortunately, there is no effective treatment to improve spermatogenesis for idiopathic male infertility patients. Intracytoplasmic sperm injection (ICSI) is the current treatment of choice for severe male infertility and has brought the joy of childbearing to couples for whom it was previously impossible; however, several problems exist with this treatment. In addition, if there are no spermatozoa in the testis of these patients, they do not have paternity potential even if ICSI is conducted. Ultimately, fertilization is better in vivo than in vitro. Recently, on the other hand, gene transfer to sperm and testis has been developed to find more effective and simple methods to obtain transgenic animals. This technique has the potential to be the most useful approach for the future treatment of male infertility. In this review, we will give an overview of the recent advanced technique of gene transfer to sperm and testis, and discuss the future prospects of gene therapy for the treatment of male infertility. In conclusion, although more investigations on the mechanism of spermatogenesis and male infertility and the establishment of techniques for more efficient and safer gene transfer to the sperm and testis will be needed, gene therapy will enable a revolutionary advance for reproductive treatment and provide great benefit for patients with male infertility in the future.

Hematopoietic stem and progenitor cells (HSC) have been widely used in allogeneic transplant procedures, therefore their intrinsic characteristics, the biology of their niche in the bone marrow, and the mobilization and homing processes have been extensively investigated. With the development of gene therapy strategies, new therapeutic options based on autologous HSC have become available which may reduce the morbidity and mortality associated to allogeneic transplantation, but require an ex vivo manipulation of the cells to be corrected before re-infusion. For the success of these approaches it is necessary to optimize culture conditions in order to achieve efficient cell transduction while preserving the biological properties of the stem cells. We review here the factors critical for achieving efficient HSC transduction and maintenance of HSC stemness and homing capacity upon ex vivo culture. When HSC gene therapy is used in genetic disorders, permanent integration of therapeutic genes into the chromosomes of affected cells is needed. Indeed, by use of integrating vectors, such as retroviruses, gene therapy has met significant success in immunodeficiency syndromes characterized by a selective advantage of the transduced cells. However, retroviral integration can take place in stem cells at a variety of chromosomal sites, and examples have been reported of integration of therapeutic vectors causing cancer in patients. The clinical benefit arising from the long-term correction of the genetic defect, due to vector integration into the HSC genome, and the adverse consequences of these events are also here discussed, together with the new and challenging perspectives of HSC gene therapy.