Current Gene Therapy - Volume 7, Issue 6, 2007

Technical advances in transplant surgery and the development of powerful and effective immunosuppressive drugs have contributed to the success of organ transplantation as a medical treatment for patients with end-stage diseases. Associated with this procedure, however, is a dependence on life-long immunosuppressive drugs, which are required to prevent graft rejection. These agents render the patient susceptible to infections, tumors and various side affects. The ability to achieve tolerance to organ grafts would free transplant patients from lifelong dependency on pharmacological agents with harmful side effects. Several laboratories have shown that tolerance can be achieved by the induction of mixed cell chimerism and/or by molecular chimerism achieved by gene transfer techniques prior to graft placement. Molecular chimerism, induced by transplantation of autologous bone marrow expressing either allo- or xenoantigens has the potential to induce tolerance without the development of graft vs. host disease. The application of gene transfer techniques to induce chimerism has been shown to reshape the immune repertoire by mechanisms that include clonal deletion, the induction of central tolerance or generation of regulatory T cells that would eliminate the need for immunosuppressive drugs. Optimization of this methodology for clinical use could therefore revolutionize the field of transplantation. This review summarizes the recent studies which have compared the efficacy of different vectors, conditioning regimens, and transduction conditions leading to new and improved techniques for the application of gene therapy to induce chimerism and transplant tolerance to both allografts and xenografts.

Several studies utilize gene therapy technology to study the molecular mechanisms and therapeutic approaches to a variety of neurological diseases. Although gene therapy for neuro-oncology and neurodegenerative diseases has advanced to the clinical arena, those of cerebrovascular nature have remained in the experimental stage and demonstrate promising results. Before gene therapy in cerebrovascular disorders can be successful, various obstacles need to be addressed. In this review, we focus on the fundamentals of gene therapy adapted to cerebrovascular diseases, which include cerebral ischemia, post-subarachnoid hemorrhagic vasospasm, arteriovenous malformations, etc. We discuss: 1) the utilization of gene delivery vehicle, through viral, non-viral, or cellular vectors; 2) the routes and specific delivery of the vector to its target cells or tissue in the central nervous system; 3) the studies that have utilized in vivo and ex vivo gene delivery approaches and their success in the attenuation of cerebrovascular injuries; and finally 4) the future of gene therapy in this field.

Inherited retinal degeneration (IRD) affects around 1/3000 of the population in Europe and the United States. It is a diverse group of conditions that results from mutations in any one of over 100 different genes. Many of the genes have now been identified and their functions elucidated, providing a major impetus to develop gene-based treatments. Whilst gene replacement and gene silencing strategies offer prospects for the treatment of specific inherited retinal disorders, other disorders may be less amenable to these corrective approaches. These conditions include, in particular, those associated with abnormal retinal development and those in which retinal degeneration is advanced at birth. Furthermore, the development of individualized corrective gene therapy strategies for patients with disorders due to very rare mutations may be unfeasible. However, generic gene therapy strategies that aim not to correct the gene defect but to ameliorate its consequences offer the possibility of therapies that are widely applicable across a range of conditions. One potential strategy in these cases is to halt or delay the process of cell death, so that useful visual function can be maintained throughout the lifetime of an affected individual. It has been shown in variety of experimental models over the last three decades, that neurotrophic factors have the potential to delay neuronal apoptosis. Neurotrophic factors are small proteins which have relatively short half lives and a requirement for repeated administration has limited their clinical application. Since these proteins do not ordinarily cross the blood-brain barrier, previous approaches have relied upon intrathecal infusion pumps or similar complex devices to sustain elevated neurotrophin levels within the central nervous system (CNS). However, sustained delivery through viral vector mediated expression of genes encoding neurotrophic factors may circumvent the potential side effects of repeated administration. In this review we shall explore some of the concepts of neurotrophic gene therapy and how this might be applicable to preserving vision in inherited retinal degenerations.

Despite advances in surgery, radiotherapy, and the incorporation of novel systemic agents into treatment, longterm outcomes of patients with head and neck cancer remain unsatisfactory. The growing understanding of head and neck cancer biology suggests that targeting molecular events governing carcinogenesis or tumor progression may provide novel therapeutic approaches for head and neck cancer. Squamous cell carcinoma of the head and neck (SCCHN) is characterized by locoregional spread and is clinically accessible, making it an attractive target for intratumoral gene therapy, a potentially efficacious experimental treatment. Systemic delivery of gene therapy may be also possible, albeit with several limitations. In this review we will discuss the rationale, delivery methods, and accumulated clinical data with cancer gene therapy in SCCHN.

Most of the current hematopoietic stem cell (HSC) -directed gene therapy applications have focused on the replacement of defective or deficient genes in an autologous setting. More recently HSC gene therapy applications have also included the enhancement or improvement of HSC features. Allogeneic HSCs have been used to facilitate and improve allogeneic transplantation and to achieve tolerance to transplanted cells, tissues or organs. Different gene transfer approaches addressing a variety of immunomodulatory mediators contributing to graft tolerance or immunological ignorance may have a critical role in improving long-term graft survival. Allogeneic tissues are frequently recognized by allospecific T cells as foreign and are rapidly rejected in the absence of immunosuppression. The higher susceptibility to cancer and infectious diseases of immunosuppressed patients led to investigation of new therapies to induce graft-specific tolerance. Peripheral tolerance to allogeneic grafts can be achieved by a variety of mechanisms including clonal deletion, suppression caused by regulatory T cells and anergy induction associated with microchimerism effect. In the last decades, potential candidates to confer allograft protection were identified. In this review, we summarize ongoing strategies and developments in genetic manipulation of cells, tissues and organs for allogeneic transplantation including modulating the effector arm of the immune response.

Cytotoxic chemotherapy is associated with modest survival advantage as initial treatment of advanced lung cancer. However, toxicity and minimal benefit to use second line treatment justifies exploration of alternative approaches. Recent understanding of mechanisms by which tumor antigen recognition can be enhanced has justified development of a recent flurry of vaccine trials in lung cancer. Preliminary results suggest a remarkably high safety profile and significant activity with respect to improvement in time to progression and survival in comparison to historical controls or lower dose treated cohorts, particularly in non small cell lung cancer. This review summarizes current results of vaccine trial development in non small cell and small cell lung cancer.