Gene therapy using adenoviral vectors
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Hemophilia A and B gene therapy requires long-term and stable expression of coagulation factor VIII (FVIII) or factor IX (FIX), respectively, and would need to compare favorably with protein replacement therapy. Onco-retroviral and lentiviral vectors are attractive vectors for gene therapy of hemophilia. These vectors have the potential for long-term expression because they integrate stably in the target cell genome. Whereas onco-retroviral vectors can only transduce dividing cells, lentiviral vectors can transduce a broad variety of cell types irrespective of cell division. Several preclinical and clinical studies have explored the use of onco-retroviral and, more recently, lentiviral vectors for gene therapy of hemophilia A or B. Both ex vivo and in vivo gene therapy approaches have been evaluated, resulting in therapeutic FVIII or FIX levels in preclinical animal models. Whereas in vivo gene therapy using onco-retroviral or lentiviral vectors often led to long-term FVIII or FIX expression from transduced hepatocytes, ex vivo approaches were generally hampered by either low or transient expression of FVIII or FIX levels in vivo and/or inefficient engraftment. Furthermore, immune responses against the transgene product remain a major issue that must be resolved before the full potential of these vectors eventually can be exploited clinically. Nevertheless, the continued progress in vector design combined with a better understanding of vector biology may ultimately yield more effective gene therapy approaches using these integrating vectors.
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Transduction (biophysics)
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Gene therapy is the process of introducing foreign genomic materials into host cells to elicit a therapeutic benefit. Although initially the main focus of gene therapy was on special genetic disorders, now diverse diseases with different patterns of inheritance and acquired diseases are targets of gene therapy. There are 2 major categories of gene therapy, including germline gene therapy and somatic gene therapy. Although germline gene therapy may have great potential, because it is currently ethically forbidden, it cannot be used; however, to date human gene therapy has been limited to somatic cells. Although numerous viral and nonviral gene delivery systems have been developed in the last 3 decades, no delivery system has been designed that can be applied in gene therapy of all kinds of cell types in vitro and in vivo with no limitation and side effects. In this review we explain about the history of gene therapy, all types of gene delivery systems for germline (nuclei, egg cells, embryonic stem cells, pronuclear, microinjection, sperm cells) and somatic cells by viral [retroviral, adenoviral, adeno association, helper-dependent adenoviral systems, hybrid adenoviral systems, herpes simplex, pox virus, lentivirus, Epstein-Barr virus)] and nonviral systems (physical: Naked DNA, DNA bombardant, electroporation, hydrodynamic, ultrasound, magnetofection) and (chemical: Cationic lipids, different cationic polymers, lipid polymers). In addition to the above-mentioned, advantages, disadvantages, and practical use of each system are discussed.
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Effective delivery of therapeutic genes to target cells is an essential goal of all innovative gene therapy endeavours and recombinant vaccine technology. Current use of viral vectors in achieving this goal has been associated with minimal success and plethora of unwanted adverse events. As a result, there is an ongoing search for suitable vector platforms for the delivery of therapeutic genes to target cells. Such agent should be easily manipulated to accommodate small and large gene inserts and safely deliver Transgenes. This will ensure effective expression of the gene in target cells. The resulting optimal expression of this gene may correct defective or deficient gene in individuals receiving gene therapy. This chapter examines the applications of biopolymers as non-viral gene delivery vectors either alone or as copolymers.
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1. Present and Future Status of Gene Therapy 2. DNA Packaging in Non Viral Systems 3. Biological Barriers to Gene Transfer 4. Therapeutic Applications of Lipid-Based Gene Delivery Systems 5. Polycation-based Delivery Systems for Receptor-Mediated Gene Delivery 6. DNA Delivery Systems Based on Synthetic Peptides 7. Expression Plasmids for Non-Viral Gene Therapy 8. Gene Therapy Clinical Trials for Cystic Fibrosis 9. Polymeric Gene Delivery Systems for In Vivo Gene Therapy 10. Intravascular Delivery of Naked Plasmid DNA 11. Cationic Lipid-Based Gene Delivery Systems 12. Gene-based Vaccines 13. Gene Therapy for Cancer: Strategies and Review of Clinical Trials
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As lentiviral vector holds the characteristics of higher transfection to non-dividing cells, larger capacity of transfer gene fragments, long-term expression of therapeutic gene and lower rate of immunological response, therefore it becomes potential viral vector in gene therapy. Improvements of lentiviral vector, human immunodeficiency virus type-I as example, and its application in gene transfer for gene therapy of hematological diseases are emphasized in this review.
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Gene Therapy for Inherited Genetic Disease Possibilities and Problems C. Coutelle. Gene Delivery and Therapy: The Case for Cystic Fibrosis E.W.F.W. Alton. Immune Responses with Direct Gene Transfer: DNA Vaccines and Implications for Gene Therapy H.L. Davis. Oligonucleotides: Molecular Versions for Optimal Use In Vivo E. Saison-Behmoaras, et al. Retrovirus Vectors in Gene Therapy: Targeting to Specific Cells A.J. Kingsman, et al. Adenovirus as Vectors for Gene Therapy M.G. Lee. Receptor-mediated Gene Delivery with Synthetic Virus-Like Particles E. Wagner, et al. Controllable Gene Therapy-Recent Advances in Non-Viral Gene Delivery A. Rolland. Genetic Chemistry: Towards Non-Enzymatic Ligation. Sequence-Selective Recognition of DNA and Self-Assembling Systems for Gene Delivery J.-P. Behr. Integrin-Mediated Gene Delivery S.L. Hart, et al. Design, Synthesis and Cellular Delivery of Antibody Targeted, Radiolabelled Oligonucleotide Conjugates for Cancer Therapy C.S.R. Gooden, A.A. Epenetos. 7 Additional Articles. Index.
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As a new promising therapeutical strategy for the treatment of liver diseases, gene therapy has drawn people's great attention. In gene therapy of hepatic diseases, it is critical to get therapeutic genes into hepatocyte for appropriate expression specifically. Over the past twenty years, receptor mediated gene delivery system have been extensively studied for liver-targeted gene delivery. However, non-viral gene delivery is still inefficient. This article reviewed the current non-viral vector used commonly, including their physicochemical properties, advantages and limitations, mechanisms of action for gene delivery, and applications modified for liver-targeted gene therapy, and the physical methods for hepatocyte gene delivery, such as electroporation and hydrodynamic injection. It also reviewed how to achieve optimal transfection efficiency.
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