Gene therapy is an experimental form of treatment whereby sequences of nucleic acids (i.e., genes) are delivered to cells to change their biologic function. The concept initially arose as replacement therapy for monogenic inherited disorders. For these disorders, the aim is to replace a defective gene with the normal counterpart. The delivered genetic material undergoes transcription and translation using the host cell's machinery, leading to in situ production of the normal protein and thereby correction of the phenotypic defect.
[...] The only vector-related death in gene therapy trials to date occurred acutely following infusion of a high dose of adenovirus into the hepatic artery. Efforts to improve the cell specificity, safety, and efficacy of adenoviral vectors are being made by imparting targeting properties to the vector. These strategies involve genetic modification of the capsid proteins or the use of separate adapter molecules to attach cell-specific ligands and thereby avoid the virus's reliance on CAR. This is especially relevant for tumor therapy, because most tumors tend to have low CAR levels. [...]
[...] Thus, the effects of tumor suppressor gene therapy extend beyond the initial hypothesis in complex and often ill-defined manners. Despite these bystander effects, however, clinical trials of tumor suppressor genes have had disappointing efficacy, albeit with minimal toxicity. The basic issue of gene delivery efficiency remains a significant problem. MOLECULAR CHEMOTHERAPY In molecular chemotherapy the rationale is to achieve tumor expression of enzymes that convert nontoxic systemically administered prodrugs into their toxic counterparts, to achieve high tumor concentrations while avoiding systemic side effects. [...]
[...] CYSTIC FIBROSIS The discovery of the mutated gene in cystic fibrosis, the gene for a chloride channel (the cystic fibrosis transmembrane regulator) in conjunction with the beginnings of clinical gene therapy research, led to expectations during the 1990s that a cure would be developed. This has been much more difficult to implement than hoped. Despite the fact that genetic correction of only of airway epithelium could correct the net chloride transport abnormality, even this seemingly modest goal has been beyond current gene delivery techniques in human trials. [...]
[...] At present no gene therapy approach has entered standard clinical practice. Nevertheless, a limited number of settings have seen early efficacy. Strategies for inherited immunodeficiency disease, hemophilia, and ischemic vascular disease are the closest to being incorporated into mainstream therapeutics. Gene Delivery Strategies THE EXPRESSION CASSETTE Genes are delivered into cells as engineered expression cassettes. Cassettes are a stretch of nucleic acid comprised of a promoter region, the gene itself, followed by a polyA sequence. The promoter region controls attachment of cellular transcription machinery. [...]
[...] The concept of gene therapy has since broadened from that of replacement to one of using genes as an indirect method for delivering a variety of therapeutic proteins. These proteins may be identical to the natural human protein, whereby therapy occurs via the magnitude and location of expression, or the delivered genes may be engineered to produce novel proteins with distinct therapeutic properties. Delivering therapies as genes has several potential advantages over the use of proteins. Depending on the gene delivery technique used, long-term, sustained protein production can be achieved. [...]
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