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Gene therapy is an emerging medical approach which seeks to apply molecular techniques to attack diseases at the fundamental level of the genes. The first techniques which were developed for genetic manipulation of mammalian cells involved direct introduction of genes in the forms of expression plasmids by physical methods. However, other gene therapy applications require stable persistence of the transferred gene in the target cells, so that the gene will be retained with each cell division and inherited by all progeny cells. The viruses which have been adapted and most widely studied for gene transfer include retroviruses, adenovirus (Ad), adeno-associated virus (AAV), herpesviruses, and, most recently, lentiviruses. Importantly, lentiviral vectors tolerate complex genetic elements better than retroviral vectors, possibly aided by the Rev/Rev response element-mediated mechanism for nuclear-to-cytoplasmic export of HIV-1 transcripts. Complement fixation (CF) appeared to be an attractive target for gene therapy, and extensive preclinical studies of the safety and toxicity of an AAV-CF transmembrane regulator (CFTR) vector were performed by delivery of vector particles directly to the lungs in rabbits and nonhuman primates. Importantly, sperm is generally negative for vector sequences, which diminishes the likelihood of modifying germ line cells. The use of viruses with improved initial intratumoral distribution and carrying genes that both overcome innate immune responses and promote an intra-cellular proapoptotic state should improve the potency of herpes simplex virus (HSV) cancer gene therapy vectors without compromising safety. |
