Gene Targeting, Therapeutic Strategies
More than 2,000 inherited disorders are known today, with up 15% of newborn infants presenting some genetic disorder that may cause disease or impairment at some stage of life. Examples of genetic disorders with different degrees of severity are diabetes (juvenile and mellitus), cystic fibrosis, familial hypercholesterolemia, hemophilia, phenylketonuria, Down syndrome, familial cancers, Parkinson, myocardiopathies, arthritis, among others. Accordingly, medical research is concentrating efforts in the development of new strategies for gene therapy, aiming at correcting, restoring, or modifying the mutated gene involved. Gene targeting, utilizing vectors to transport DNA to the affected cells, became a central focus in this field of research.
Another therapeutic gene targeting approach is trying to devise ways of turning specific expressed genes in tumor cells against themselves. Termed suicide gene therapy, this strategy makes cancer cells more vulnerable to chemotherapy, radiation, or to new drugs. One approach, for instance, is the use of retroviral genes to activate a relatively nontoxic prodrug to form a highly toxic compound. The transfection of tumor cells with the thymidine kinase gene of Herpes simplex virus (HSVtk) makes tumor cells sensitive to ganciclovir, an anti-herpes drug, thus leading to tumor cells death when ganciclovir is given to patients. This suicide gene therapeutic approach allowed the transfer of HSVtk into 30-60% of proliferating brain tumor cells, resulting in the complete destruction of brain tumors in 80% of the patients included in the trial.
Gene targeting therapeutic strategies are also under scrutiny for the protection of hematopoietic stem cells during cancer treatment, since many anti-cancer drugs and gamma radiation induce the suicide (apoptosis) of these cells and causes severe side effects in cancer patients, such as temporary immune suppression. The general idea is to confer stem cells the multiple drug resistance type 1 (MDR-1) that is developed by some tumor cells exposed to chemotherapy. The gene responsible for MDR-1 has to be identified and isolated from tumor cells. After transduction of MDR-1 gene to a retroviral vector, bone marrow stem cells would be transfected with the viral vector, thus becoming capable of pumping out chemotherapeutic drugs received by the patient.
Clinical trials for a variety of gene targeting therapeutic strategies are now possible due to gene cloning techniques and because of an increasing number of new methodologies for gene transfer. Although this is an experimental field with huge obstacles yet to be overcome, gene therapy holds the promise of becoming a standard tool in clinical practice for the treatment of a growing number of genetic disorders in this century.
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