Gene therapy to human diseases: Ex vivo and in vivo studies (Review)

The identification of defective genes associated with a number of human disorders (tyrosine hydroxylase for Parkinson's disease, aspartylglucosaminidase in lysosomal storage disease, CFTR in cystic fibrosis, and LDL receptor in familial hypercholesterolemia) has promoted the development of strategies aimed at transferring to the somatic cells of the patient or of animal models vectors carrying the corrected gene. The obstacles to overcome include targeting the specific cell type or organ (liver for Factors VIII and IX in hemophilia), enhancing entry to cells into non-lysosomal compartments, nuclear import, percentage of cells transduced with the therapeutic gene, sustained expression of the transgene in human tissues, and immunogenicity of the transduced cells expressing the recombinant or viral proteins. Improvements in each single of these steps are likely to enhance enormously the potential of gene transfer for the treatment of human diseases. A number of human diseases including HIV infections and hypertension are approached by somatic gene transfer. VEGF regulating vascular permeability, growth of endothelial cells and angiogenesis, and TGF-B implicated in wound healing and in stimulation in synthesis of extracellular matrix, are potential targets for restenosis, atherosclerosis, and cancer.