Recombinant AAV Vectors as Tools to Study and Treat Human Disorders

Gene transfer, especially for the goal of human gene therapy, is the principle of administrating therapeutic coding sequences in a target for sustained expression instead of providing a final product with short pharmacological half-life. The identification of genes associated with diverse human pathologies and the expansion of gene transfer vectors has allowed to develop a broad range of models of human disorders and to establish the first human clinical trials, to find applications at clinical levels for genetic disorders, neurologic and muscle disorders, cardiovascular diseases, infectious and other acquired diseases, for degenerative, chronic, inflammatory, or age-related diseases, and for tumors. The most common strategies are gene replacement therapies (gene targeting) or gene addition (growth and transcription factors, cytokines, and antagonists), the transfer of inhibitory nucleic acids, and the application of enhancers of immune responses (genetic vaccines). Evidence of the functionality of a gene transfer protocol necessitates an evaluation in culture systems in vitro prior to translation in vivo by either transplantation of cells genetically modified ex vivo or by direct administration of the candidate treatment in vivo. Direct approaches are simpler, as the cells are not manipulated before reimplantion, but indirect strategies permit a thorough characterization of the modified cells, without injecting viral particles, and are better suited when cell repopulation is an issue like for regenerative medicine. Critical to the success of a gene transfer approach is the identification of a vector capable of both efficiently and durably expressing a transgene, often with a rapid onset and without being detrimental to the host. The systems used are based on either nonviral compounds (naked DNA, gene gun, electroporation, ultrasound-facilitated and