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The pros and cons of using the mechanism of AAV site-specific recombination in gene delivery

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The field of gene therapy is progressing with continuous improvements in vector development and regulated transgene expression. These contributions will eventually allow matching the best vector system for the specific disease indication. However one essential component of gene delivery that may be more retractile to this type of development and critical to all methods of delivery relates to the molecular fate of the therapeutic nucleic acids after successful in vivo delivery. The importance of this was illustrated in the clinic when leukemias were a result of insertional mutagenesis after attempting to achieve long-term gene expression via retroviral vectors. These results echo the fact that safer methods of achieving long-term gene expression are needed for successful gene therapy vectors. One mechanism to be considered to obtain the desired gene therapy results of safe long-term gene expression is that of the targeted integration. A number of recombination systems both eukaryotic and prokaryotic are being evaluated for this purpose. Included in this list is the targeted recombination of the Adeno-Associated Virus (AAV). AAV is a unique virus in that it can establish latency in human cells by targeting the recombination of its genome to a specific locus on chromosome 19. This review discusses the current understanding of the cis and trans requirements for AAV site-specific recombination and the mechanism involved. The risks of AAV-based site-specific recombination are also addressed as well as the current state of gene delivery vectors based on the site-specific integration of AAV.


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