Targeted approaches for gene therapy and the emergence of engineered meganucleases.

ABSTRACT

BACKGROUND: In spite of significant advances in gene transfer strategies in the field of gene therapy, there is a strong emphasis on the development of alternative methods, providing better control of transgene expression and insertion patterns. OBJECTIVE: Several new approaches consist of targeting a desired transgene or gene modification in a well defined locus, and we collectively refer to them as 'targeted approaches'. The use of redesigned meganucleases is one of these emerging technologies. Here we try to define the potential of this method, in the larger scope of targeted strategies. METHODS: We survey the different types of targeted strategies, presenting the achievements and the potential applications, with a special emphasis on the use of redesigned endonucleases. CONCLUSION: redesigned endonucleases represent one of the most promising tools for targeted approaches, and the opening of a clinical trial for AIDS patients has recently shown the maturity of these strategies. However, there is still a 'quest' for the best reagents, that is the endonucleases providing the best efficacytoxicity ratio. New advances in protein design have allowed the engineering of new scaffolds, such as meganucleases, and the landscape of existing methods is likely to change over the next few years.