Engineered Endonucleases Could Become Major Gene Therapy Tools

Artificial endonucleases with tailored specificities, known as meganucleases, may become major therapeutic tools, as they have the potential to reduce or eliminate toxic effects due to random gene insertion.

Investigators at Cellectis S.A. (Romainville Cedex, France) have already demonstrated the efficiency of meganucleases in model systems using cultured cells. However, in a review article published in the February 2007 issue of Current Gene Therapy, they described the many difficulties that must be overcome before such treatment will be available for human patients.

Many diseases fall outside the scope of the targeted approach, as they require much higher levels of efficacy than is currently possible. In addition, the specificity and toxicity of engineered endonucleases must be quantitatively characterized. The mutagenic effect is the most difficult to evaluate, since scattered sporadic point mutations along the genome are difficult to monitor. A combination of animal models and genomic analysis using micro-array technologies might be the best way to fully address this point.

Nevertheless, the investigators stressed that the time when therapeutic applications were pure fantasy has passed. Despite the lack of data relative to specificity and toxicity, the high levels of recombination observed in human T cells and mouse hepatocytes are compatible with certain therapeutic applications. Increasing further the current efficacies is probably just a matter of time, and progress in cell biology (and especially in the biology of recombination mechanisms), as well as in the use of vectors will be more important than new achievements in protein engineering. Specificity is likely a tougher issue, but the use of homing endonucleases has opened up novel perspectives, for they display high levels of specificity that seem to be preserved in engineered derivatives. The years to come will see several developments that will definitively establish the range of applications for meganuclease-induced recombination.


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