Targeted Gene Correction: Gene Therapy Promoted by Meganucleases

Targeted gene correction is an especially powerful strategy for gene therapy because it uses molecules and mechanisms optimized over billions of years of evolution to correct deleterious mutations in human cells. Cleavage by a meganuclease at a site near the disease mutation initiates repair by homologous recombination, using an exogenous template for gene correction. We are working to increase the efficacy and safety of targeted gene correction. We have shown that a nick effectively initiates correction, without creating the DNA damage associated with DNA double‐strand breaks. We are now optimizing nick‐initiated cleavage. Our strategy is to apply fundamental understanding of recombination mechanisms to improving gene correction, by modulating repair pathways and chromatin structure and epigenetics of the repair target and template.