Initial attempts to use homologous recombination (the cell’s natural high fidelity DNA repair mechanism) revolved around the generation of transgenic mice using plasmid-based techniques in embryonic stem cells. This approach, while fine for transgenic mice isn’t effective for the development of somatic cell lines due to the very low rates of homologous recombination in these cells. Instead, the process needs to be stimulated or an alternative approach used. An alternative to homologous recombination involves the use of nucleases to create a double-stranded DNA break at specific locations, then using the more error prone non homologous end-joining (NHEJ) mechanism to repair the break. Examples are Zinc Finger Nuclease (ZFN), Transcription Activator-Like Effector Nuclease (TALENs), and engineered meganucleases. Horizon’s approach is to amplify the basal levels of homologous recombination by 1000X to 10,000X through its proprietary rAAV technology.