The present invention is in the field of a method for genome engineering based on the type II CRISPR system, particularly a method for improving specificity and reducing potential off-site. The method is based on the use of nickase architectures of Cas9 and single or multiple crRNA(s) harboring two different targets lowering the risk of producing off-site cleavage. The present invention also relates to polypeptides, polynucleotides, vectors, compositions, therapeutic applications related to the method described here.
