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In some embodiments, the transgene encodes a protein for treatment of a patient in need thereof and is integrated using the methods and compositions of the invention into a safe harbor locus. In some embodiments, the composition is administered to a patient and then re-administered 7, 14, 21, 28, 30, 40, 50, 75, 100, 200 or more days after the first administration. The term also applies to amino acid polymers in which one or more amino acids are chemical analogues or modified derivatives of a corresponding naturally-occurring amino acids. In some embodiments, the nucleic acid encodes an engineered nuclease wherein the nuclease comprises a DNA binding domain and a cleavage domain. In some embodiments, the DNA cleavage domain is FokI. In other embodiments, the DNA-binding domain is a TALE DNA-binding domain. These are single chain fusion proteins linking a TALE DNA binding domain to a TevI nuclease domain. Especially preferred are compositions comprising an LNP comprising mRNAs encoding a nuclease, and an AAV comprising a DNA donor. In another aspect, fusion polypeptides comprising a DNA binding domain and an engineered cleavage half-domain as described herein are provided

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