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Blood. 2015 Oct 8;126(15):1777-84. doi: 10.1182/blood-2014-12-615492. Epub 2015 Aug 21.

In vivo genome editing of the albumin locus as a platform for protein replacement therapy.

Author information

Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA;
Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA; Howard Hughes Medical Institute, Philadelphia, PA; and.
Sangamo BioSciences, Richmond, CA.


Site-specific genome editing provides a promising approach for achieving long-term, stable therapeutic gene expression. Genome editing has been successfully applied in a variety of preclinical models, generally focused on targeting the diseased locus itself; however, limited targeting efficiency or insufficient expression from the endogenous promoter may impede the translation of these approaches, particularly if the desired editing event does not confer a selective growth advantage. Here we report a general strategy for liver-directed protein replacement therapies that addresses these issues: zinc finger nuclease (ZFN) -mediated site-specific integration of therapeutic transgenes within the albumin gene. By using adeno-associated viral (AAV) vector delivery in vivo, we achieved long-term expression of human factors VIII and IX (hFVIII and hFIX) in mouse models of hemophilia A and B at therapeutic levels. By using the same targeting reagents in wild-type mice, lysosomal enzymes were expressed that are deficient in Fabry and Gaucher diseases and in Hurler and Hunter syndromes. The establishment of a universal nuclease-based platform for secreted protein production would represent a critical advance in the development of safe, permanent, and functional cures for diverse genetic and nongenetic diseases.

[Indexed for MEDLINE]
Free PMC Article

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