| First Author | Sharma R | Year | 2015 |
| Journal | Blood | Volume | 126 |
| Issue | 15 | Pages | 1777-84 |
| PubMed ID | 26297739 | Mgi Jnum | J:230678 |
| Mgi Id | MGI:5763531 | Doi | 10.1182/blood-2014-12-615492 |
| Citation | Sharma R, et al. (2015) In vivo genome editing of the albumin locus as a platform for protein replacement therapy. Blood 126(15):1777-84 |
| abstractText | 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. |
