In vivo genome editing of the albumin locus as a platform for protein replacement therapy
| Autor: | Katherine A. High, Thomas Wechsler, Jeffrey C. Miller, Philip D. Gregory, Edward J. Rebar, Robert J. Davidson, Russell Dekelver, Julianne M. Rieders, Rajiv Sharma, David Paschon, Michael C. Holmes, Yannick Doyon, Scott Sproul, Xavier M. Anguela, David A. Shivak, Shangzhen Zhou |
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| Rok vydání: | 2015 |
| Předmět: |
Mucopolysaccharidosis I
Transgene Genetic Vectors Immunology Computational biology Biology Hemophilia A Real-Time Polymerase Chain Reaction Hemophilia B Biochemistry Genome Factor IX Mice Protein replacement therapy Genome editing Albumins Animals Humans Enzyme Replacement Therapy RNA Messenger Transgenes Promoter Regions Genetic Gene Mucopolysaccharidosis II Zinc finger Genetics Factor VIII Gaucher Disease Reverse Transcriptase Polymerase Chain Reaction High-Throughput Nucleotide Sequencing Zinc Fingers Genetic Therapy Gene Therapy Cell Biology Hematology Dependovirus Endonucleases Zinc finger nuclease Mice Inbred C57BL Liver RNA editing Fabry Disease RNA Editing Lysosomes |
| Zdroj: | Blood. 126:1777-1784 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2014-12-615492 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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