期刊
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
卷 3, 期 -, 页码 -出版社
CELL PRESS
DOI: 10.1038/mtm.2016.42
关键词
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资金
- FAMRI [062572YCSA]
- alpha-1 Foundation Research Grant
- Boston University School of Medicine Department of Medicine Career Investment Award
- [K08 HL103771]
- [5T32HL007035-38]
- [5T32AI089673-03]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [T32HL007035] Funding Source: NIH RePORTER
In vivo gene delivery has long represented an appealing potential treatment approach for monogenic diseases such as alpha(1)-antitrypsin deficiency (AATD) but has proven challenging to achieve in practice. Alternate pseudotyping of recombinant adeno-associated virus (AAV) vectors is producing vectors with increasingly heterogeneous tropic specificity, giving researchers the ability to target numerous end-organs affected by disease. Herein, we describe sustained pulmonary transgene expression for at least 52 weeks after a single intratracheal instillation of AAV2/8 and characterize the multiple cell types transduced within the lung utilizing this approach. We demonstrate that lung-directed AAV2/8 is able to achieve therapeutic alpha-1 antitrypsin (AAT) protein levels within the lung epithelial lining fluid and that AAT gene delivery ameliorates the severity of experimental emphysema in mice. We find that AAV2/8 efficiently transduces hepatocytes in vivo after intratracheal administration, a finding that may have significance for MV-based human gene therapy studies. These results support direct transgene delivery to the lung as a potential alternative approach to achieve the goal of developing a gene therapy for AATD.
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