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Mol Ther Methods Clin Dev. 2016 Jun 29;3:16042. doi: 10.1038/mtm.2016.42. eCollection 2016.

Multilineage transduction of resident lung cells in vivo by AAV2/8 for α1-antitrypsin gene therapy.

Author information

1
Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, Massachusetts, USA; The Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA.
2
Department of Biomedical Engineering, Boston University , Boston, Massachusetts, USA.
3
Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center , Boston, Massachusetts, USA.
4
Ragon Institute of MGH, MIT and Harvard , Cambridge, Massachusetts, USA.

Abstract

In vivo gene delivery has long represented an appealing potential treatment approach for monogenic diseases such as α1-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 α-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 AAV-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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