A lung tropic AAV vector improves survival in a mouse model of surfactant B deficiency

Martin H. Kang, Laura P. Lieshout, Liqun Xu, Jakob M. Domm, Arul Vadivel, Laurent Renesme, Christian Mühlfeld, Maria Hurskainen, Ivana Mižíková, Yanlong Pei, Jacob P. Vloten, Sylvia P. Thomas, Claudia Milazzo, Chanèle Cyr-Depauw, Jeffrey A. Whitsett, Lawrence M. Nogee, Sarah K. Wootton () and Bernard Thébaud ()
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Martin H. Kang: Ottawa Hospital Research Institute
Laura P. Lieshout: University of Guelph
Liqun Xu: Ottawa Hospital Research Institute
Jakob M. Domm: University of Guelph
Arul Vadivel: Ottawa Hospital Research Institute
Laurent Renesme: Ottawa Hospital Research Institute
Christian Mühlfeld: Hannover Medical School
Maria Hurskainen: Ottawa Hospital Research Institute
Ivana Mižíková: Ottawa Hospital Research Institute
Yanlong Pei: University of Guelph
Jacob P. Vloten: University of Guelph
Sylvia P. Thomas: University of Guelph
Claudia Milazzo: Ottawa Hospital Research Institute
Chanèle Cyr-Depauw: Ottawa Hospital Research Institute
Jeffrey A. Whitsett: Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine
Lawrence M. Nogee: Johns Hopkins University School of Medicine
Sarah K. Wootton: University of Guelph
Bernard Thébaud: Ottawa Hospital Research Institute

Nature Communications, 2020, vol. 11, issue 1, 1-20

Abstract: Abstract Surfactant protein B (SP-B) deficiency is an autosomal recessive disorder that impairs surfactant homeostasis and manifests as lethal respiratory distress. A compelling argument exists for gene therapy to treat this disease, as de novo protein synthesis of SP-B in alveolar type 2 epithelial cells is required for proper surfactant production. Here we report a rationally designed adeno-associated virus (AAV) 6 capsid that demonstrates efficiency in lung epithelial cell transduction based on imaging and flow cytometry analysis. Intratracheal administration of this vector delivering murine or human proSFTPB cDNA into SP-B deficient mice restores surfactant homeostasis, prevents lung injury, and improves lung physiology. Untreated SP-B deficient mice develop fatal respiratory distress within two days. Gene therapy results in an improvement in median survival to greater than 200 days. This vector also transduces human lung tissue, demonstrating its potential for clinical translation against this lethal disease.

Date: 2020
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DOI: 10.1038/s41467-020-17577-8

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