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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.
Surfactant protein B (SP-B) deficiency is a genetic lung disease that results in lethal respiratory distress within months of birth. Here, the authors describe a gene therapy strategy using a rationally designed AAV6 capsid that restores surfactant homeostasis, prevents lung injury, and improves survival in a mouse model of SP-B deficiency.
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1 Ottawa Hospital Research Institute, Sinclair Center for Regenerative Medicine, Ottawa, Canada (GRID:grid.412687.e) (ISNI:0000 0000 9606 5108); University of Ottawa, Department of Cellular and Molecular Medicine, Ottawa, Canada (GRID:grid.28046.38) (ISNI:0000 0001 2182 2255)
2 University of Guelph, Department of Pathobiology, Ontario Veterinary College, Guelph, Canada (GRID:grid.34429.38) (ISNI:0000 0004 1936 8198)
3 Hannover Medical School, Institute of Functional and Applied Anatomy, Hannover, Germany (GRID:grid.10423.34) (ISNI:0000 0000 9529 9877)
4 Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Divisions of Neonatology and Pulmonary Biology, Cincinnati, USA (GRID:grid.24827.3b) (ISNI:0000 0001 2179 9593)
5 Johns Hopkins University School of Medicine, Division of Neonatology, Department of Pediatrics, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311)
6 Ottawa Hospital Research Institute, Sinclair Center for Regenerative Medicine, Ottawa, Canada (GRID:grid.412687.e) (ISNI:0000 0000 9606 5108); University of Ottawa, Department of Cellular and Molecular Medicine, Ottawa, Canada (GRID:grid.28046.38) (ISNI:0000 0001 2182 2255); Children’s Hospital of Eastern Ontario (CHEO) and CHEO Research Institute, Neonatology, Department of Pediatrics, Ottawa, Canada (GRID:grid.414148.c) (ISNI:0000 0000 9402 6172)