Meyer-Berg, HelenaZhou Yang, Luciade Lucas, Maria PilarZambrano, AlbertoHyde, Stephen CGill, Deborah R2021-02-012021-02-012020Stem Cell Res Ther. 2020 Oct 23;11(1):448.http://hdl.handle.net/20.500.12105/11768Gene therapy is being investigated for a range of serious lung diseases, such as cystic fibrosis and emphysema. Recombinant adeno-associated virus (rAAV) is a well-established, safe, viral vector for gene delivery with multiple naturally occurring and artificial serotypes available displaying alternate cell, tissue, and species-specific tropisms. Efficient AAV serotypes for the transduction of the conducting airways have been identified for several species; however, efficient serotypes for human lung parenchyma have not yet been identified. Here, we screened the ability of multiple AAV serotypes to transduce lung bud organoids (LBOs)-a model of human lung parenchyma generated from human embryonic stem cells. Microinjection of LBOs allowed us to model transduction from the luminal surface, similar to dosing via vector inhalation. We identified the naturally occurring rAAV2 and rAAV6 serotypes, along with synthetic rAAV6 variants, as having tropism for the human lung parenchyma. Positive staining of LBOs for surfactant proteins B and C confirmed distal lung identity and suggested the suitability of these vectors for the transduction of alveolar type II cells. Our findings establish LBOs as a new model for pulmonary gene therapy and stress the relevance of LBOs as a viral infection model of the lung parenchyma as relevant in SARS-CoV-2 research.engVoRhttp://creativecommons.org/licenses/by/4.0/AAV capsidsAAV serotypesAlveolar type II cellsGene therapyHuman embryonic stem cellsLung organoidsrAAVStem cell-based tissue modelViral infection modelCell LineDependovirusGene Transfer TechniquesGenetic TherapyGenetic VectorsHuman Embryonic Stem CellsHumansLungLung DiseasesModels, BiologicalOrganoidsParenchymal TissueAtribución 4.0 Internacional3309709411144810.1186/s13287-020-01950-x1757-6512Stem cell research & therapyopen access