Identification of AAV serotypes for lung gene therapy in human embryonic stem cell-derived lung organoids
Abstract Gene 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 displayi...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2020-10-01
|
| Series: | Stem Cell Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13287-020-01950-x |
| _version_ | 1819073687186309120 |
|---|---|
| author | Helena Meyer-Berg Lucia Zhou Yang María Pilar de Lucas Alberto Zambrano Stephen C. Hyde Deborah R. Gill |
| author_facet | Helena Meyer-Berg Lucia Zhou Yang María Pilar de Lucas Alberto Zambrano Stephen C. Hyde Deborah R. Gill |
| author_sort | Helena Meyer-Berg |
| collection | DOAJ |
| description | Abstract Gene 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. |
| first_indexed | 2024-12-21T17:57:35Z |
| format | Article |
| id | doaj.art-cfd60483467343929fab9a7c02913e3f |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-12-21T17:57:35Z |
| publishDate | 2020-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj.art-cfd60483467343929fab9a7c02913e3f2022-12-21T18:55:10ZengBMCStem Cell Research & Therapy1757-65122020-10-011111610.1186/s13287-020-01950-xIdentification of AAV serotypes for lung gene therapy in human embryonic stem cell-derived lung organoidsHelena Meyer-Berg0Lucia Zhou Yang1María Pilar de Lucas2Alberto Zambrano3Stephen C. Hyde4Deborah R. Gill5Gene Medicine Research Group, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of OxfordDepartment of Biotechnology of Stem Cells and Organoids, Functional Unit for Research into Chronic Diseases, Instituto de Salud Carlos IIIDepartment of Cellular Biology, Functional Unit for Research into Chronic Diseases, Instituto de Salud Carlos IIIDepartment of Biotechnology of Stem Cells and Organoids, Functional Unit for Research into Chronic Diseases, Instituto de Salud Carlos IIIGene Medicine Research Group, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of OxfordGene Medicine Research Group, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of OxfordAbstract Gene 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.http://link.springer.com/article/10.1186/s13287-020-01950-xhuman embryonic stem cellsstem cell-based tissue modelgene therapyrAAVAAV capsidsAAV serotypes |
| spellingShingle | Helena Meyer-Berg Lucia Zhou Yang María Pilar de Lucas Alberto Zambrano Stephen C. Hyde Deborah R. Gill Identification of AAV serotypes for lung gene therapy in human embryonic stem cell-derived lung organoids Stem Cell Research & Therapy human embryonic stem cells stem cell-based tissue model gene therapy rAAV AAV capsids AAV serotypes |
| title | Identification of AAV serotypes for lung gene therapy in human embryonic stem cell-derived lung organoids |
| title_full | Identification of AAV serotypes for lung gene therapy in human embryonic stem cell-derived lung organoids |
| title_fullStr | Identification of AAV serotypes for lung gene therapy in human embryonic stem cell-derived lung organoids |
| title_full_unstemmed | Identification of AAV serotypes for lung gene therapy in human embryonic stem cell-derived lung organoids |
| title_short | Identification of AAV serotypes for lung gene therapy in human embryonic stem cell-derived lung organoids |
| title_sort | identification of aav serotypes for lung gene therapy in human embryonic stem cell derived lung organoids |
| topic | human embryonic stem cells stem cell-based tissue model gene therapy rAAV AAV capsids AAV serotypes |
| url | http://link.springer.com/article/10.1186/s13287-020-01950-x |
| work_keys_str_mv | AT helenameyerberg identificationofaavserotypesforlunggenetherapyinhumanembryonicstemcellderivedlungorganoids AT luciazhouyang identificationofaavserotypesforlunggenetherapyinhumanembryonicstemcellderivedlungorganoids AT mariapilardelucas identificationofaavserotypesforlunggenetherapyinhumanembryonicstemcellderivedlungorganoids AT albertozambrano identificationofaavserotypesforlunggenetherapyinhumanembryonicstemcellderivedlungorganoids AT stephenchyde identificationofaavserotypesforlunggenetherapyinhumanembryonicstemcellderivedlungorganoids AT deborahrgill identificationofaavserotypesforlunggenetherapyinhumanembryonicstemcellderivedlungorganoids |