AAV5 Delivery of CRISPR/Cas9 Mediates Genome Editing in the Lungs of Young Rhesus Monkeys

Shun Qing Liang; Andrew W. Navia; Michelle Ramseier; Xuntao Zhou; Michele Martinez; Charles Lee; Chen Zhou; Joae Wu; Jun Xie; Qin Su; Dan Wang; Terence R. Flotte; Daniel G. Anderson; Alice F. Tarantal; Alex K. Shalek; Guangping Gao; Wen Xue

doi:10.1089/hum.2024.035

AAV5 Delivery of CRISPR/Cas9 Mediates Genome Editing in the Lungs of Young Rhesus Monkeys

Shun Qing Liang, Andrew W. Navia, Michelle Ramseier, Xuntao Zhou, Michele Martinez, Charles Lee, Chen Zhou, Joae Wu, Jun Xie, Qin Su, Dan Wang, Terence R. Flotte, Daniel G. Anderson, Alice F. Tarantal, Alex K. Shalek, Guangping Gao, Wen Xue

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Genome editing has the potential to treat genetic diseases in a variety of tissues, including the lung. We have previously developed and validated a dual adeno-associated virus (AAV) CRISPR platform that supports effective editing in the airways of mice. To validate this delivery vehicle in a large animal model, we have shown that intratracheal instillation of CRISPR/Cas9 in AAV5 can edit a housekeeping gene or a disease-related gene in the lungs of young rhesus monkeys. We observed up to 8% editing of angiotensin-converting enzyme 2 (ACE2) in lung lobes after single-dose administration. Single-nuclear RNA sequencing revealed that AAV5 transduces multiple cell types in the caudal lung lobes, including alveolar cells, macrophages, fibroblasts, endothelial cells, and B cells. These results demonstrate that AAV5 is efficient in the delivery of CRISPR/Cas9 in the lung lobes of young rhesus monkeys.

Original language	English (US)
Pages (from-to)	814-824
Number of pages	11
Journal	Human gene therapy
Volume	35
Issue number	19-20
DOIs	https://doi.org/10.1089/hum.2024.035
State	Published - Oct 1 2024
Externally published	Yes

Bibliographical note

Publisher Copyright:
ª 2024 by Mary Ann Liebert, Inc.

Keywords

AAV5
CRISPR
lung
rhesus monkey

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

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10.1089/hum.2024.035

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Liang, S. Q., Navia, A. W., Ramseier, M., Zhou, X., Martinez, M., Lee, C., Zhou, C., Wu, J., Xie, J., Su, Q., Wang, D., Flotte, T. R., Anderson, D. G., Tarantal, A. F., Shalek, A. K., Gao, G., & Xue, W. (2024). AAV5 Delivery of CRISPR/Cas9 Mediates Genome Editing in the Lungs of Young Rhesus Monkeys. Human gene therapy, 35(19-20), 814-824. https://doi.org/10.1089/hum.2024.035

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abstract = "Genome editing has the potential to treat genetic diseases in a variety of tissues, including the lung. We have previously developed and validated a dual adeno-associated virus (AAV) CRISPR platform that supports effective editing in the airways of mice. To validate this delivery vehicle in a large animal model, we have shown that intratracheal instillation of CRISPR/Cas9 in AAV5 can edit a housekeeping gene or a disease-related gene in the lungs of young rhesus monkeys. We observed up to 8% editing of angiotensin-converting enzyme 2 (ACE2) in lung lobes after single-dose administration. Single-nuclear RNA sequencing revealed that AAV5 transduces multiple cell types in the caudal lung lobes, including alveolar cells, macrophages, fibroblasts, endothelial cells, and B cells. These results demonstrate that AAV5 is efficient in the delivery of CRISPR/Cas9 in the lung lobes of young rhesus monkeys.",

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AU - Martinez, Michele

AU - Lee, Charles

AU - Zhou, Chen

AU - Wu, Joae

AU - Xie, Jun

AU - Su, Qin

AU - Wang, Dan

AU - Flotte, Terence R.

AU - Anderson, Daniel G.

AU - Tarantal, Alice F.

AU - Shalek, Alex K.

AU - Gao, Guangping

AU - Xue, Wen

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AB - Genome editing has the potential to treat genetic diseases in a variety of tissues, including the lung. We have previously developed and validated a dual adeno-associated virus (AAV) CRISPR platform that supports effective editing in the airways of mice. To validate this delivery vehicle in a large animal model, we have shown that intratracheal instillation of CRISPR/Cas9 in AAV5 can edit a housekeeping gene or a disease-related gene in the lungs of young rhesus monkeys. We observed up to 8% editing of angiotensin-converting enzyme 2 (ACE2) in lung lobes after single-dose administration. Single-nuclear RNA sequencing revealed that AAV5 transduces multiple cell types in the caudal lung lobes, including alveolar cells, macrophages, fibroblasts, endothelial cells, and B cells. These results demonstrate that AAV5 is efficient in the delivery of CRISPR/Cas9 in the lung lobes of young rhesus monkeys.

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KW - CRISPR

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AAV5 Delivery of CRISPR/Cas9 Mediates Genome Editing in the Lungs of Young Rhesus Monkeys

Abstract

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Keywords

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