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Gene delivery followed by ex vivo lung perfusion using an adeno-associated viral vector in a rodent lung transplant model.

Publication ,  Journal Article
Gao, Q; Kahan, R; Gonzalez, TJ; Zhang, M; Alderete, IS; DeLaura, I; Kesseli, SJ; Song, M; Asokan, A; Barbas, AS; Hartwig, MG
Published in: J Thorac Cardiovasc Surg
September 9, 2023

OBJECTIVE: Ex vivo lung perfusion has emerged as a platform for organ preservation, evaluation, and restoration. Gene delivery using a clinically relevant adeno-associated vector during ex vivo lung perfusion may be useful in optimizing donor allografts while the graft is maintained physiologically active. We evaluated the feasibility of adeno-associated vector-mediated gene delivery during ex vivo lung perfusion in a rat transplant model. Additionally, we assessed off-target effects and explored different routes of delivery. METHODS: Rat heart-lung blocks were procured and underwent 1-hour ex vivo lung perfusion. Before ex vivo lung perfusion, 4e11 viral genome luciferase encoding adeno-associated vector 9 was administered via the left bronchus (Br group, n = 4), via the left pulmonary artery (PA group, n = 3), or directly into the circuit (Circuit group, n = 3). Donor lungs in the Control group (n = 3) underwent ex vivo lung perfusion without adeno-associated vector 9. Only the left lung was transplanted. Animals underwent bioluminescence imaging weekly before being killed at 2 weeks. Tissues were collected for luciferase activity measurement. RESULTS: All recipients tolerated the transplant well. At 2 weeks post-transplant, luciferase activity in the transplanted lung was significantly higher among animals in the Br group compared with the other 3 groups (Br: 1.1 × 106 RLU/g, PA: 8.3 × 104 RLU/g, Circuit: 3.8 × 103 RLU/g, Control: 2.5 × 103 RLU/g, P = .0003). No off-target transgene expression was observed. CONCLUSIONS: In this work, we demonstrate that a clinically relevant adeno-associated vector 9 vector mediates gene transduction during ex vivo lung perfusion in rat lung grafts when administered via the airway and potentially the pulmonary artery. Our preliminary results suggest a higher transduction efficiency when adeno-associated vector 9 was delivered via the airway, and delivery during ex vivo lung perfusion reduces off-target effects after graft implant.

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Published In

J Thorac Cardiovasc Surg

DOI

EISSN

1097-685X

Publication Date

September 9, 2023

Location

United States

Related Subject Headings

  • Respiratory System
  • 3202 Clinical sciences
  • 3201 Cardiovascular medicine and haematology
  • 1103 Clinical Sciences
  • 1102 Cardiorespiratory Medicine and Haematology
 

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Gao, Q., Kahan, R., Gonzalez, T. J., Zhang, M., Alderete, I. S., DeLaura, I., … Hartwig, M. G. (2023). Gene delivery followed by ex vivo lung perfusion using an adeno-associated viral vector in a rodent lung transplant model. J Thorac Cardiovasc Surg. https://doi.org/10.1016/j.jtcvs.2023.08.047
Gao, Qimeng, Riley Kahan, Trevor J. Gonzalez, Min Zhang, Isaac S. Alderete, Isabel DeLaura, Samuel J. Kesseli, et al. “Gene delivery followed by ex vivo lung perfusion using an adeno-associated viral vector in a rodent lung transplant model.J Thorac Cardiovasc Surg, September 9, 2023. https://doi.org/10.1016/j.jtcvs.2023.08.047.
Gao Q, Kahan R, Gonzalez TJ, Zhang M, Alderete IS, DeLaura I, et al. Gene delivery followed by ex vivo lung perfusion using an adeno-associated viral vector in a rodent lung transplant model. J Thorac Cardiovasc Surg. 2023 Sep 9;
Gao, Qimeng, et al. “Gene delivery followed by ex vivo lung perfusion using an adeno-associated viral vector in a rodent lung transplant model.J Thorac Cardiovasc Surg, Sept. 2023. Pubmed, doi:10.1016/j.jtcvs.2023.08.047.
Gao Q, Kahan R, Gonzalez TJ, Zhang M, Alderete IS, DeLaura I, Kesseli SJ, Song M, Asokan A, Barbas AS, Hartwig MG. Gene delivery followed by ex vivo lung perfusion using an adeno-associated viral vector in a rodent lung transplant model. J Thorac Cardiovasc Surg. 2023 Sep 9;
Journal cover image

Published In

J Thorac Cardiovasc Surg

DOI

EISSN

1097-685X

Publication Date

September 9, 2023

Location

United States

Related Subject Headings

  • Respiratory System
  • 3202 Clinical sciences
  • 3201 Cardiovascular medicine and haematology
  • 1103 Clinical Sciences
  • 1102 Cardiorespiratory Medicine and Haematology