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Correction of a chronic pulmonary disease through lentiviral vector-mediated protein expression

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Title: Correction of a chronic pulmonary disease through lentiviral vector-mediated protein expression
Authors: Alton, E
Lund-Palau, H
Juarez-Molina, C
Meng, C
Bhargava, A
Pilou, A
Aziz, K
Clarke, N
Atsumi, N
Ashek, A
Wilson, M
Takata, M
Padley, S
Gill, D
Hyde, S
Morgan, C
Griesenbach, U
Item Type: Journal Article
Abstract: We have developed a novel lentiviral vector, pseudotyped with the F and HN proteins from Sendai virus (rSIV.F/HN), which produces long-lasting, high efficiency transduction of the respiratory epithelium. Here, we addressed whether this platform technology can secrete sufficient levels of a therapeutic protein into the lung to ameliorate a fatal pulmonary disease, as an exemplar of its translational capability. Pulmonary Alveolar Proteinosis (PAP) results from alveolar GM-CSF insufficiency, resulting in abnormal surfactant homeostasis and consequent ventilatory problems. Lungs of GM-CSF knockout mice were transduced with a single dose of rSIV.F/HN expressing murine (m)GM-CSF (1e5-92e7 TU/mouse); mGM-CSF expression was dose-related and persisted for at least 11 months. PAP disease biomarkers were rapidly and persistently corrected, but we noted a narrow toxicity/efficacy window. rSIV.F/HN may be a useful platform technology to deliver therapeutic proteins for lung diseases requiring long-lasting and stable expression of secreted proteins.
Issue Date: 9-Jun-2022
Date of Acceptance: 10-Apr-2022
URI: http://hdl.handle.net/10044/1/96335
DOI: 10.1016/j.omtm.2022.04.002
ISSN: 2329-0501
Publisher: Cell Press
Start Page: 382
End Page: 391
Journal / Book Title: Molecular Therapy - Methods and Clinical Development
Volume: 25
Copyright Statement: © 2022 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: GM-CSF
alveolar macrophage
autoimmune pulmonary alveolar proteinosis
gene therapy
granulocyte-macrophage colony-stimulating factor
lentiviral vector
lung gene therapy
surfactant protein
Publication Status: Published
Online Publication Date: 2022-04-14
Appears in Collections:Department of Surgery and Cancer
National Heart and Lung Institute
Faculty of Medicine

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