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The murine lung as a factory to produce secreted intrapulmonary and circulatory proteins

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Title: The murine lung as a factory to produce secreted intrapulmonary and circulatory proteins
Authors: Paul-Smith, M
Pytel, K
Gelinas, J-F
McIntosh, J
Pringle, I
Davies, L
Chan, M
Meng, C
Bell, R
Cammack, L
Moran, C
Cameron, L
Inoue, M
Tsugumine, S
Hironaka, T
Gill, D
Hyde, S
Nathwani, A
Alton, E
Griesenbach, U
Item Type: Journal Article
Abstract: We have shown that a lentiviral vector (rSIV.F/HN) pseudotyped with the F and HN proteins from Sendai virus generates high levels of intracellular proteins after lung transduction. Here, we evaluate the use of rSIV.F/HN for production of secreted proteins. We assessed whether rSIV.F/HN transduction of the lung generates therapeutically relevant levels of secreted proteins in the lung and systemic circulation using 1-anti-trypsin (hAAT) and factor VIII (hFVIII) as exemplars. Sedated mice were transduced with rSIV.F/HN carrying either the secreted reporter gene Gaussia luciferase (GLux) or the hAAT or hFVIII cDNAs by nasal sniffing. rSIV.F/HN-hAAT transduction lead to therapeutically relevant hAAT levels (70 g/ml) in ELF, with stable expression persisting for at least 19 months from a single application. Secreted proteins produced in the lung were released into the circulation and stable expression was detectable in blood. The levels of hFVIII in murine blood approached therapeutically relevant targets. rSIV.F/HN was also able to produce secreted hAAT and hFVIII in transduced human primary airway cells. rSIV.F/HN transduction of the murine lungs leads to long-lasting and therapeutically relevant levels of secreted proteins in the lung and systemic circulation. These data broaden the use of this vector platform for a large range of disease indications.
Issue Date: 18-Jul-2018
Date of Acceptance: 16-May-2018
URI: http://hdl.handle.net/10044/1/60209
DOI: https://dx.doi.org/10.1038/s41434-018-0025-8
ISSN: 0969-7128
Publisher: Nature Publishing Group
Start Page: 345
End Page: 358
Journal / Book Title: Gene Therapy
Volume: 25
Copyright Statement: © 2019 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Sponsor/Funder: Imperial Innovations Ltd
Funder's Grant Number: 6375
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Biotechnology & Applied Microbiology
Genetics & Heredity
Medicine, Research & Experimental
Research & Experimental Medicine
MEDIATED GENE-TRANSFER
FACTOR-IX GENE
CYSTIC-FIBROSIS
ALPHA-1-ANTITRYPSIN DEFICIENCY
PSEUDOTYPED LENTIVIRUS
AUGMENTATION THERAPY
IMMUNE-RESPONSES
NASAL EPITHELIA
CLINICAL-TRIAL
DOUBLE-BLIND
Animals
DNA, Complementary
Factor VIII
Gene Transfer Techniques
Genes, Reporter
Genetic Therapy
Genetic Vectors
HN Protein
Humans
Lentivirus Infections
Lung
Mice
Protein Translocation Systems
Sendai virus
Transduction, Genetic
Transfection
Viral Fusion Proteins
Lung
Animals
Humans
Mice
Sendai virus
Lentivirus Infections
Factor VIII
HN Protein
Viral Fusion Proteins
DNA, Complementary
Gene Transfer Techniques
Transduction, Genetic
Transfection
Genes, Reporter
Genetic Vectors
Genetic Therapy
Protein Translocation Systems
06 Biological Sciences
11 Medical and Health Sciences
Biotechnology
Publication Status: Published
Appears in Collections:National Heart and Lung Institute
Department of Medicine
Faculty of Medicine



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