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

Helena Lund-Palau; Claudia Ivette Juarez-Molina; Cuixiang Meng; Anushka Bhargava; Aikaterini Pilou; Kiran Aziz; Nora Clarke; Naoko Atsumi; Ali Ashek; Michael R. Wilson; Masao Takata; Simon Padley; Deborah R. Gill; Stephen C. Hyde; Cliff Morgan; Eric W.F.W. Alton; Uta Griesenbach

Molecular Therapy: Methods & Clinical Development (Jun 2022)

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

Helena Lund-Palau,
Claudia Ivette Juarez-Molina,
Cuixiang Meng,
Anushka Bhargava,
Aikaterini Pilou,
Kiran Aziz,
Nora Clarke,
Naoko Atsumi,
Ali Ashek,
Michael R. Wilson,
Masao Takata,
Simon Padley,
Deborah R. Gill,
Stephen C. Hyde,
Cliff Morgan,
Eric W.F.W. Alton,
Uta Griesenbach

Affiliations

Helena Lund-Palau: National Heart and Lung Institute, Gene Therapy Group, Imperial College London, Faculty of Medicine, Manresa Road, London SW3 6LR, UK; UK Respiratory Gene Therapy Consortium, London SW3 6LR, UK
Claudia Ivette Juarez-Molina: National Heart and Lung Institute, Gene Therapy Group, Imperial College London, Faculty of Medicine, Manresa Road, London SW3 6LR, UK; UK Respiratory Gene Therapy Consortium, London SW3 6LR, UK
Cuixiang Meng: National Heart and Lung Institute, Gene Therapy Group, Imperial College London, Faculty of Medicine, Manresa Road, London SW3 6LR, UK
Anushka Bhargava: National Heart and Lung Institute, Gene Therapy Group, Imperial College London, Faculty of Medicine, Manresa Road, London SW3 6LR, UK; UK Respiratory Gene Therapy Consortium, London SW3 6LR, UK
Aikaterini Pilou: National Heart and Lung Institute, Gene Therapy Group, Imperial College London, Faculty of Medicine, Manresa Road, London SW3 6LR, UK; UK Respiratory Gene Therapy Consortium, London SW3 6LR, UK
Kiran Aziz: National Heart and Lung Institute, Gene Therapy Group, Imperial College London, Faculty of Medicine, Manresa Road, London SW3 6LR, UK; UK Respiratory Gene Therapy Consortium, London SW3 6LR, UK
Nora Clarke: National Heart and Lung Institute, Gene Therapy Group, Imperial College London, Faculty of Medicine, Manresa Road, London SW3 6LR, UK; UK Respiratory Gene Therapy Consortium, London SW3 6LR, UK
Naoko Atsumi: National Heart and Lung Institute, Gene Therapy Group, Imperial College London, Faculty of Medicine, Manresa Road, London SW3 6LR, UK; UK Respiratory Gene Therapy Consortium, London SW3 6LR, UK
Ali Ashek: National Heart and Lung Institute, Gene Therapy Group, Imperial College London, Faculty of Medicine, Manresa Road, London SW3 6LR, UK
Michael R. Wilson: Division of Anesthetics, Pain Medicine, and Intensive Care, Department of Surgery and Cancer, Imperial College London, London, UK
Masao Takata: Division of Anesthetics, Pain Medicine, and Intensive Care, Department of Surgery and Cancer, Imperial College London, London, UK
Simon Padley: Royal Brompton Hospital & Harefield Hospitals, London, UK
Deborah R. Gill: Radcliffe Department of Medicine, University of Oxford, Oxford, UK; UK Respiratory Gene Therapy Consortium, London SW3 6LR, UK
Stephen C. Hyde: Radcliffe Department of Medicine, University of Oxford, Oxford, UK; UK Respiratory Gene Therapy Consortium, London SW3 6LR, UK
Cliff Morgan: Royal Brompton Hospital & Harefield Hospitals, London, UK
Eric W.F.W. Alton: National Heart and Lung Institute, Gene Therapy Group, Imperial College London, Faculty of Medicine, Manresa Road, London SW3 6LR, UK; UK Respiratory Gene Therapy Consortium, London SW3 6LR, UK; Corresponding author Eric W.F.W. Alton, National Heart and Lung Institute, Gene Therapy Group, Imperial College London, Faculty of Medicine, Manresa Road, London SW3 6LR, UK.
Uta Griesenbach: National Heart and Lung Institute, Gene Therapy Group, Imperial College London, Faculty of Medicine, Manresa Road, London SW3 6LR, UK; UK Respiratory Gene Therapy Consortium, London SW3 6LR, UK

Journal volume & issue: Vol. 25
pp. 382 – 391

Abstract

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We developed a novel lentiviral vector, pseudotyped with the F and HN proteins from Sendai virus (rSIV.F/HN), that 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 lungs to ameliorate a fatal pulmonary disease as an example of its translational capability. Pulmonary alveolar proteinosis (PAP) results from alveolar granulocyte-macrophage colony-stimulating factor (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 GM-CSF (mGM-CSF; 1e5–92e7 transduction units [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.

Published in Molecular Therapy: Methods & Clinical Development

ISSN: 2329-0501 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Biology (General): Genetics; Science: Biology (General): Cytology
Website: http://www.cell.com/molecular-therapy-family/methods/latest-content

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