An Adeno-Associated Viral Vector Capable of Penetrating the Mucus Barrier to Inhaled Gene Therapy
Diffusion of the viral vectors evaluated in inhaled gene therapy clinical trials to date are largely hindered within airway mucus, which limits their access to, and transduction of, the underlying airway epithelium prior to clearance from the lung. Here, we discovered that adeno-associated virus (AA...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-06-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050118300354 |
| _version_ | 1819012587259428864 |
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| author | Gregg A. Duncan Namho Kim Yanerys Colon-Cortes Jason Rodriguez Marina Mazur Susan E. Birket Steven M. Rowe Natalie E. West Alessandra Livraghi-Butrico Richard C. Boucher Justin Hanes George Aslanidi Jung Soo Suk |
| author_facet | Gregg A. Duncan Namho Kim Yanerys Colon-Cortes Jason Rodriguez Marina Mazur Susan E. Birket Steven M. Rowe Natalie E. West Alessandra Livraghi-Butrico Richard C. Boucher Justin Hanes George Aslanidi Jung Soo Suk |
| author_sort | Gregg A. Duncan |
| collection | DOAJ |
| description | Diffusion of the viral vectors evaluated in inhaled gene therapy clinical trials to date are largely hindered within airway mucus, which limits their access to, and transduction of, the underlying airway epithelium prior to clearance from the lung. Here, we discovered that adeno-associated virus (AAV) serotype 6 was able to rapidly diffuse through mucus collected from cystic fibrosis (CF) patients, unlike previously tested AAV serotypes. A point mutation of the AAV6 capsid suggests a potential mechanism by which AAV6 avoids adhesion to the mucus mesh. Significantly greater transgene expression was achieved with AAV6 compared to a mucoadhesive serotype, AAV1, in air-liquid interface cultures of human CF bronchial epithelium with naturally secreted mucus or induced mucus hypersecretion. In addition, AAV6 achieved superior distribution and overall level of transgene expression compared to AAV1 in the airways and whole lungs, respectively, of transgenic mice with airway mucus obstruction. Our findings motivate further evaluation and clinical development of AAV6 for inhaled gene therapy. Keywords: inhaled gene therapy, muco-obstructive lung disease, adeno-associated virus, airway mucus |
| first_indexed | 2024-12-21T01:46:25Z |
| format | Article |
| id | doaj.art-5332708677764322aae6c72388bddfc5 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-12-21T01:46:25Z |
| publishDate | 2018-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-5332708677764322aae6c72388bddfc52022-12-21T19:20:00ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012018-06-019296304An Adeno-Associated Viral Vector Capable of Penetrating the Mucus Barrier to Inhaled Gene TherapyGregg A. Duncan0Namho Kim1Yanerys Colon-Cortes2Jason Rodriguez3Marina Mazur4Susan E. Birket5Steven M. Rowe6Natalie E. West7Alessandra Livraghi-Butrico8Richard C. Boucher9Justin Hanes10George Aslanidi11Jung Soo Suk12Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USACenter for Nanomedicine, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USADepartment of Pediatrics, University of Florida, Gainesville, FL 32610, USACenter for Nanomedicine, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USADepartment of Medicine, Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Medicine, Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Medicine, Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USADepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USAMarsico Lung Institute/Cystic Fibrosis Research Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USAMarsico Lung Institute/Cystic Fibrosis Research Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USACenter for Nanomedicine, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Departments of Biomedical Engineering, Environmental and Health Sciences, Oncology, Neurosurgery, and Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD 21287, USADepartment of Pediatrics, University of Florida, Gainesville, FL 32610, USA; The Hormel Institute, University of Minnesota, Austin, MN 55912, USACenter for Nanomedicine, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Corresponding author: Jung Soo Suk, PhD, Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N. Broadway, Robert H. and Clarice Smith Building, 6029, Baltimore, MD 21231, USA.Diffusion of the viral vectors evaluated in inhaled gene therapy clinical trials to date are largely hindered within airway mucus, which limits their access to, and transduction of, the underlying airway epithelium prior to clearance from the lung. Here, we discovered that adeno-associated virus (AAV) serotype 6 was able to rapidly diffuse through mucus collected from cystic fibrosis (CF) patients, unlike previously tested AAV serotypes. A point mutation of the AAV6 capsid suggests a potential mechanism by which AAV6 avoids adhesion to the mucus mesh. Significantly greater transgene expression was achieved with AAV6 compared to a mucoadhesive serotype, AAV1, in air-liquid interface cultures of human CF bronchial epithelium with naturally secreted mucus or induced mucus hypersecretion. In addition, AAV6 achieved superior distribution and overall level of transgene expression compared to AAV1 in the airways and whole lungs, respectively, of transgenic mice with airway mucus obstruction. Our findings motivate further evaluation and clinical development of AAV6 for inhaled gene therapy. Keywords: inhaled gene therapy, muco-obstructive lung disease, adeno-associated virus, airway mucushttp://www.sciencedirect.com/science/article/pii/S2329050118300354 |
| spellingShingle | Gregg A. Duncan Namho Kim Yanerys Colon-Cortes Jason Rodriguez Marina Mazur Susan E. Birket Steven M. Rowe Natalie E. West Alessandra Livraghi-Butrico Richard C. Boucher Justin Hanes George Aslanidi Jung Soo Suk An Adeno-Associated Viral Vector Capable of Penetrating the Mucus Barrier to Inhaled Gene Therapy Molecular Therapy: Methods & Clinical Development |
| title | An Adeno-Associated Viral Vector Capable of Penetrating the Mucus Barrier to Inhaled Gene Therapy |
| title_full | An Adeno-Associated Viral Vector Capable of Penetrating the Mucus Barrier to Inhaled Gene Therapy |
| title_fullStr | An Adeno-Associated Viral Vector Capable of Penetrating the Mucus Barrier to Inhaled Gene Therapy |
| title_full_unstemmed | An Adeno-Associated Viral Vector Capable of Penetrating the Mucus Barrier to Inhaled Gene Therapy |
| title_short | An Adeno-Associated Viral Vector Capable of Penetrating the Mucus Barrier to Inhaled Gene Therapy |
| title_sort | adeno associated viral vector capable of penetrating the mucus barrier to inhaled gene therapy |
| url | http://www.sciencedirect.com/science/article/pii/S2329050118300354 |
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