An Adeno-Associated Viral Vector Capable of Penetrating the Mucus Barrier to Inhaled Gene Therapy

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

Molecular Therapy: Methods & Clinical Development (Jun 2018)

An Adeno-Associated Viral Vector Capable of Penetrating the Mucus Barrier to Inhaled Gene Therapy

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

Affiliations

Gregg A. Duncan: Center 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, USA
Namho Kim: Center 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, USA
Yanerys Colon-Cortes: Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA
Jason Rodriguez: Center 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
Marina Mazur: Department of Medicine, Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Susan E. Birket: Department of Medicine, Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Steven M. Rowe: Department of Medicine, Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Natalie E. West: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Alessandra Livraghi-Butrico: Marsico Lung Institute/Cystic Fibrosis Research Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA
Richard C. Boucher: Marsico Lung Institute/Cystic Fibrosis Research Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA
Justin Hanes: Center 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, USA
George Aslanidi: Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA; The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
Jung Soo Suk: Center 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.

Journal volume & issue: Vol. 9
pp. 296 – 304

Abstract

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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

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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