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 S Hanes, George Aslanidi, Jung Soo Suk

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)296-304
Number of pages9
JournalMolecular Therapy - Methods and Clinical Development
Volume9
DOIs
StatePublished - Jun 15 2018

Fingerprint

Mucus
Genetic Therapy
Dependovirus
Transgenes
Cystic Fibrosis
Epithelium
Lung
Capsid
Airway Obstruction
Point Mutation
Transgenic Mice
Air
Clinical Trials
Serogroup

Keywords

  • adeno-associated virus
  • airway mucus
  • inhaled gene therapy
  • muco-obstructive lung disease

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

An Adeno-Associated Viral Vector Capable of Penetrating the Mucus Barrier to Inhaled Gene Therapy. / Duncan, Gregg A.; Kim, Namho; Colon-Cortes, Yanerys; Rodriguez, Jason; Mazur, Marina; Birket, Susan E.; Rowe, Steven M.; West, Natalie E; Livraghi-Butrico, Alessandra; Boucher, Richard C.; Hanes, Justin S; Aslanidi, George; Suk, Jung Soo.

In: Molecular Therapy - Methods and Clinical Development, Vol. 9, 15.06.2018, p. 296-304.

Research output: Contribution to journalArticle

Duncan, GA, Kim, N, Colon-Cortes, Y, Rodriguez, J, Mazur, M, Birket, SE, Rowe, SM, West, NE, Livraghi-Butrico, A, Boucher, RC, Hanes, JS, Aslanidi, G & Suk, JS 2018, 'An Adeno-Associated Viral Vector Capable of Penetrating the Mucus Barrier to Inhaled Gene Therapy', Molecular Therapy - Methods and Clinical Development, vol. 9, pp. 296-304. https://doi.org/10.1016/j.omtm.2018.03.006
Duncan, Gregg A. ; Kim, Namho ; Colon-Cortes, Yanerys ; Rodriguez, Jason ; Mazur, Marina ; Birket, Susan E. ; Rowe, Steven M. ; West, Natalie E ; Livraghi-Butrico, Alessandra ; Boucher, Richard C. ; Hanes, Justin S ; Aslanidi, George ; Suk, Jung Soo. / An Adeno-Associated Viral Vector Capable of Penetrating the Mucus Barrier to Inhaled Gene Therapy. In: Molecular Therapy - Methods and Clinical Development. 2018 ; Vol. 9. pp. 296-304.
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