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

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