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 language||English (US)|
|Number of pages||9|
|Journal||Molecular Therapy - Methods and Clinical Development|
|State||Published - Jun 15 2018|
Bibliographical noteFunding Information:
We thank Liudmilla Ceboratu and William Guggino for providing the CFBE41o - cells used in this work. This work was supported by the NIH ( R01HL127413 , R01HL136617 , R35HL135816 , P30DK072482 , P30DK065988 , and P30EY001765 ) and the Cystic Fibrosis Foundation ( HANES16XX0 , SUK18I0 , and R026-CR11 ).
- adeno-associated virus
- airway mucus
- inhaled gene therapy
- muco-obstructive lung disease