Common gene therapy viral vectors do not efficiently penetrate sputum from cystic fibrosis patients.
PLoS One
; 6(5): e19919, 2011.
Article
en En
| MEDLINE
| ID: mdl-21637751
ABSTRACT
Norwalk virus and human papilloma virus, two viruses that infect humans at mucosal surfaces, have been found capable of rapidly penetrating human mucus secretions. Viral vectors for gene therapy of Cystic Fibrosis (CF) must similarly penetrate purulent lung airway mucus (sputum) to deliver DNA to airway epithelial cells. However, surprisingly little is known about the rates at which gene delivery vehicles penetrate sputum, including viral vectors used in clinical trials for CF gene therapy. We find that sputum spontaneously expectorated by CF patients efficiently traps two viral vectors commonly used in CF gene therapy trials, adenovirus (dâ¼80 nm) and adeno-associated virus (AAV serotype 5; dâ¼20 nm), leading to average effective diffusivities that are â¼3,000-fold and 12,000-fold slower than their theoretical speeds in water, respectively. Both viral vectors are slowed by adhesion, as engineered muco-inert nanoparticles with diameters as large as 200 nm penetrate the same sputum samples at rates only â¼40-fold reduced compared to in pure water. A limited fraction of AAV exhibit sufficiently fast mobility to penetrate physiologically thick sputum layers, likely because of the lower viscous drag and smaller surface area for adhesion to sputum constituents. Nevertheless, poor penetration of CF sputum is likely a major contributor to the ineffectiveness of viral vector based gene therapy in the lungs of CF patients observed to date.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Esputo
/
Terapia Genética
/
Adenoviridae
/
Dependovirus
/
Fibrosis Quística
/
Vectores Genéticos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Año:
2011
Tipo del documento:
Article