Common gene therapy viral vectors do not efficiently penetrate sputum from cystic fibrosis patients

Kaoru Hida, Samuel K. Lai, Jung Soo Suk, Sang Y. Won, Michael P. Boyle, Justin S Hanes

Research output: Contribution to journalArticle

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 (d∼80 nm) and adeno-associated virus (AAV serotype 5; d∼20 nm), leading to average effective diffusivities that are ∼3,000-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 ∼40-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.

Original languageEnglish (US)
Article numbere19919
JournalPLoS One
Volume6
Issue number5
DOIs
StatePublished - 2011

Fingerprint

Gene therapy
gene therapy
cystic fibrosis
Sputum
Cystic Fibrosis
Genetic Therapy
Viruses
mucus
Dependovirus
Adhesion
Mucus
adhesion
Papillomaviridae
Norwalk virus
lungs
Water
vertebrate viruses
papilloma
Lung
Adenoviridae

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Common gene therapy viral vectors do not efficiently penetrate sputum from cystic fibrosis patients. / Hida, Kaoru; Lai, Samuel K.; Suk, Jung Soo; Won, Sang Y.; Boyle, Michael P.; Hanes, Justin S.

In: PLoS One, Vol. 6, No. 5, e19919, 2011.

Research output: Contribution to journalArticle

Hida, Kaoru ; Lai, Samuel K. ; Suk, Jung Soo ; Won, Sang Y. ; Boyle, Michael P. ; Hanes, Justin S. / Common gene therapy viral vectors do not efficiently penetrate sputum from cystic fibrosis patients. In: PLoS One. 2011 ; Vol. 6, No. 5.
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