ArticleMolecular therapy : the journal of the American Society of Gene Therapy2014
Overcoming the cystic fibrosis sputum barrier to leading adeno-associated virus gene therapy vectors.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 88 citations in OpenAlex.
- Micro/nanoscale bubble-mediated mucolytic conditioning of the lung model of cystic fibrosis enhances nanoparticle transport through the mucus.Biomaterials · 2026Article
- Airway mucins function as endogenous inhibitors of neutrophil extracellular traps.bioRxiv : the preprint server for biology · 2026Article
- Barrier Function of the Extracellular Matrix in AAV Gene Therapy.Cellular and molecular bioengineering · 2026Article
- Aerosol Delivery of Polyelectrolyte Surfactant-Antimicrobial Nanoparticles to the Lungs.Pharmaceutical research · 2026Article
- A highly mobile adeno-associated virus targeting vascular smooth muscle cells for the treatment of pulmonary arterial hypertension.Nature biomedical engineering · 2025Article
- Antimicrobial Loaded Graft-Copolymer Nanoparticles for Treatment ofbioRxiv : the preprint server for biology · 2025Article
- Recent strategies for enhanced delivery of mRNA to the lungs.Nanomedicine (London, England) · 2025Review
- AAV-based gene delivery of antimicrobial peptides to combat drug-resistant pathogens.Applied and environmental microbiology · 2025Review
- Inhalable and bioactive lipid-nanomedicine based on bergapten for targeted acute lung injury therapy via orchestrating macrophage polarization.Bioactive materials · 2025Article
- Recent Advances in Therapeutics and Manufacturing Processes of Recombinant Adeno-Associated Virus for the Treatment of Lung Diseases.Current gene therapy · 2025Review
- Synthetic mucus barrier arrays as a nanoparticle formulation screening platform.RSC pharmaceutics · 2024Article
- Tyrosine-Mutant AAV8 Vector Mediated Efficient and Safe Gene Transfer of Pigment Epithelium-Derived Factor to Mouse Lungs.Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology · 2023Article
- Effective viral-mediated lung gene therapy: is airway surface preparation necessary?Gene therapy · 2023Review
- Airway mucus in pulmonary diseases: Muco-adhesive and muco-penetrating particles to overcome the airway mucus barriers.International journal of pharmaceutics · 2023Review
- Increasing stiffness promotes pulmonary retention of ligand-directed dexamethasone-loaded nanoparticle for enhanced acute lung inflammation therapy.Bioactive materials · 2023Article
- Cervicovaginal mucus barrier properties during pregnancy are impacted by the vaginal microbiome.Frontiers in cellular and infection microbiology · 2023Article
- Article
- An optimized protocol for assessment of sputum macrorheology in health and muco-obstructive lung disease.Frontiers in physiology · 2022Article
- Gene Therapy Approach with an Emphasis on Growth Factors: Theoretical and Clinical Outcomes in Neurodegenerative Diseases.Molecular neurobiology · 2022Review
- Tissue and cell-type-specific transduction using rAAV vectors in lung diseases.Journal of molecular medicine (Berlin, Germany) · 2021Review
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 1 country.
Funding
Abstract
Gene therapy has not yet improved cystic fibrosis (CF) patient lung function in human trials, despite promising preclinical studies. In the human CF lung, inhaled gene vectors must penetrate the viscoelastic secretions coating the airways to reach target cells in the underlying epithelium. We investigated whether CF sputum acts as a barrier to leading adeno-associated virus (AAV) gene vectors, including AAV2, the only serotype tested in CF clinical trials, and AAV1, a leading candidate for future trials. Using multiple particle tracking, we found that sputum strongly impeded diffusion of AAV, regardless of serotype, by adhesive interactions and steric obstruction. Approximately 50% of AAV vectors diffused >1,000-fold more slowly in sputum than in water, with large patient-to-patient variation. We thus tested two strategies to improve AAV diffusion in sputum. We showed that an AAV2 mutant engineered to have reduced heparin binding diffused twice as fast as AAV2 on average, presumably because of reduced adhesion to sputum. We also discovered that the mucolytic N-acetylcysteine could markedly enhance AAV diffusion by altering the sputum microstructure. These studies underscore that sputum is a major barrier to CF gene delivery, and offer strategies for increasing AAV penetration through sputum to improve clinical outcomes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.