The effect of mucolytic agents on gene transfer across a CF sputum barrier in vitro

Stern, M; Caplen, NJ; Browning, J. A.; Griesenbach, Uta; Sorgi, F; Huang, Leaf; Gruenert, D. C.; Marriot, C; Crystal, RG; Geddes, D M; Alton, Eric W.F.W.

doi:10.1038/sj.gt.3300556

Cited by 109 publications

(59 citation statements)

References 11 publications

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“…The effect of both gene transfer agents was significantly attenuated by CF sputum in our model system, in keeping with our previous observations using UVA-irradiated CF sputum on cell lines. 26 To our knowledge, this is the first demonstration that fresh, untreated CF sputum represents an important barrier in native airways. These studies suggest that efforts to maximise the removal of secretions should be an important prelude to clinical studies.…”

Section: Discussionmentioning

confidence: 80%

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The extra- and intracellular barriers to lipid and adenovirus-mediated pulmonary gene transfer in native sheep airway epithelium

Kitson¹,

Ángel²,

Judd³

et al. 1999

Gene Ther

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123

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Gene transfer to the respiratory epithelium is currently apical membrane represented a significant barrier to both suboptimal and may be helped by the identification of limitagents. Adenovirus-mediated expression could be signifiing biological barriers. We have, therefore, developed an cantly augmented by increasing contact time or by preex vivo model which retains many of the characteristics of treatment of tissues with a nominally calcium-free medium. in vivo native airways including mucociliary clearance,The presence of these extracellular and plasma membrane mucus coverage and an intact cellular structure. Using this barriers appeared to be the key parameters responsible for model we have demonstrated several barriers to gene the approximately three log difference in gene expression transfer. Liposome-mediated gene transfer was inhibited found in vitro compared with our ex vivo model. Cytoskeleby normal mucus, with removal of this layer increasing tal elements and the cell cycle also influenced in vitro gene expression approximately 25-fold. In addition both lipotransfer, and represent further barriers which need to be some and adenovirus were inhibited by CF sputum. The overcome.

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Section: Discussionmentioning

confidence: 80%

“…Expression was significantly reduced for both agents in the presence of sputum (Figure 4), in agreement with our previous demonstration in cell lines in vitro. 26 Is the plasma membrane a barrier to gene transfer?…”

Section: Is Mucus a Barrier To Respiratory Gene Transfer?mentioning

confidence: 99%

The extra- and intracellular barriers to lipid and adenovirus-mediated pulmonary gene transfer in native sheep airway epithelium

Kitson¹,

Ángel²,

Judd³

et al. 1999

Gene Ther

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123

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show abstract

“…NAL has also been shown to enhance cationic liposome-mediated gene transfer to the airways. 13,14 In spite of this wealth of knowledge, no studies have assessed the efficacy of NAL in enhancing adenoviral vector-mediated gene delivery to the lung.…”

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confidence: 99%

Nacystelyn enhances adenoviral vector-mediated gene delivery to mouse airways

2007

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Adenoviral vector-mediated gene delivery has been vastly investigated for cystic fibrosis (CF) gene therapy; however, one of its drawbacks is the low efficiency of gene transfer, which is due to basolateral colocalization of viral receptors, immune responses to viral vectors and the presence of a thick mucus layer in the airways of CF patients. Therefore, enhancement of gene transfer can lead to reduction in the viral dosage, which could further reduce the acute toxicity associated with the use of adenoviral vectors. Nacystelyn (NAL) is a mucolytic agent with anti-inflammatory and antioxidant properties, and has been used clinically in CF patients to reduce mucus viscosity in the airways. In this study, we show that pretreatment of the airways with NAL followed by administration of adenoviral vectors in complex with DEAE-Dextran can significantly enhance gene delivery to the airways of mice without any harmful effects. Moreover, NAL pretreatment can reduce the airway inflammation, which is normally observed after delivery of adenoviral particles. Taken together, these results indicate that NAL pretreatment followed by adenoviral vector-mediated gene delivery can be beneficial to CF patients by increasing the efficiency of gene transfer to the airways, and reducing the acute toxicity associated with the administration of adenoviral vectors.

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“…Several studies have shown that extracellular barriers such as mucus and sputum 3,4 and mucocilary clearance significantly reduce transfection efficiency. To circumvent these topical barriers, we have assessed the feasibility of intravenous (i.v.)…”

Section: Introductionmentioning

confidence: 99%

“…Several in vitro studies have shown that intracellular transport of DNA is sizedependent and smaller ODNs are able to move more quickly in the cytoplasm. 6,7 (4) ODNs are relevant to CF in the context of gene repair and downregulation of genes involved in the pathogenesis of lung disease.…”

Section: Introductionmentioning

confidence: 99%

Intravenously administered oligonucleotides can be delivered to conducting airway epithelium via the bronchial circulation

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Griesenbach

et al. 2006

Gene Ther

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The effect of mucolytic agents on gene transfer across a CF sputum barrier in vitro

Cited by 109 publications

References 11 publications

The extra- and intracellular barriers to lipid and adenovirus-mediated pulmonary gene transfer in native sheep airway epithelium

The extra- and intracellular barriers to lipid and adenovirus-mediated pulmonary gene transfer in native sheep airway epithelium

Nacystelyn enhances adenoviral vector-mediated gene delivery to mouse airways

Intravenously administered oligonucleotides can be delivered to conducting airway epithelium via the bronchial circulation

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