Mucus altering agents as adjuncts for nonviral gene transfer to airway epithelium

Ferrari, Stefano; Kitson, Christopher; Farley, Raymond; Steel, Rachel; Marriott, Christopher; Parkins, David A.; Scarpa, Maurizio; Wainwright, Brandon; Mj, Evans; Colledge, William H; Geddes, D M; Alton, Eric W.F.W.

doi:10.1038/sj.gt.3301525

Cited by 111 publications

(82 citation statements)

References 26 publications

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“…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.…”

mentioning

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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confidence: 99%

Nacystelyn enhances adenoviral vector-mediated gene delivery to mouse airways

2007

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“…NAC is a mucolytic agent, which exhibited an improved gene transfer in pulmonary epithelium for both viral and nonviral vectors. 25,26 Studies on the effect of mucus and the role of NAC in gene transfer of the gastrointestinal tract are limited. An earlier study showed that NAC removed the mucus between the villi, but no attempt of gene transfer was made.…”

Section: Discussionmentioning

confidence: 99%

Gene therapy for barrett's esophagus: adenoviral gene transfer in different intestinal models

et al. 2005

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Caco-2 cells, closed intestinal loops and a Barrett's esophagus rat model to test transduction of adenoviruses expressing green fluorescent protein. We observed a decreased adenoviral transduction from 18.6 to 2.3% in undifferentiated and differentiated Caco-2 cells, respectively. This could be improved by the use of the mucolytic agent N-acetylcysteine (NAC) and the polycation diethylaminoethyl-dextran (DEAE-dextran), which improved transduction in differentiated cells five-and ten-fold, respectively. Also an RGD-retargeted adenovirus showed an improved transduction in differentiated cells. In closed intestinal loops adenoviral transduction was limited and the use of NAC and DEAE-dextran or RGD targeting had little effect. The Barrett's esophagus rat model consisted of an esophagojejunostomy, which results in a Barrett's esophagus and esophageal tumors within 6 months. Adenoviral transduction in this model was limited and mainly localized in the basal layer of normal esophagus and stromal tissue of a Barrett's segment. We conclude that although the adenovirus shows promising results in vitro, the current adenoviral vectors are probably not suitable for patients with Barrett's esophagus.

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“…However, transfection efficiency could be increased through pre-treatment with mucolytics or the antichiolinergic drug glycopyrolate in vitro and in vivo. 6 In addition to mucus, sputum and bronchoalveolar lavage fluid recovered from CF patients have been shown to inhibit liposome, 7 adenovirus 8 and AAV-mediated gene transfer efficiency. 9 Although recombinant DNase reduced sputum viscoelasticity and improved nanosphere migration in vitro, 10 the effect of DNase on gene transfer in vivo is unclear.…”

Section: Encouraging Progress Has Been Made To Overcome Some Of the Ementioning

confidence: 99%