A second dose of a CFTR cDNA–liposome complex is as effective as the first dose in restoring cAMP-dependent chloride secretion to null CF mice trachea

Goddard, Catharine A.; Ratcliff, Rosemary; Anderson, Janice R.; Glenn, E. Myles; Brown, Sarah C. Leigh; Gill, Deborah R.; Hyde, Stephen C.; MacVinish, Lesley J.; Huang, Lee Wen; Higgins, Claire A.; Cuthbert, A. W.; Evans, Martin; Colledge, William H

doi:10.1038/sj.gt.3300515

Cited by 31 publications

(24 citation statements)

References 9 publications

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“…[11][12][13] Therefore, repeated administration is likely to be required for long-term gene expression. We have previously shown that repeated administration of DNA/liposomes can correct the CF ion transport defect in mice 18 and here we describe a clinical study to evaluate repeated administration of DNA/liposomes in CF patients.…”

Section: Discussionmentioning

confidence: 99%

“…These data are also consistent with our pre-clinical studies which indicated that a second dose of DC-Chol/DOPE liposomes was as effective as the first dose in restoring the ion transport abnormalities of CF transgenic mice. 18 This is in contrast to recombinant adenovirus, whereupon repeated administration, efficacy was markedly diminished, as anti-adenoviral antibody titre increased. 9 Thus DNA/liposomes offer a distinct advantage over current recombinant adenoviruses, in that efficacy upon repeat administration is possible without the requirement for immunosuppressive interventions.…”

Section: Figure 7 Low Chloride In Vivo Nasal Potential Difference Meamentioning

confidence: 99%

“…17 This formulation has transiently corrected the CF chloride channel defect in the nasal 16 and tracheal epithelia of mice after single and multiple doses. 18 We have previously reported the results of a single-dose clinical study in the nasal epithelium of CF patients. 12 In that study, the correction observed with our formulation was also transient, confirming the need for repeated administration.…”

Section: Introductionmentioning

confidence: 99%

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Repeat administration of DNA/liposomes to the nasal epithelium of patients with cystic fibrosis

et al. 2000

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Section: Discussionmentioning

confidence: 99%

Section: Figure 7 Low Chloride In Vivo Nasal Potential Difference Meamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Repeat administration of DNA/liposomes to the nasal epithelium of patients with cystic fibrosis

et al. 2000

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“…Previous studies have demonstrated no diminution in gene expression following repeat intratracheal administration of the LID vector in PBS 9 or intratracheal and intranasal administration of liposomes using HEPES as the diluent. 30,31 However, following repeated dosing of the vector in water, there was a 50% reduction in luciferase activity. It is possible that this was because of immune activation following LID vector instillation or possibly because of the effects of inhaled anaesthetics that have been shown to reduce luciferase expression regulated by a CMV promoter.…”

Section: Formation Of Lid Vector Complexes In Water Alters Rg Jenkinsmentioning

confidence: 99%

Formation of LID vector complexes in water alters physicochemical properties and enhances pulmonary gene expression in vivo

et al. 2003

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There is currently an urgent need to develop efficient genedelivery systems for the lung that are free of inflammatory effects. The LID vector is a synthetic gene delivery system, comprised of lipofectin (L), an integrin-targeting peptide (I) and DNA (D) that has previously been shown to have high transfection efficiency in the lung. We have assessed the effect of alternative methods of complex preparation on structural features of the complex, levels and duration of reporter gene expression and the host response to the LID vector. We have demonstrated that making the complex in water affects the structure of the LID complexes making them smaller and more stable with a more cationic surface charge than complexes prepared in phosphate-buffered saline (PBS). When the LID vector was constituted in water and instilled intratracheally into the lungs of mice there was a 10-fold increase in luciferase activity compared with preparation in PBS. Furthermore, luciferase activity was still evident 1 week following vector instillation. This enhancement may be because of altered complex structure, although effects of the hypotonic vector solution on the lung cannot be excluded. The inflammatory effects of instilling the LID vector in water were minimal, even after three administrations of the LID vector, with only mild alterations in cytokine and broncho-alveolar lavage fluid (BALF) cell profiles. These results demonstrate that the LID vector can generate high, and prolonged, levels of gene expression in the lung from small quantities of DNA and that careful attention to synthetic polyplex structure may be important to optimize efficiency of gene expression in vivo.

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“…Studies have shown that repeated application of liposomemediated gene transfer to the lungs is feasible. 13,14 Finally, contact time of the DNA-lipid complex with the surface epithelium has been shown to be an important variable determining gene transfer efficiency. 7,11 Limited data in man have shown that during periods of sleep there is a significant reduction in the rate of mucociliary clearance.…”

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Effects of altering dosing on cationic liposome-mediated gene transfer to the respiratory epithelium

Hillery

Cheng²,

Geddes

et al. 1999

Gene Ther

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Liposome-mediated gene transfer is currently sub-optimal tering an equivalent DNA dose in aliquots over a 1-3 day with respect to both the extent and duration of transgene period resulted in significantly lower gene expression and expression. We investigated whether simple changes in did not increase the duration of expression. Administration DNA dosing could enhance either of these outcomes.at different times of the day (and hence wake/sleep cycles Increasing DNA doses produced highest transgene of the animals) did not alter gene expression. We conclude expression at an intermediate dose with toxicity observed that such simple changes in dosing regimes are unlikely to at higher doses, thereby likely limiting expression. Adminiscontribute to improvements in gene transfer efficiency.

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A second dose of a CFTR cDNA–liposome complex is as effective as the first dose in restoring cAMP-dependent chloride secretion to null CF mice trachea

Cited by 31 publications

References 9 publications

Repeat administration of DNA/liposomes to the nasal epithelium of patients with cystic fibrosis

Repeat administration of DNA/liposomes to the nasal epithelium of patients with cystic fibrosis

Formation of LID vector complexes in water alters physicochemical properties and enhances pulmonary gene expression in vivo

Effects of altering dosing on cationic liposome-mediated gene transfer to the respiratory epithelium

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