Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus

Harvey, Ben-Gary; Leopold, Philip L.; Hackett, Neil R.; Grasso, T M; Williams, P. Mickey; Tucker, Amy L.; Kaner, Robert J.; Ferris, Barbara; Gonda, Igor; Sweeney, Theresa D.; Ramachandran, Rithwik; Kovesdi, Imre; Shak, Steven; Crystal, Ronald G.

doi:10.1172/jci7935

Cited by 216 publications

(124 citation statements)

References 54 publications

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“…Reports on repeat administration of adenovirus or adeno-associated virus to the lungs vary, with some studies reporting successful re-administration, 9-11 whereas other studies failed to detect gene expression after repeat administration. 6,12 Differences are likely due to different models being used, as well as different number of doses being administered. In some publications, single-dose controls are also missing, which makes an assessment of efficacy after repeated administration difficult.…”

Section: Discussionmentioning

confidence: 99%

Validation of recombinant Sendai virus in a non-natural host model

et al. 2010

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We have previously shown that recombinant Sendai virus (SeV) vector, derived from murine parainfluenza virus, is one of the most efficient vectors for airway gene transfer. We have also shown that SeV-mediated transfection on second administration, although reduced by 60% when compared with levels achieved after a single dose, is still high because of the efficient transfection achieved by SeV vector in murine airways. Here, we show that these levels further decrease on subsequent doses. In addition, we validated SeV vector repeat administration in a non-natural host model, the sheep. As part of these studies we first assessed viral stability in a Pari LC Plus nebuliser, a polyethylene catheter (PEC) and the Trudell AeroProbe. We also compared the distribution of gene expression after PEC and Trudell AeroProbe administration and quantified virus shedding after sheep transduction. In addition, we show that bronchial brushings and biopsies, collected in anaesthetized sheep, can be used to assess SeV-mediated gene expression over time. Similar to mice, gene expression in sheep was transient and had returned to baseline values by day 14. In conclusion, the SeV vector should be strongly considered for lung-related applications requiring a single administration of the vector even though it might not be suitable for diseases requiring repeat administration.

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Section: Discussionmentioning

confidence: 99%

Validation of recombinant Sendai virus in a non-natural host model

et al. 2010

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“…One of the first extensively studied vectors for lung gene therapy was recombinant adenovirus (rAd), but promising results observed in animal models were not recapitulated in early clinical trials, casting doubt on the efficacy of rAd in the human lung; transgene expression from rAd, although robust, was transient, likely due to a strong CD8 + cytotoxic T-cell response to adenovirus genes expressed in the transduced cells [11]. One way to circumvent this issue is to completely avoid the inclusion of viral coding-regions or proteins in the vector, focusing instead on non-viral mediated gene delivery; this approach continues to be extensively studied for gene therapy in the lung.…”

Section: A Brief History Of In-vivo Gene Therapymentioning

confidence: 99%

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Haasteren

Hyde

Gill

2018

Expert Opinion on Biological Therapy

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Introduction: Ex-vivo gene therapy has had significant clinical impact over the last couple of years and in-vivo gene therapy products are being approved for clinical use. Gene therapy and gene editing approaches have huge potential to treat genetic disease and chronic illness. Areas covered: This article provides a review of in-vivo approaches for gene therapy in the lung and liver, exploiting non-viral and viral vectors with varying serotypes and pseudotypes to target-specific cells. Antibody responses inhibiting viral vectors continue to constrain effective repeat administration. Lessons learned from ex-vivo gene therapy and genome editing are also discussed. Expert opinion: The fields of lung and liver in-vivo gene therapy are thriving and a comparison highlights obstacles and opportunities for both. Overcoming immunological issues associated with repeated administration of viral vectors remains a key challenge. The addition of targeted small molecules in combination with viral vectors may offer one solution. A substantial bottleneck to the widespread adoption of in-vivo gene therapy is how to ensure sufficient capacity for clinical-grade vector production. In the future, the exploitation of gene editing approaches for in-vivo disease treatment may facilitate the resurgence of non-viral gene transfer approaches, which tend to be eclipsed by more efficient viral vectors.

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“…[1][2][3][4][5][6][7][8][9][10][11] Results from these protocols have successfully demonstrated that human gene transfer is possible, and that transferred gene expression could be at sufficiently high levels to evoke biological responses which cure or control disease. [1][2][3][4][5][6][7][8][9][10][11] These results provide a theoretical basis for the feasibility of human gene therapy, suggesting broader applications for gene transfer in other common disorders such as lung injury, pulmonary fibrosis, chronic pulmonary airway diseases and asthma. [12][13][14] Among lung disorders, acute lung injury (ALI) is caused by many conditions including sepsis, multiple trauma, and pancreatitis, leading to the generalized intravascular activation of inflammatory cells and endothelial or parenchymal cell injury.…”

Section: Introductionmentioning

confidence: 99%