Cystic fibrosis, gene therapy, and lung inflammation: for better or worse?

Schwiebert, Lisa M.

doi:10.1152/ajplung.00363.2003

Cited by 5 publications

(5 citation statements)

References 20 publications

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“…3, a N:P ratio of 20:1 was effective in delivering the luciferase reporter plasmid into cells. The aerosolized mixture can successfully deliver transgenes to the lung, and the mixture is being used clinically (38;39). In particular, PEI does not induce cellular protective responses that are characteristic of viral gene delivery.…”

Section: Resultsmentioning

confidence: 99%

REV1 Is Implicated in the Development of Carcinogen-Induced Lung Cancer

Dumstorf¹,

Mukhopadhyay²,

Krishnan³

et al. 2009

Molecular Cancer Research

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The somatic mutation hypothesis of cancer predicts that reducing the frequency of mutations induced by carcinogens will reduce the incidence of cancer. To examine this, we developed an antimutator strategy based on the manipulation of the level of a protein required for mutagenic bypass of DNA damage induced by the ubiquitous carcinogen benzo [a]pyrene. The expression of this protein, REV1, was reduced in mouse cells using a vector encoding a gene-specific targeting ribozyme. In the latter cells, mutagenesis induced by the activated form of benzo[a]pyrene was reduced by >90%. To examine if REV1 transcripts could be lowered in vivo, the plasmid was complexed with polyethyleneimine, a nonviral cationic polymer, and delivered to the lung via aerosol. The endogenous REV1 transcript in the bronchial epithelium as determined by quantitative real-time PCR in laser capture microdissected cells was reduced by 60%. There was a significant decrease in the multiplicity of carcinogen-induced lung tumors from 6.4 to 3.7 tumors per mouse. Additionally, REV1 inhibition completely abolished tumor formation in 27% of the carcinogen-exposed mice. These data support the central role of the translesion synthesis pathway in the development of lung cancer. Further, the selective modulation of members of this pathway presents novel potential targets for cancer prevention. The somatic mutation hypothesis of cancer predicts that the frequency of cancers will also be reduced.

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Section: Resultsmentioning

confidence: 99%

REV1 Is Implicated in the Development of Carcinogen-Induced Lung Cancer

Dumstorf¹,

Mukhopadhyay²,

Krishnan³

et al. 2009

Molecular Cancer Research

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“…Lung is the affected organ in the case of many serious and potentially fatal diseases, such as cystic fibrosis, lung cancer, influenza, and severe acute respiratory syndrome, and therefore serves as the target for their treatment by gene delivery. The first two diseases, e.g., may be treated by delivering plasmid DNA containing the cystic fibrosis transmembrane conductance gene (CFTR gene) and the tumor suppressor p53 gene, respectively (1,44,45). The last two diseases may be treated by the delivery of siRNA against specific genes of the viruses (6,46).…”

Section: Resultsmentioning

confidence: 99%

“…Gene therapy, the treatment or prevention of inherited (1)(2)(3) or acquired (4)(5)(6) diseases by the delivery of DNA, has attracted much attention as a promising therapeutic strategy during the past two decades (7). However, after more than a thousand clinical trials, no gene therapy protocol has yet been approved by the U.S. Food and Drug Administration.…”

Section: Introductionmentioning

confidence: 99%

Cross-linked Small Polyethylenimines: While Still Nontoxic, Deliver DNA Efficiently to Mammalian Cells in Vitro and in Vivo

et al. 2005

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“…The response of the CF lung to infection is neutrophildominated, but complex interactions occur. 35 It is unclear why a chronic monocyte/macrophage response does not develop over time, as is the usual consequence of an ongoing proinflammatory stimulus. Recently, an exciting observation was made with the finding that the resolution of inflammation might be reduced in CF cells, thus prolonging the proinflammatory, neutrophil-dominated phase of inflammation.…”

Section: Lipid Products and Inflammation: Too Little Resolution?mentioning

confidence: 99%

CFTR: More than just a chloride channel

Mehta

2005

Pediatric Pulmonology

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This review examines the cystic fibrosis transmembrane conductance regulator (CFTR) protein. After summarizing the ion channels regulated by CFTR, the review focuses on the functions of CFTR that do not relate directly to a disease mechanism based on a channelopathy. The key concept is that newly synthesized CFTR has to enter lipid vesicles which bud from the endoplasmic reticulum. This is abnormally low in DeltaF508 CFTR. Normal wild type vesicular CFTR enters a recycling pool of lipid vesicles which transiently dock with the apical membrane only for CFTR to be retrieved shortly after into a sub-apical recycling compartment. This retrieval is abnormally fast in DeltaF508 CFTR. The review discusses the relationship between this process and the difficult topic of fat metabolism and then explores the possible links between abnormal fatty acid turnover and inflammatory cascades that are abnormal in cystic fibrosis. Finally the review concentrates on the emerging functions of a protein kinase (AMP-activated kinase) which is bound near the C terminus of the CFTR protein whose functions could intergrate some of the abnormalities in lipid metabolism that result from mislocalization of CFTR in clinical disease.

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Cystic fibrosis, gene therapy, and lung inflammation: for better or worse?

Cited by 5 publications

References 20 publications

REV1 Is Implicated in the Development of Carcinogen-Induced Lung Cancer

REV1 Is Implicated in the Development of Carcinogen-Induced Lung Cancer

Cross-linked Small Polyethylenimines: While Still Nontoxic, Deliver DNA Efficiently to Mammalian Cells in Vitro and in Vivo

CFTR: More than just a chloride channel

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