Repeat administration of an adenovirus vector encoding cystic fibrosis transmembrane conductance regulator to the nasal epithelium of patients with cystic fibrosis.

Zabner, Joseph; Ramsey, Bonnie W.; Meeker, David P.; Aitken, Moira L.; Balfour, Rosemary; Gibson, Ronald L.; Launspach, Janice L.; Moscicki, Richard A.; Richards, Susan; Standaert, T. A.

doi:10.1172/jci118573

Cited by 253 publications

(146 citation statements)

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“…16 -20 IL -12 activates NK 27 The immune response induced by an adenovirus can lead to the rapid elimination of the vector, resulting in reduced effectiveness on subsequent administration. 8 Nonviral vectors offer several advantages over viral ones and have received increasing attention as potential vehicles for gene delivery in clinical practice. Specifically, PEI, a cationic polymer, has been shown to be an effective gene delivery vehicle in vivo, 28 -32 and PEI /DNA complexes have been shown to be stable and to deposit uniformly throughout the lung when administered in aerosol form.…”

Section: Discussionmentioning

confidence: 99%

“…Nonviral gene -delivery systems avoid the strong immune response that has limited gene expression and hampered the use of adenoviral gene therapy in many patients. 8 Additionally, liposomes (Lip) and polyethylenimine (PEI ) have both been shown to be efficient vectors for gene transfer in vivo. 9 -11 PEI is an organic macromolecule having the highest cationic charge density potential.…”

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Eradication of osteosarcoma lung metastases following intranasal interleukin-12 gene therapy using a nonviral polyethylenimine vector

et al. 2002

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The use of adenoviral vectors for therapeutic delivery of genes via pulmonary application poses several problems in terms of immune responses. The purpose of this study was to determine whether polyethylenimine ( PEI ), a polycationic DNA carrier, can be used to deliver the IL -12 gene into the lungs of mice having microscopic osteosarcoma ( OS ) lung metastases. Incubation of SAOS -LM6 cells in vitro with PEI containing the murine IL -12 ( mIL -12 ) gene ( PEI:IL -12 ) resulted in expression of both the p35 and p40 subunits of IL -12 mRNA and production of mIL -12 protein. Using our newly developed OS nude mouse model, we demonstrated that treatment of mice using intranasal PEI:IL -12 resulted in significant IL -12 mRNA expression in the lung but not the liver. Furthermore, plasma IL -12 was undetectable after up to 4 weeks of intranasal PEI:IL -12 therapy given twice weekly. No IL -12 expression was seen following intranasal PEI therapy alone. The number of lung metastases in animals that received intranasal PEI:IL -12 twice weekly for 4 weeks starting 6 weeks after tumor inoculation was significantly decreased ( median, 11; range, 0 -47 ) compared with those that received PEI alone ( median, 89; range, 2 to >200; P = .012 ). Also, the size of the nodules was significantly smaller in the PEI:IL -12 -treated animals, with 90% measuring 0.5 mm in diameter compared with 56% in the PEI -alone group. Animals that received PEI alone also had numerous large nodules ( 3 -6 mm ) throughout the lungs. Intranasal therapy is a noninvasive way to administer agents and has the advantage of targeting the pulmonary region, resulting in higher concentrations in the tumor area. Additionally, delivery of IL -12 to the lung via the airway using PEI may avoid systemic toxicity. Because OS metastasizes almost exclusively to the lung, this may be a novel approach to the treatment of pulmonary OS metastases. Cancer Gene Therapy ( 2002 ) 9, 260 -266 DOI: 10.1038 / sj / cgt / 7700432Keywords: osteosarcoma; lung metastasis; PEI; IL -12; intranasal therapy D espite multiple changes in the adjuvant chemotherapy regimens used to treat osteosarcoma (OS ), the 2-year metastasis -free survival rate in patients having this disease has stagnated at 65 -70%. 1 -3 The majority of OS patients who have a relapse do so within the first year while receiving chemotherapy. In these patients, the lung is the most common site of metastatic spread. Those who initially present with metastatic lung disease have an even higher rate of treatment failure, as no more than 15% achieve long -term metastasis -free survival. Although the majority of OS patients having pulmonary metastases can be rendered disease-free using thoracic surgery, 80 -85% will have a relapse in the lung within 1 year; 4,5 salvage chemotherapy has been disappointing in improving this progression-free interval. This indicates that patients may benefit from new approaches and agents targeted specifically to pulmonary metastases.Our laboratory has recently developed an experimental OS lung me...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Eradication of osteosarcoma lung metastases following intranasal interleukin-12 gene therapy using a nonviral polyethylenimine vector

et al. 2002

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“…The two most widely used gene transfer systems are cationic lipids and adenoviruses, with both assessed in phase I studies of nasal and pulmonary delivery. [1][2][3][4][5][6][7][8] Results have been encouraging, though only limited correction of the CF bioelectric defect has been observed. With respect to the extent of gene transfer needed, a present best estimate might be approximately 5% of normal cystic fibrosis transmembrane conductance regulator (CFTR) mRNA levels within every cell, 9 complete correction of the chloride defect in approximately 5% of cells within the airway epithelium, 10 or likely some combination of the two.…”

Section: Introductionmentioning

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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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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“…Recombinant adenoviruses have been used to transfer the gene encoding CFTR in vitro and in vivo, and clinical trials are in progress at several major CF centers in the USA. [5][6][7][8][9][10] Several potential barriers to successful adenovirus-mediated gene transfer to the airways have been recognized which include the need for repeated delivery to maintain transgene expression, 11 the host inflammatory response to the vector, and specific immune responses to adenovirus vectors. [12][13][14] In vivo models used so far to conduct published studies of adenovirus-mediated gene transfer to the lungs have employed animals with uninfected, uninflamed lungs at the time of vector administration.…”

Section: Introductionmentioning

confidence: 99%

Effects of bronchopulmonary inflammation induced by Pseudomonas aeruginosa on adenovirus-mediated gene transfer to airway epithelial cells in mice

1998

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Repeat administration of an adenovirus vector encoding cystic fibrosis transmembrane conductance regulator to the nasal epithelium of patients with cystic fibrosis.

Cited by 253 publications

References 30 publications

Eradication of osteosarcoma lung metastases following intranasal interleukin-12 gene therapy using a nonviral polyethylenimine vector

Eradication of osteosarcoma lung metastases following intranasal interleukin-12 gene therapy using a nonviral polyethylenimine vector

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

Effects of bronchopulmonary inflammation induced by Pseudomonas aeruginosa on adenovirus-mediated gene transfer to airway epithelial cells in mice

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