Long-term expression of human adenosine deaminase in vascular smooth muscle cells of rats: a model for gene therapy.

Lynch, Carmel M.; Clowes, Monika M.; Osborne, WR; Clowes, A W; Miller, A D

doi:10.1073/pnas.89.3.1138

Cited by 118 publications

(47 citation statements)

References 25 publications

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“…4 When the target cell type for the ADA vector is skin fibroblasts gene expression is shut down, however, the same vector maintains high levels of expression in vascular endothelial cells. 5 Several vector designs expressing the lysosomal enzyme ␤-glucuronidase (GUSB) are down-regulated in most cells, but consistently maintain expression in a small subset (1-5%) in both fibroblasts and hematopoietic cells. [6][7][8][9][10][11][12] The presence of the selectable marker sequence, bacterial neomycin resistance gene (neo), has produced inconsistent effects on retroviral vector expression.…”

Section: Introductionmentioning

confidence: 99%

Modification of multiple transcriptional regulatory elements in a Moloney murine leukemia virus gene transfer vector circumvents silencing in fibroblast grafts and increases levels of expression of the transferred enzyme

et al. 2002

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Section: Introductionmentioning

confidence: 99%

Modification of multiple transcriptional regulatory elements in a Moloney murine leukemia virus gene transfer vector circumvents silencing in fibroblast grafts and increases levels of expression of the transferred enzyme

et al. 2002

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“…We have previously demonstrated that this cell-seeding technique gives long-term and biologically significant gene expression in the intima. 10 In the present study, we demonstrate that increased PAI-1 expression in the rat carotid artery inhibits neointimal formation, increases platelet accumulation, and accelerates endothelialization of the injured carotid artery. Our findings demonstrate that PAI-1 plays an important role in neointimal formation in the rat and suggests that PAI-1 may influence the biology of the atherosclerotic lesion in humans.…”

mentioning

confidence: 74%

“…Transduced SMCs were seeded onto the luminal surface as previously described. 10 SMCs (10 5 ) were infused into the carotid artery and allowed to attach for 10 minutes.…”

Section: Smc Seeding In Vivomentioning

confidence: 99%

Local Plasminogen Activator Inhibitor Type 1 Overexpression in Rat Carotid Artery Enhances Thrombosis and Endothelial Regeneration While Inhibiting Intimal Thickening

Hasenstab

Lea

Clowes

2000

ATVB

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Abstract-Elevated levels of plasminogen activator inhibitor type 1 (PAI-1) are found in advanced atherosclerotic plaque compared with normal vessel and may contribute to plaque progression and complications associated with plaque rupture. Increased expression of PAI-1 probably contributes to the thrombotic properties of advanced atherosclerotic plaque by impeding plasmin generation and degradation of fibrin. To test this hypothesis, we have deliberately created synthetic neointimas by seeding onto the denuded luminal surface of rat carotid arteries smooth muscle cells transduced with replication-defective retrovirus encoding rat PAI-1. This cell-based gene transfer method results in stable, long-term, and localized gene expression. PAI-1 overexpression increases mural thrombus accumulation at 4 days but decreases neointimal area by 30% and 25% at 1 week and 2 weeks, respectively. PAI-1 overexpression accelerates reendothelialization of injured arteries compared with control arteries at 1 week, 2 weeks, and 1 month. PAI-1 overexpression does not alter matrix accumulation at 1 week. Increased PAI-1 expression in the rat carotid artery enhances thrombosis and endothelial regeneration while inhibiting intimal thickening. These results suggest that PAI-1 could play a direct role in the development of advanced atherosclerotic plaque and in the repair of the diseased vessel after fibrous cap disruption. Key Words: plasminogen activator inhibitor type 1 Ⅲ carotid arteries Ⅲ thrombosis Ⅲ fibrinolysis Ⅲ endothelium P lasminogen activator inhibitor type 1 (PAI-1) is the primary physiological inhibitor of the plasminogen activator system and thereby blocks the conversion of plasminogen to plasmin. The plasminogen activator (PA) system is composed of urokinase PA (uPA) and tissue PA that proteolytically convert plasminogen to the serine protease plasmin. Components of the PA system are localized to the cell surface by receptors or extracellular matrix binding sites.Increased expression of PAI-1 has been demonstrated in atherosclerotic arteries. 1,2 PAI-1 is elevated in mesenchymalappearing intimal cells at the base of the plaque and in the necrotic core. Its function in the advanced atherosclerotic lesion is not known. PAI-1 may limit the fibrinolytic capacity of the plaque. 3 It also might modulate cellular proliferation or migration in the lesion through changes in matrix composition and growth factor release. The effects of PAI-1 are likely to be exerted locally in view of the fact that a majority of patients with generalized atherosclerosis have normal plasma fibrinolytic profiles. 4,5 The various biological effects of PAI-1 generate a dilemma. 6 On the one hand, local PAI-1 overexpression should enhance fibrin accumulation and thereby contribute to the growth of atherosclerotic lesions. 3,7 On the other hand, increased PAI-1 inhibits smooth muscle cell (SMC) migration and the formation of neointima in injured mouse vessels; this result supports the hypothesis that PAI-1 overexpression retards the growth of atherosclerot...

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“…There have been various cell types which have been studied for their potential usefulness in gene therapy, including epithelial cells, endothelial cells, skin fibroblasts and myoblasts, but each of these cell lines has had problems with viability, secretion, long-term culture or rejection. 1,3,[7][8][9][10] The use of endothelial YS cells in gene therapy offers several advantages over currently used systems. These cells have a long lifespan even after being grafted in animals, they retain their phenotype over an extended period of time, they are good secretors of exogenous foreign proteins, and they are not tumorigenic when grafted in immunocompromised animals.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4][5][6][7][8][9][10] The ultimate cell to be used for cell-based gene therapy has the requirements of being easily cultured, easily transfected with genetic material, able to secrete high levels of an exogenous protein, able to be transplanted in vivo, nonmalignant, and no observed host-versus-graft effects. Atherosclerotic cardiovascular disease is the leading cause of death in the Western world today.…”

Section: Introductionmentioning

confidence: 99%

A novel endothelial cell-based gene therapy platform for the in vivo delivery of apolipoprotein E

Cioffi¹,

Sturtz²,

Wittmer³

et al. 1999

Gene Ther

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A major focus in gene therapy has been the use of recomand lesions at a young age. After transplantation of the binant viruses to deliver genes in vivo. Although this apoE secreting Pro 175 endothelial cells into apoEapproach shows much promise, there are many safety deficient mice, serum cholesterol levels were measured at concerns associated with the use of viral materials in the 2 week intervals. During the 3 months after the initiation of treatment of human diseases. Our alternative cell-based these experiments, levels of cholesterol in the animals havgene therapy approach utilizes endothelial cells (Pro 175) ing received the apoE secreting endothelial cells were statisolated from the murine embryonic yolk sac. These endoistically lower compared with the levels of age-matched thelial cells were evaluated for their potential use in gene controls having received non-secreting endothelial cells. therapy as a gene delivery platform. As a test model, we Concomitant with cholesterol reduction, atherosclerotic used these cells to deliver apolipoprotein E (apoE) in the aortic plaques were noticeably reduced in the experimental murine apoE knockout atherosclerosis model. The lack of apoE+ animals. These results highlight the potential of apoE protein in these animals results in high levels of these unique endothelial cells as an efficient delivery serum cholesterol and formation of severe aortic plaques platform for somatic gene therapy.

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Long-term expression of human adenosine deaminase in vascular smooth muscle cells of rats: a model for gene therapy.

Cited by 118 publications

References 25 publications

Modification of multiple transcriptional regulatory elements in a Moloney murine leukemia virus gene transfer vector circumvents silencing in fibroblast grafts and increases levels of expression of the transferred enzyme

Modification of multiple transcriptional regulatory elements in a Moloney murine leukemia virus gene transfer vector circumvents silencing in fibroblast grafts and increases levels of expression of the transferred enzyme

Local Plasminogen Activator Inhibitor Type 1 Overexpression in Rat Carotid Artery Enhances Thrombosis and Endothelial Regeneration While Inhibiting Intimal Thickening

A novel endothelial cell-based gene therapy platform for the in vivo delivery of apolipoprotein E

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