Gene therapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney

Isaka, Yoshitaka; Brees, Douglas K.; Ikegaya, Kazuko; Kaneda, Yasufumi; Imai, Enyu; Noble, Nancy A.; Border, Wayne A.

doi:10.1038/nm0496-418

Cited by 463 publications

(288 citation statements)

References 29 publications

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“…4,31,32 Additionally, it has also been shown that decorin inhibits TGF-b mRNA transcription and TGF-b protein synthesis. 13,33 However, these functions appear to be highly cell-type specific. In certain cellular systems, decorin blocks the activity of TGF-b, whereas in others its binding augments the bioactivity of the cytokine.…”

Section: Discussionmentioning

confidence: 99%

Effects of ectopic decorin in modulating intracranial glioma progression in vivo, in a rat syngeneic model

et al. 2004

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Given the failure of conventional treatments for glioblastoma, gene therapy has gained interest considerable in recent years. Gliomas are associated with a state of immunosuppression, which appears to be partially mediated by an increase in secretion of transforming growth factor-b (TGF-b) from glioma cells. Decorin, a small proteoglycan which can bind to and inactivate TGF-b, has been successfully used as an antitumor strategy on stably transfected tumor cells and has been shown to cause growth suppression in neoplastic cells of various histological origins. In this paper, we investigated the use of gene therapy to deliver the decorin transgene in a site-specific manner in an experimental model of intracranial gliomas. Our aim was to inhibit the glioma-associated immunosuppressive state, and prolong the survival of tumor-bearing rats.We studied the effects of decorin gene transfer in the rat CNS-1 glioma model. To assess the effect of ectopic expression of decorin on glioma progression in vivo, stably transfected CNS-1 cells expressing decorin were implanted into the brain parenchyma of syngeneic Lewis rats. The rats implanted with CNS-1 cells expressing decorin survived significantly longer than those in the control groups which received CNS-1 cells that did not express decorin (Po.0001). We then investigated whether the survival observed with decorin expressing cells could be mimicked in vivo, using recombinant adenoviruses (RAds) expressing the decorin gene under the control of two different promoters: the human immediate-early cytomegalovirus (h-IE-CMV) and the glial fibrillary acidic protein (GFAP). In vivo results showed that administration of RAd expressing the human decorin under the control of h-IE-CMV promoter has a small, but significant effect in prolonging the survival of experimental tumor bearing rats (Po.0001). Our data indicate that ectopic decorin expression has the potential to slow glioma progression in vivo. Our results also indicate that expression of decorin has to be present in all cells which constitute the intracranial tumor mass for the inhibition of tumor growth and prolongation of the life expectancy of tumor-bearing rats to be effective.

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Section: Discussionmentioning

confidence: 99%

Effects of ectopic decorin in modulating intracranial glioma progression in vivo, in a rat syngeneic model

et al. 2004

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“…[22][23][24] Moreover, TGF-β antagonism with neutralizing antibodies, soluble TGF-β receptors, and over expression decorin or dominant negative TGF-β receptors has resulted in attenuation of tissue fibrosis can be attenuated in a variety of different tissues including the heart. [25][26][27] Further, expression of Smad7, an endogenous inhibitor of TGF-β induced signaling, attenuates experimentally induced lung and kidney fibrosis. 28,29 Taken together, these observations suggest that sustained activation of TGF-β can lead to pathological tissue fibrosis and/or tissue dysfunction in a variety of organs, including the heart.…”

Section: Tgf-β Signaling and Myocardial Fibrosismentioning

confidence: 99%

Transforming growth factor-β receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor

Sakata¹,

Chancey²,

Divakaran³

et al. 2007

Basic Res Cardiol

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The mechanisms that are responsible for the development of myocardial fibrosis in the inflammatory cardiomyopathy are unknown. Previously we have generated lines of transgenic mice with cardiac restricted overexpression of tumor necrosis factor (MHCsTNF mice), a proinflammatory cytokine. The MHCsTNF mice develop a heart failure phenotype that is characterized by progressive myocardial fibrosis, as well as increase levels transforming growth factor-β (TGF-β) mRNA and protein. In order to determine whether TGF-β mediated signaling was responsible for the myocardial fibrosis observed in the MHCsTNF mice, we treated MHCsTNF and littermate control mice from 4 to 12 weeks of age with a novel orally available TGF-β receptor antagonist (NP-40208). At the time of terminal study myocardial collagen content was determined using the picrosirius red technique, and LV systolic and diastolic function were determined using the Langendorff method. Treatment with NP-40208 resulted in a significant decrease in the nuclear translocation of Smad 2/3, a decrease in heart-weight to body-weight ratio, decreased fibrillar collagen content and decreased LV chamber stiffness in the MHCsTNF mice when compared to diluent treated controls. Treatment with NP-40208 had no discernable effect on LV systolic function, nor any effect on fetal gene expression in the MHCsTNF mice. Taken together, these observations suggest that sustained pro-inflammatory signaling in the adult heart is associated with a pro-fibrotic phenotype that arises, at least in part, from TGF-β mediated signaling, with resultant activation of Smad 2/3, leading to increased myocardial fibrosis and increased LV diastolic chamber stiffness.

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“…4,[6][7][8][9] Expression of therapeutic proteins in even a small number of myofibers may be adequate to treat inherited or acquired metabolic disorders, or to induce an immune response in the context of a vaccine. 45,46 Effective methods for muscle gene transfer require vector systems that transduce cells with high efficiency and allow for persistent transgene expression.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4][5][6][7][8] Moreover, the post-mitotic nature and longevity of muscle fibers permits stable expression of transferred genes, even if they are not integrated into chromosomal DNA. 9,10 High level gene expression in a relatively small number of muscle fibers may be adequate to treat inherited or acquired metabolic disorders, or to induce an immune response sufficient for vaccination.…”

Section: Introductionmentioning

confidence: 99%

Efficient infection of mature skeletal muscle with herpes simplex virus vectors by using dextran sulfate as a co-receptor

1999

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The use of herpes simplex virus (HSV) vectors for gene chondroitin ABC lyase, HSV infection was restored, which delivery to skeletal muscle is hampered by a maturationsuggests that virus secondary receptors were present but dependent loss of muscle fiber infectivity. Previous studies not readily accessible to the virus in the intact myofiber. of HSV type 1 (HSV-1) infection in the rodent show that Surprisingly, we also found that HSV-1 infectivity could be the loss of infectivity may be due, at least in part, to the restored in vitro and in vivo by exposing myofibers to low development of the basal lamina throughout the course of concentrations of the glycosaminoglycan analog dextran maturation, which may block the initial events in HSV infecsulfate, which appears to act as a surrogate receptor to tion. To initiate infection, HSV normally attaches to cell surstabilize the virus at the myofiber surface such that HSV face heparan sulfate, which stabilizes the virus such that can engage additional receptors. This demonstration that it can interact with secondary protein receptors required the basal lamina is not an absolute block to HSV-1 infecfor entry into host cells. In this study, we demonstrate that tion is remarkable because it allows for the nondestructive heparan sulfate biosynthesis is downregulated during skeltargeting of HSV-1 to mature myofibers and greatly etal muscle maturation. When myofibers were treated with expands the usefulness of HSV as a gene therapy vector a variety of enzymes, including collagenase type IV or for the treatment of inherited and acquired diseases.

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Gene therapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney

Cited by 463 publications

References 29 publications

Effects of ectopic decorin in modulating intracranial glioma progression in vivo, in a rat syngeneic model

Effects of ectopic decorin in modulating intracranial glioma progression in vivo, in a rat syngeneic model

Transforming growth factor-β receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor

Efficient infection of mature skeletal muscle with herpes simplex virus vectors by using dextran sulfate as a co-receptor

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