Gene therapy in autoimmune, demyelinating disease of the central nervous system

Baker, David; Hankey, Deborah J.R.

doi:10.1038/sj.gt.3302025

Cited by 39 publications

(23 citation statements)

References 122 publications

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“…In recent years, a variety of gene therapy strategies have been used in EAE. [14][15][16][17][18] One approach has been to genetically modify antigen-specific T cells to deliver immunoregulatory molecules. [45][46][47][48][49] Direct injection of naked DNA encoding anti-inflammatory cytokines has also been the focus of a significant number of EAE studies.…”

Section: Discussionmentioning

confidence: 99%

“…5,13 Development of therapies aimed at specifically deleting or tolerizing (anergizing) these cells, so they no longer respond to myelin antigen, is the ultimate goal of this and other studies. [14][15][16][17][18] Murine experimental autoimmune encephalomyelitis (EAE) is considered to be a powerful animal model for the study of both the immunological mechanisms of myelin destruction and for the testing of potential therapies for MS. [19][20][21] The disease can be induced by injection of genetically susceptible animals with myelin proteins and closely resembles the course, clinical manifestations and pathology of relapsing and remitting MS. In female SJL/J mice used in this study, the first attack is mediated by CD4 T cells specific for proteolipid protein (PLP) amino acids 139-151.…”

Section: Introductionmentioning

confidence: 99%

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Cell-based gene therapy experiments in murine experimental autoimmune encephalomyelitis

Louie

Weiner

et al. 2005

Gene Ther

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With the ultimate goal of developing a novel treatment for multiple sclerosis (MS), we have developed a cell-based gene therapy protocol for the treatment of murine experimental autoimmune encephalomyelitis (EAE), a powerful animal model for MS. We have determined that transduced fibroblasts secreting encephalogenic epitopes, when injected into mice with EAE, cause a striking abrogation of disease. Both myelin basic protein (MBP) and proteolipid protein mini-gene constructs expressed in syngeneic fibroblast cells were capable of ameliorating ongoing EAE induced by MBP protein. These experiments are crucial since they suggest that not all encephalogenic epitopes need be secreted for the control of disease. We also demonstrate the success of this protocol when transduced syngeneic, and most importantly, allogeneic cells are sequestered within an implantable chamber. Furthermore, we find that through modifying antigen expression by changing the signal sequence of the mini-gene construct, we were able to significantly reduce the dose of cells required for treatment. These improvements to the minigene delivery system are critical for the eventual translation of our protocol to the clinic.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cell-based gene therapy experiments in murine experimental autoimmune encephalomyelitis

Louie

Weiner

et al. 2005

Gene Ther

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“…[9][10][11] In this study, the eukaryotic cell expression plasmid VEGF-PE38 were directly administered via multiple local intratumoral delivery. After 16 d, the tumor volume in mice treated with pVEGF165PE38-IRES2-EGFP was significantly lower than that in the control groups.…”

Section: Discussionmentioning

confidence: 99%

“…[9][10][11] In addition, normal adult vasculature endothelial cells are usually in a state of dormancy, where there is very little expression of VEGF receptor except during wound healing and in the ovarian cycle. 12 Therefore, VEGFRbearing tumor vasculature endothelial cells can serve as a potential therapeutic target for cancer in vivo.…”

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confidence: 99%

Investigation of a plasmid containing a novel immunotoxin VEGF165‐PE38 gene for antiangiogenic therapy in a malignant glioma model

Chen

et al. 2010

Intl Journal of Cancer

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Inhibition of tumor neovascularization has profound effects on the growth of solid tumors. Our previous studies have shown the effect of VEGF165-PE38 recombinant immunotoxin on proliferation and apoptosis in human umbilical vein endothelial cells in vitro. In this study, we explored the direct inhibition of angiogenesis in chick chorioallantoic membrane and antiangiogenic therapy in a malignant glioma model. HEK293 cells were transfected with the pVEGF165PE38-IRES2-EGFP plasmid. ELISA was used to confirm the expression of VEGF165-PE38 in the transfected cells. These cells released 1396 6 131.9 pg VEGF165-PE38/1310 4 cells/48 h into the culture medium and the supernatant was capable of inhibiting the growth of capillary-like structures in chick chorioallantoic membrane assay. In a murine malignant glioma model, plasmid was directly administered via multiple local intratumoral delivery. After day 16 the tumor volume in mice treated with pVEGF165PE38-IRES2-EGFP was significantly lower than that in mice in the control groups. Immunohistochemistry studies showed that the treated group had decreased expression of CD31. ). Immunohistochemistry analysis indicated that immunotoxin VEGF165-PE38 was distributed in the treated group in malignant glioma tissue. Our findings provide evidence that the in vivo production of VEGF165-PE38 through gene therapy using a eukaryotic expression plasmid had potential antiangiogenic activity in malignant glioma in vivo.A promising approach to cancer therapy is based on an attack on new blood vessels rather than a direct attack on cancer cells. This approach may, thus, multiply the effects of anticancer drugs. 1 In addition, such a stromal therapy approach carries the prospect of being less prone to resistance mechanisms theoretically due to genetic stability.2 Several reports have indicated that therapies aimed at tumor vasculature such as angiostatin, endostatin, humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF; bevacizumab) and other small molecule receptor tyrosine kinase inhibitors (sorafenib and sunitinib) 3 can lead to rapid regression of existing tumors. However, these inhibitors of angiogenesis do not destroy tumor vasculature, which can regenerate when these drugs are discontinued.4 These concerns raise the following questions with respect to improving antiangiogenic therapy: is it possible to find a therapeutic strategy aimed at destroying tumor vasculature endothelial cells but not inhibiting normal vasculature endothelial cell growth? Is it possible to completely destroy the tumor vasculature network system?Immunotoxin is a hybrid molecule that consists of a targeting moiety and a toxic moiety. 5,6 Pseudomonas exotoxin (PE) is often used as a toxic moiety because it is highly toxic to eukaryotic cells. Monoclonal antibodies as well as cytokines and

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“…Gene therapy as a delivery tool has been used repeatedly and proven to be effective in animal EAE treatment. [13][14][15] Therefore, we also hypothesized that a recombinant immunotoxin could be expressed in vivo and achieve the therapeutic efficacy. Based on these assumptions, we constructed a recombinant immunotoxin in an eukaryotic cell expression plasmid consisting of regulated on activation normal T cells expressed and secreted (RANTES) as the targeting moiety and DT390 as the toxic moiety in the hope that it could be expressed in vivo and useful in the treatment of EAE.…”

Section: Introductionmentioning

confidence: 99%

Prevention of murine experimental autoimmune encephalomyelitis by in vivo expression of a novel recombinant immunotoxin DT390-RANTES

Chen

et al. 2006

Gene Ther

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Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated autoimmune disease. Chemokine receptor CCR5 has been shown to be essential for the T-cell recruitment to the inflammatory site in EAE. In this study, we assumed that an immunotoxin directed at CCR5 + cells would be able to reduce the disease activity of EAE. A recombinant immunotoxin, DT390-RANTES-SRa, was constructed in an eukaryotic cell expression plasmid consisting of regulated on activation normal T cells expressed and secreted (RANTES) as the targeting moiety and DT390 as the toxic moiety. DT390-RANTES was expressed in vitro and was highly toxic to activated mouse T cells with the inhibitory concentration 50 at 0.18 ng/ml. To evaluate whether DT390-RANTES was effective in preventing EAE, C57BL/6 mice were immunized with myelin basic protein, emulsified with complete Freund's adjuvant and were treated by injecting cationic liposome-embedded plasmid DNA into the muscle of hind limbs. Mice treated with DT390-RANTES-SRa developed a much milder EAE compared to mice treated with phosphate-buffered saline or the empty plasmid DNA. Much less CCR5 + -infiltrating cells were found in the central nervous system in DT390-RANTES-SRa-treated mice than in the control mice. This study indicates that recombinant immunotoxin can be expressed in vivo, and targeting CCR5 can attenuate the disease activity of EAE in mice.

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Gene therapy in autoimmune, demyelinating disease of the central nervous system

Cited by 39 publications

References 122 publications

Cell-based gene therapy experiments in murine experimental autoimmune encephalomyelitis

Cell-based gene therapy experiments in murine experimental autoimmune encephalomyelitis

Investigation of a plasmid containing a novel immunotoxin VEGF165‐PE38 gene for antiangiogenic therapy in a malignant glioma model

Prevention of murine experimental autoimmune encephalomyelitis by in vivo expression of a novel recombinant immunotoxin DT390-RANTES

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