Papers by Yuti Chernajovsky
The development of transcriptionally controlled systems which function in eukaryotic cells are im... more The development of transcriptionally controlled systems which function in eukaryotic cells are important for achieving regulated gene expression in gene therapy. In this study we combined the components of the tetracycline-inducible system in self-contained retroviral and plasmid vectors. Regulated reporter gene expression from the autoregulatory plas-mid pGTRTL in response to doxycycline (Dox) induction surpasses the expression observed from other self-contained retroviral and plasmid vectors. Induction kinetics and expression levels of luciferase and the therapeutic molecule, truncated soluble complement receptor 1 (sCR1) were characterised in a mouse fibroblast and a human neuroblas-toma cell line. The regulatory characteristics of the plasmids
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Journal of Neuroimmunology, 2014
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Gene Therapy for Autoimmune and Inflammatory Diseases, 2010
... Faseb J 20(9): 1315–1327 46 Reu FJ, Leaman DW, Maitra RR, Bae SI, Cherkassky L, Fox MW, Rempi... more ... Faseb J 20(9): 1315–1327 46 Reu FJ, Leaman DW, Maitra RR, Bae SI, Cherkassky L, Fox MW, Rempinski DR, Beaulieu N, MacLeod AR, Borden EC ... 7(7): 2152–2159 59 Di Poi E, Perin A, Morassi MP, Del Frate M, Ferraccioli GF, De Vita S (2007) Switching to etan-ercept in ...
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Arthritis & Rheumatism, 2010
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Annals of the Rheumatic Diseases, 2013
Latent cytokines are engineered by fusing the latency associated peptide (LAP) derived from trans... more Latent cytokines are engineered by fusing the latency associated peptide (LAP) derived from transforming growth factor-β (TGF-β) with the therapeutic cytokine, in this case interferon-β (IFN-β), via an inflammation-specific matrix metalloproteinase (MMP) cleavage site. To demonstrate latency and specific delivery in vivo and to compare therapeutic efficacy of aggrecanase-mediated release of latent IFN-β in arthritic joints to the original MMP-specific release. Recombinant fusion proteins with MMP, aggrecanase or devoid of cleavage site were expressed in CHO cells, purified and characterised in vitro by Western blotting and anti-viral protection assays. Therapeutic efficacy and half-life were assessed in vivo using the mouse collagen-induced arthritis model (CIA) of rheumatoid arthritis and a model of acute paw inflammation, respectively. Transgenic mice with an IFN-regulated luciferase gene were used to assess latency in vivo and targeted delivery to sites of disease. Efficient localised delivery of IFN-β to inflamed paws, with low levels of systemic delivery, was demonstrated in transgenic mice using latent IFN-β. Engineering of latent IFN-β with an aggrecanase-sensitive cleavage site resulted in efficient cleavage by ADAMTS-4, ADAMTS-5 and synovial fluid from arthritic patients, with an extended half-life similar to the MMP-specific molecule and greater therapeutic efficacy in the CIA model. Latent cytokines require cleavage in vivo for therapeutic efficacy, and they are delivered in a dose dependent fashion only to arthritic joints. The aggrecanase-specific cleavage site is a viable alternative to the MMP cleavage site for the targeting of latent cytokines to arthritic joints.
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Clinical and experimental immunology, Jan 24, 2014
Endoplasmic reticulum aminopeptidase 1 (ERAP1) processes peptides for MHC class I presentation an... more Endoplasmic reticulum aminopeptidase 1 (ERAP1) processes peptides for MHC class I presentation and promotes cytokine receptor ectodomain shedding. These known functions of ERAP1 may explain its genetic association with several autoimmune inflammatory diseases. In this study, we identified four novel alternatively spliced variants of ERAP1 mRNA, designated as ΔExon-11, ΔExon-13, ΔExon-14 and ΔExon-15. We also observed a rapid and differential modulation of ERAP1 mRNA levels and spliced variants in different cell types pre-treated with LPS. We have studied three full-length allelic forms of ERAP1 (R127-K528, P127-K528, P127-R528) and one spliced variant (ΔExon-11) and assessed their interactions with tumor necrosis factor receptor 1 (TNFR1) in transfected cells. We observed variation in cellular expression of different ERAP1 isoforms, with R127-K528 being expressed at a much lower level. Furthermore, the cellular expression of full-length P127-K528 and ΔExon-11 spliced variant was sig...
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European Journal of Biochemistry, 1994
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European Journal of Biochemistry, 1981
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Proceedings of the National Academy of Sciences, 1979
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In a murine relapsing experimental allergic encephalomyelitis (EAE) model, gene therapy to block ... more In a murine relapsing experimental allergic encephalomyelitis (EAE) model, gene therapy to block TNF was investigated with the use of a retroviral dimeric p75 TNF receptor (dTNFR) construct. To effectively produce these TNF inhibitors in vivo, a condi- tionally immortalized syngeneic fibroblast line was established, using a temperature-sensitive SV40 large T Ag-expressing retro- virus. These cells were subsequently infected with a retrovirus expressing soluble dTNFR. CNS-injected cells could be detected 3 mo after transplantation and were shown to produce the transgene product by immunocytochemistry and ELISA of tissue fluids. These levels of dTNFR protein were biologically active and could significantly ameliorate both acute and relapsing EAE. This cell-based gene-vector approach is ideal for delivering proteins to the CNS and has particular relevance to the control of inflam- matory CNS disease. The Journal of Immunology, 2000, 164: 2776 -2781.
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Nature Reviews Immunology, 2004
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Molecular Immunology, 1999
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Journal of Molecular Medicine, 2012
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Gene Therapy, 2003
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Biomaterials, 2009
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Arthritis & Rheumatism, 2005
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Arthritis & Rheumatism, 2010
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Proceedings of the National Academy of Sciences of the United States of America, May 29, 2012
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Papers by Yuti Chernajovsky