{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:18:29Z","timestamp":1790360309129,"version":"4.1.0"},"reference-count":48,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2009,3,30]],"date-time":"2009-03-30T00:00:00Z","timestamp":1238371200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2009,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Mediation of RNA interference by oligonucleotides constitutes a powerful approach for the silencing of genes involved in the pathogenesis of inflammatory disease, but in vivo application of this technique requires effective delivery to immune cells and\/or sites of inflammation. The aim of the present study was to develop a new carrier system to mediate systemic administration of oligonucleotides to rheumatoid arthritis (RA) joints, and to develop an antisense oligonucleotide (ASO)\u2013based approach to interfere with CD40\u2013CD154 interactions in an experimental model of RA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A novel liposomal carrier with amphoteric properties, termed Nov038, was developed and assessed for its ability to systemically deliver an ASO directed against CD40 (CD40\u2010ASO). Male DBA\/1 mice with collagen\u2010induced arthritis were treated with Nov038\u2010encapsulated CD40\u2010ASO, and the effects of treatment on various parameters of disease activity, including clinical score, paw swelling, lymph node responses, and inflammatory cytokine production in the joints, were assessed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Nov038 was well tolerated, devoid of immune\u2010stimulatory effects, and efficacious in mediating systemic oligonucleotide delivery to sites of inflammation. In mice with collagen\u2010induced arthritis, Nov038 enabled the therapeutic administration of CD40\u2010ASO and improved established disease, while unassisted CD40\u2010ASO was ineffective, and anti\u2013tumor necrosis factor \u03b1 (anti\u2010TNF\u03b1) treatment was less effective in this model. Nov038\/CD40\u2010ASO efficacy was attributed to its tropism for monocyte\/macrophages and myeloid dendritic cells (DCs), resulting in rapid down\u2010regulation of CD40, inhibition of DC antigen presentation, and reduction in collagen\u2010specific T cell responses, as well as decreased levels of TNF\u03b1, interleukin\u20106 (IL\u20106), and IL\u201017 in arthritic joints.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Amphoteric liposomes represent a novel carrier concept for systemic and antigen\u2010presenting cell\u2013targeted oligonucleotide delivery with clinical applicability and numerous potential applications, including target validation in vivo and inflammatory disease therapeutics. Moreover, Nov038\/CD40\u2010ASO constitutes a potent alternative to monoclonal antibody\u2013based approaches for interfering with CD40\u2013CD40L interactions.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.24434","type":"journal-article","created":{"date-parts":[[2009,3,31]],"date-time":"2009-03-31T01:45:08Z","timestamp":1238463908000},"page":"994-1005","source":"Crossref","is-referenced-by-count":42,"title":["Amphoteric liposomes enable systemic antigen\u2010presenting cell\u2013directed delivery of CD40 antisense and are therapeutically effective in experimental arthritis"],"prefix":"10.1002","volume":"60","author":[{"given":"Evangelos","family":"Andreakos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Una","family":"Rauchhaus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athanassios","family":"Stavropoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerold","family":"Endert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volkmar","family":"Wendisch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amina S.","family":"Benahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stavros","family":"Giaglis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Karras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Gaus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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