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Spiegelmer Inhibition of CCL2/MCP-1 Ameliorates Lupus Nephritis in MRL-(Fas)lpr Mice

Onkar Kulkarni^*, Rahul D. Pawar^*, Werner Purschke, Dirk Eulberg, Norma Selve, Klaus Buchner, Volha Ninichuk^*, Stephan Segerer^*, Volker Vielhauer^*, Sven Klussmann and Hans-Joachim Anders^*

^* Nephrological Center, Medical Policlinic, Ludwig-Maximilians-University, Munich, and NOXXON Pharma AG, Berlin, Germany

Correspondence: Dr. Hans-Joachim Anders, Medizinische Poliklinik der LMU, Pettenkoferstrasse 8a, 80336 Munich, Germany. Phone: +49-89-218075846; Fax: +49-89-218074860; E-mail: hjanders{at}med.uni-muenchen.de

Received for publication December 13, 2006. Accepted for publication May 16, 2007.

The monocyte chemoattractant protein CCL2 is crucial for monocyte and T cell recruitment from the vascular to the extravascular compartment at sites of inflammation. CCL2 is expressed in human lupus nephritis and was shown to mediate experimental lupus; therefore, CCL2 antagonists may be beneficial for therapy. This study describes the l-enantiomeric RNA oligonucleotide mNOX-E36, a so-called Spiegelmer that binds murine CCL2 with high affinity and neutralizes its action in vitro and in vivo. The mirror image configuration of the Spiegelmer confers nuclease resistance and thus excellent biostability. mNOX-E36 does not induce type I IFN via Toll-like receptor-7 or cytosolic RNA receptors, as recently shown for certain synthetic d-RNA. Autoimmune-prone MRL^lpr/lpr mice that were treated with a polyethylene glycol form of mNOX-E36 from weeks 14 to 24 of age showed prolonged survival associated with a robust improvement of lupus nephritis, peribronchial inflammation, and lupus-like inflammatory skin lesions. Thus, mNOX-E36–based inhibition of CCL2 represents a novel strategy for the treatment of autoimmune tissue injury, such as lupus nephritis.

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				V. Ninichuk, S. Clauss, O. Kulkarni, H. Schmid, S. Segerer, E. Radomska, D. Eulberg, K. Buchner, N. Selve, S. Klussmann, et al. Late Onset of Ccl2 Blockade with the Spiegelmer mNOX-E36-3'PEG Prevents Glomerulosclerosis and Improves Glomerular Filtration Rate in db/db Mice Am. J. Pathol., March 1, 2008; 172(3): 628 - 637. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673