Spiegelmers are synthetic target-binding oligonucleotides built from non-natural l-nucleotides. Like aptamers, Spiegelmers fold into distinct shapes that bind the targets with high affinity and selectivity. Furthermore, the mirror-image configuration confers plasma stability and immunological passivity. Various Spiegelmers against pharmacologically attractive targets were shown to be efficacious in animal models. Three Spiegelmer candidates: emapticap pegol (NOX-E36; anti-CCL2), olaptesed pegol (NOX-A12; anti-CXCL12) and lexaptepid pegol (NOX-H94; anti-hepcidin), underwent regulatory safety studies, demonstrated good safety profiles in healthy volunteers and were taken into Phase IIa studies in patients. Proof-of-concept for emapticap pegol has recently been demonstrated in diabetic nephropathy patients. Furthermore, promising interim Phase IIa data of olaptesed pegol and lexapteptid pegol also suggest efficacy in the respective patient populations.
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Systemic Monocyte Chemotactic Protein-1 Inhibition Modifies Renal Macrophages and Restores Glomerular Endothelial Glycocalyx and Barrier Function in Diabetic Nephropathy.
Am J Pathol
November 2017
Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:
Inhibition of monocyte chemotactic protein-1 (MCP-1) with the Spiegelmer emapticap pegol (NOX-E36) shows long-lasting albuminuria-reducing effects in diabetic nephropathy. MCP-1 regulates inflammatory cell recruitment and differentiation of macrophages. Because the endothelial glycocalyx is also reduced in diabetic nephropathy, we hypothesized that MCP-1 inhibition restores glomerular barrier function through influencing macrophage cathepsin L secretion, thus reducing activation of the glycocalyx-degrading enzyme heparanase.
View Article and Find Full Text PDFC-C motif-ligand 2 inhibition with emapticap pegol (NOX-E36) in type 2 diabetic patients with albuminuria.
Nephrol Dial Transplant
February 2017
Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.
Background: Emapticap pegol (NOX-E36) is a Spiegelmer® that specifically binds and inhibits the pro-inflammatory chemokine C-C motif-ligand 2 (CCL2) (also called monocyte-chemotactic protein 1). The objective of this exploratory study was to evaluate the safety and tolerability as well as the renoprotective and anti-diabetic potential of emapticap in type 2 diabetic patients with albuminuria.
Methods: A randomized, double-blind, placebo-controlled Phase IIa study was initiated in 75 albuminuric type 2 diabetics.
Targeting inflammation in diabetic kidney disease: early clinical trials.
Expert Opin Investig Drugs
September 2016
a Division of Nephrology and Hypertension and FRIAT, IIS-Fundacion Jimenez Diaz, School of Medicine, UAM , Madrid , Spain.
Introduction: The age-standardized death rate from diabetic kidney disease increased by 106% from 1990 to 2013, indicating that novel therapeutic approaches are needed, in addition to the renin-angiotensin system (RAS) blockers currently in use. Clinical trial results of anti-fibrotic therapy have been disappointing. However, promising anti-inflammatory drugs are currently on phase 1 and 2 randomized controlled trials.
View Article and Find Full Text PDFCrystal structure of a mirror-image L-RNA aptamer (Spiegelmer) in complex with the natural L-protein target CCL2.
Nat Commun
April 2015
Laboratory for Structural Biology of Infection and Inflammation, University of Hamburg, c/o DESY Building 22a, Notkestrasse 85, 22607 Hamburg, Germany.
We report the crystal structure of a 40 mer mirror-image RNA oligonucleotide completely built from nucleotides of the non-natural L-chirality in complex with the pro-inflammatory chemokine L-CLL2 (monocyte chemoattractant protein-1), a natural protein composed of regular L-amino acids. The L-oligonucleotide is an L-aptamer (a Spiegelmer) identified to bind L-CCL2 with high affinity, thereby neutralizing the chemokine's activity. CCL2 plays a key role in attracting and positioning monocytes; its overexpression in several inflammatory diseases makes CCL2 an interesting pharmacological target.
View Article and Find Full Text PDFTurning mirror-image oligonucleotides into drugs: the evolution of Spiegelmer(®) therapeutics.
Drug Discov Today
January 2015
NOXXON Pharma AG, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
Spiegelmers are synthetic target-binding oligonucleotides built from non-natural l-nucleotides. Like aptamers, Spiegelmers fold into distinct shapes that bind the targets with high affinity and selectivity. Furthermore, the mirror-image configuration confers plasma stability and immunological passivity.
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