Inflammation plays an important role in the pathogenesis of renal and cardiovascular disease in renovascular hypertension rvh. The spiegelmer bound equally well to des1p irrespective of the presence of 4 mgml or of only 0. Noxe36 and noxh94 have also been injected subcutaneously with a reported bioavailability of approximately 50% for noxe36. Emapticap pegol noxe36 is a spiegelmer that specifically. Noxxon pharma is a biotechnology company founded in 1997 in berlin, germany. Noxa12, mnoxe36, or control spiegelmer in 5% glu cose or 5% glucose itself. Recent advances in management of diabetic nephropathy. The phase i study, conducted in the united kingdom, was performed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of the chemokine inhibitor noxe36 in 72 healthy volunteers. Studies in humans have linked renal mcp1 and kidney interstitial inflammation with albuminuria, and renin angiotensin aldosterone system raas inhibition is paralleled by suppression of renal mcp1 and positive renal outcome.
Dual blockade of the homeostatic chemokine cxcl12 and the. Emapticap pegol nox e36 is a spiegelmer that specifically binds and inhibits the proinflammatory chemokine cc motifligand 2 ccl2 also called monocytechemotactic protein 1. Biostable ldnazyme for sensing of metal ions in biological. Although biologics hold promise, many agents have yet to prove clinical efficiency in controlled trials, with further limitations related to safety and cost. Aptamers in the therapeutics and diagnostics pipelines. Moreover, mirnas extracted from exosomes can be used as signatures for disease detection and as indicators of the tissue of origin not only in cancer but also in other diseases such as neurodegenerative diseases, obesity, diabetes, lupus nephritis, cardiovascular diseases, and lung diseases. Newer antiepileptic drugs in patients with renal failure. About 1 in 3 patients with diabetes mellitus develops diabetic nephropathy, a progressive kidney disease that is one of the main causes of endstage renal disease and the need for dialysis. Pdf background emapticap pegol noxe36 is a spiegelmer that specifically binds and. This book provides a comprehensive overview of the development of therapeutic oligonucleotides for therapeutic applications, touching on a number of additional oligonucleotides including a number of small interfering rnas currently in various phases of clinical development. Listing a study does not mean it has been evaluated by the u. Identification and characterization of a mirrorimage. Identification and characterization of a mirrorimage oligonucleotide that binds and neutralizes sphingosine 1phosphate, a central mediator of angiogenesis.
Emapticap pegol noxe36 noxxon pharma ag opportunity. Pdf reprint of dual blockade of the proinflammatory. Noxxon presents positive results from emapticap pegol. Physicochemical stability of nox e36, a 40mer lrna spiegelmer for therapeutic applications article pdf available in nucleic acids symposium series 5252. Pdf role of chemokines in proteinuric kidney disorders. The antihuman ccl2 blocking spiegelmer noxe36 has been studied in a number of phase 1 and phase 2 clinical trials, but results have not been published to date.
Purschke, kai hoehlig, klaus buchner, dirk zboralski, frank schwoebel, axel vater, sven klussmann. The primary selfspecificity in sle is doublestranded ds dna. These are primarily macrophages and t and b lymphocytes recruited to the interstitium by chemokines and adhesion molecules expressed by damaged tubular epithelium. Noxxon is planning to develop noxe36 for the treatment of inflammatory kidney diseases including diabetic nephropathy. E36 in diabetic mice resulted in reduced ccr2 expression in circulating monocytes and a reduction in albuminuria, the albumin.
Mcp1 binding nucleic acids and use thereof noxxon pharma ag. Current therapies for treating systemic lupus erythematosus sle mainly rely upon nonspecific and toxic immunosuppression by corticosteroids and cytotoxics. However, the use of dnazymes in practical applications has been impeded by the intrinsic drawbacks of natural nucleic acids, such as interferences from nuclease digestion and protein binding, as well as undesired intermolecular interactions with other nucleic acids. Pdf turning mirrorimage oligonucleotides into drugs. Diabetic kidney disease is associated with monocyte chemoattractant cc chemokine ligand 2 ccl2dependent glomerular and interstitial macrophage recruitment. Aptamerguided extracellular vesicle theranostics in oncology. With the spiegelmer noxe36 in patients with type 2. A nucleic acid molecule capable of binding to mcp1, whereby the nucleic acid molecule is for use as a medicament for the treatment andor prevention of a chronic disease or chronic disorder, preferably selected from the group consisting of chronic respiratory disease, chronic kidney disease and systemic lupus erythematosus. Background emapticap pegol nox e36 is a spiegelmer that specifically binds and inhibits the proinflammatory chemokine cc motifligand 2 ccl2 also called monocytechemotactic protein 1. In mouse models of dn, the experimental inhibition of this. Because the endothelial glycocalyx is also reduced in diabetic nephropathy, we. This combination formula with high molecular weight peg had the advantages of both nuclease resistance and decreased renal excretion. Noxe36 in patients with type 2 diabetes mellitus and albuminuria. Emapticap pegol noxe36 is a spiegelmer that specifically binds and inhibits the proinflammatory chemokine cc motifligand 2 ccl2 also called monocytechemotactic protein 1.
Noxe36 in patients with type 2 diabetes mellitus and. Seizures and chronic kidney disease are both common and often coexist. Systemic monocyte chemotactic protein1 inhibition modifies renal. Aptamers as a promising approach for the control of parasitic. Spiegelmer inhibition of ccl2mcp1 ameliorates lupus nephritis. Crystal structure of a mirrorimage l rna aptamer spiegelmer in. Anticcl2 spiegelmer improves survival and kidney disease of mrllprlpr mice. Clinical trials the european union clinical trials register allows you to search for protocol and results information on. Turning mirrorimage oligonucleotides into drugs cyberleninka. It is aimed to introduce nox e36 as the first agent to modify the course of diabetic nephropathy, to delay endstage renal disease and ultimately to save patients from the need for renal replacement therapy transplantation, hemodialysis, at least for some time 25, 87.
Ccl2 deficiency protects against chronic renal injury in. The pegylated form of the laptamer, noxe36 emapticap pegol, already showed promising efficacy in clinical phase ii studies conducted in diabetic nephropathy patients. Spiegelmer inhibition of mcp1ccr2 potential as an adjunct. Jan 01, 2015 read turning mirrorimage oligonucleotides into drugs. Spiegelmer technology april 14th, 2008 medgadget editors genetics noxxon pharma ag, a company from berlin, is trying to develop clinically useful aptamers of nucleic acids, a mirror image l. Noxxon presents positive results from emapticap pegol phase iia diabetic nephropathy study. The register also displays information on 18700 older paediatric trials in scope of article 45 of the paediatric regulation ec no 19012006. Pdf cc motifligand 2 inhibition with emapticap pegol noxe36. The other phase iia studies initiated in 2012 include the noxe36 phase iia for the treatment of diabetic nephropathy, the noxa12 phase iia for the treatment of chronic lymphocytic. The objective of this exploratory study was to evaluate the safety and tolerability as well as the renoprotective and antidiabetic potential of.
Mar 08, 2012 noxe36 in patients with type 2 diabetes mellitus and albuminuria the safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Aug 15, 2014 binding of the spiegelmer to des1p was not dependent on the presence of bsa, which had been used at 4 mgml throughout the binding reactions during in vitro selection. Protein1 spiegelmer nox e36 in patients with diabetic nephropathy. Recent novel approaches to limit oxidative stress and. Jun 08, 2009 previously completed experiments in various animal models of kidney disease demonstrate that treatment with spiegelmer mcp1 antagonists significantly delays the decline in kidney function as well as disease progression. This was accomplished by selecting natural rnas that bind the fulllength, nonnatural isomer of rnase then reversing the mirror to enable lrna to protect its natural counterpart. Pdf physicochemical stability of noxe36, a 40mer lrna. Treating seizures in patients with renal failure, including those on dialysis, is a. The eu clinical trials register currently displays 36946 clinical trials with a eudract protocol, of which 6091 are clinical trials conducted with subjects less than 18 years old.
Importantly, the activation of this pathway increases mcp1 levels and the chemotaxis of monocytes toward glomerular cells. Dual blockade of the homeostatic chemokine cxcl12 and. Cells were cultured as before, plus adding anticxcl12 or control spiegelmer. Jens kurreck, biomolecular sciences series of the royal society of chemistry rsc. Chemokine blockade has also been investigated using a selective blocker of the ccr2 ccx140b. The present invention is related to a nucleic acid, preferably binding to mcp1, selected from the group comprising type ia nucleic acids, type ib nucleic acids, type 2 nucleic acids, type 3 nucleic acids, type 4 nucleic acids and nucleic acids having a nucleic acid sequence according to any of seq. In addition, nephropathy is delayed in ccl2 mutant diabetic mice.
Mp7 is a dna aptamer that binds to the murine extracellular domain of. An aminomodified spiegelmer noxe36 oligonucleotide was conjugated with nhsesteractivated polyethylene glycol via carbodiimide coupling. Cc motifligand 2 inhibition with emapticap pegol noxe36. Diabetic nephropathy dn is a leading cause of chronic kidney disease. Ccl2 inhibition with emapticap pegol noxe36 in type 2 diabetic patients with albuminuria. A different spiegelmer noxe36, emapticap pegol has been tested for the treatment of a progressive kidney disease in diabetics, diabetic nephropathy. Emerging therapeutics for the treatment of diabetic nephropathy. The published models in which spiegelmers have been tested cover a wide range of chronic diseases e.
Dec 04, 2012 noxh94 is the third spiegelmer to enter phase ii studies and this study is the fourth phase iia trial that noxxon has started this year. Cc motifligand 2 inhibition with emapticap pegol nox. It is aimed to introduce noxe36 as the first agent to modify the course of diabetic nephropathy, to delay endstage renal disease and ultimately to save patients. The halflife of aptamers in serum can be increased by conjugation to peg to prevent renal elimination. Immunity and inflammation in diabetic kidney disease. This was the first time noxe36 would have been administered to man. Nox e36 in patients with type 2 diabetes mellitus and albuminuria the safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Endothelial glycocalyx as a shield against diabetic vascular. Ccl2 is an important mediator of inflammation, and is induced. Apr, 2018 cardiovascular mortality and progression to endstage renal disease are the two major unmet medical needs in patients with chronic kidney disease ckd plus diabetes mellitus. Interstitial infiltration of inflammatory cells occurs in the early phases of renal diseases irrespective of the initial renal insult. Eudract number 201100571011 eu clinical trials register. Eukaryotic cells are endowed with a complex external layer of pgs proteoglycans, glycoproteins, and glycolipids called extracellular matrix ecm, which regulates outsidein signaling, protects the cell from exterior aggression, and maintains tissue integrity.
In type ii diabetic patients, chronic kidney disease ckd is. Cc motifligand 2 inhibition with emapticap pegol noxe36 in. Ccl2mcp1 is one of the key chemokines that plays a crucial role in infiltration and positioning. Physicochemical stability of noxe36, a 40mer lrna spiegelmer for therapeutic applications article pdf available in nucleic acids symposium series 5252. On human renal progenitors, recombinant cxcl12 was added at different concentrations, as indicated, and nephrin mrna expression was determined by realtime rtpcr. Dnazymes, an important type of metal iondependent functional nucleic acid, are widely applied in bioanalysis and biomedicine. Role of chemokines in proteinuric kidney disorders. In may 2009, noxxon pharma commenced a phase i study on healthy volunteers. Late onset of ccl2 blockade with the spiegelmer mnoxe363. Pdf cc motifligand 2 inhibition with emapticap pegol.
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