ecallantide and Diabetic-Retinopathy

Topics: Animals; Diabetic Retinopathy; Drug Development; Drugs, Investigational; Humans; Macular Edema; Plasma Kallikrein

Diabetic retinal disease is characterized by a series of retinal microvascular changes and increases in retinal vascular permeability that lead to development of diabetic retinopathy (DR) and diabetic macular edema (DME), respectively. Current treatment strategies for DR and DME are mostly limited to vascular endothelial growth factor (VEGF) inhibitors and laser photocoagulation. These treatment modalities are not universally effective in all patients, and potential side effects persist in a significant portion of patients. The plasma kallikrein-kinin system (KKS) is one of the pathways that has been identified in the vitreous in proliferative DR and DME. Preclinical studies have shown that the activation of intraocular KKS induces retinal vascular permeability, vasodilation, and retinal thickening. Proteomic analysis from vitreous of eyes with DME has shown that KKS and VEGF pathways are potentially independent biologic pathways. Furthermore, proteins associated with DME in the vitreous were significantly more correlated with the KKS pathway compared to VEGF pathway. Preclinical experiments on diabetic animals showed that inhibition of KKS components was found to be an effective approach to decrease retinal vascular permeability. An initial phase I human trial of a novel plasma kallikrein inhibitor for the treatment of DME is currently ongoing to test the safety of this approach and serves as an initial step in the translation of basic science discovery into an innovative clinical intervention.

Topics: Animals; Capillary Permeability; Diabetic Retinopathy; Humans; Kallikrein-Kinin System; Macular Edema; Plasma Kallikrein; Retinal Vessels; Vascular Endothelial Growth Factor A

Diabetic retinopathy is the leading cause of blindness in working age adults, and is projected to be a significant future health concern due to the rising incidence of diabetes. The recent advent of anti-vascular endothelial growth factor (VEGF) antibodies has revolutionized the treatment of diabetic retinopathy but a significant subset of patients fail to respond to treatment. Accumulating evidence indicates that inflammatory cytokines and chemokines other than VEGF may contribute to the disease process. The current review examines the presence of non-VEGF cytokines in the eyes of patients with diabetic retinopathy and highlights mechanistic pathways in relevant animal models. Finally, novel drug targets including components of the kinin-kallikrein system and emerging treatments such as anti-HPTP (human protein tyrosine phosphatase) β antibodies are discussed. Recognition of non-VEGF contributions to disease pathogenesis may lead to novel therapeutics to enhance existing treatments for patients who do not respond to anti-VEGF therapies.

Topics: Adalimumab; Animals; Bevacizumab; Diabetic Retinopathy; Drug Therapy; Humans; Kallikreins; Peptides; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Plasma prekallikrein is the liver-derived precursor of the trypsin-like serine protease plasma kallikrein (PK) and circulates in plasma bound to high molecular weight kininogen. The zymogen is converted to PK by activated factor XII. PK drives multiple proteolytic reaction cascades in the cardiovascular system such as the intrinsic pathway of coagulation, the kallikrein-kinin system, the fibrinolytic system, the renin-angiotensin system and the alternative complement pathway. Here, we review the biochemistry and cell biology of PK and focus on recent in vivo studies that have established important functions of the protease in procoagulant and proinflammatory disease states. Targeting PK offers novel strategies not previously appreciated to interfere with thrombosis and vascular inflammation in a broad variety of diseases.

Topics: Animals; Aprotinin; Blood Coagulation; Bradykinin; Cerebral Hemorrhage; Complement System Proteins; Cysteine; Diabetic Retinopathy; Disulfides; Factor XIIa; Fibrinolysis; Hemostasis; Humans; Inflammation; Kallikrein-Kinin System; Kallikreins; Kinins; Mice; Oligonucleotides, Antisense; Peptides; Plasma Kallikrein; Protein Structure, Tertiary; Proteolysis; Renin-Angiotensin System; Signal Transduction; Thrombosis; Trypsin

The purpose of this study was to evaluate the safety and preliminary efficacy of a single intravitreal injection of 3 dose levels of THR-149 in adults with center-involved diabetic macular edema (DME).. A phase 1, open-label, multicenter 3 + 3 dose-esclation study with 3-month follow-up. The primary endpoint was the incidence of dose-limiting toxicities (DLTs) up to and including the Day 14 visit. Additional key endpoints included the incidence of (serious) adverse events ([S]AEs), mean change from baseline in best-corrected visual acuity (BCVA) and central subfield thickness (CST), and additional imaging parameters on widefield fluorescein angiography and optical coherence tomography (OCT) angiography.. Twelve subjects were treated: 3 subjects received THR-149 0.005 mg, 3 received 0.022 mg and 6 received 0.13 mg. Baseline ocular characteristics were balanced between subjects at each dose level. There were no DLTs or ocular SAEs, and all subjects completed the study. Six subjects experienced a total of 10 AEs in the study eye; 1 case of mild anterior chamber inflammation was deemed related to THR-149 and/or the injection procedure. Mean change from Baseline in BCVA was +7.5 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters on Day 14, and +6.4 ETDRS letters by Month 3. CST was variable, and mean CST change from baseline was +30.0 µm at Month 3. There were no clinically meaningful changes in imaging parameters.. THR-149 was safe and well tolerated; preliminary efficacy in terms of BCVA improvement was observed.. This work bridges the gap between basic research and clinical care by providing first in human safety and preliminary efficacy data, supporting the further investigation of THR-149 as a potential treatment for DME.

Topics: Adult; Angiogenesis Inhibitors; Diabetes Mellitus; Diabetic Retinopathy; Humans; Macular Edema; Plasma Kallikrein; Visual Acuity

Topics: Adult; Angiogenesis Inhibitors; Bevacizumab; Diabetic Retinopathy; Female; Humans; Macula Lutea; Macular Edema; Male; Plasma Kallikrein; Receptors, Vascular Endothelial Growth Factor; Tomography, Optical Coherence; Treatment Outcome; Visual Acuity

To investigate the effect of plasma kallikrein (PKal)-inhibition by THR-149 on preventing key pathologies associated with diabetic macular edema (DME) in a rat model.. Following streptozotocin-induced diabetes, THR-149 or its vehicle was administered in the rat via either a single intravitreal injection or three consecutive intravitreal injections (with a 1-week interval; both, 12.5 µg/eye). At 4 weeks post-diabetes, the effect of all groups was compared by histological analysis of Iba1-positive retinal inflammatory cells, inflammatory cytokines, vimentin-positive Müller cells, inwardly rectifying potassium and water homeostasis-related channels (Kir4.1 and AQP4, respectively), vascular leakage (fluorescein isothiocyanate-labeled bovine serum albumin), and retinal thickness.. Single or repeated THR-149 injections resulted in reduced inflammation, as depicted by decreasing numbers and activation state of immune cells and IL-6 cytokine levels in the diabetic retina. The processes of reactive gliosis, vessel leakage, and retinal thickening were only significantly reduced after multiple THR-149 administrations. Individual retinal layer analysis showed that repeated THR-149 injections significantly decreased diabetes-induced thickening of the inner plexiform, inner nuclear, outer nuclear, and photoreceptor layers. At the glial-vascular interface, reduced Kir4.1-channel levels in the diabetic retina were restored to control non-diabetic levels in the presence of THR-149. In contrast, little or no effect of THR-149 was observed on the AQP4-channel levels.. These data demonstrate that repeated THR-149 administration reduces several DME-related key pathologies such as retinal thickening and neuropil disruption in the diabetic rat. These observations indicate that modulation of the PKal pathway using THR-149 has clinical potential to treat patients with DME.

Topics: Animals; Anticoagulants; Biomarkers; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Intravitreal Injections; Male; Plasma Kallikrein; Rats; Rats, Inbred BN; Retina; Tomography, Optical Coherence

Plasma kallikrein, a member of the kallikrein-kinin system, catalyzes the release of the bioactive peptide bradykinin, which induces inflammation, vasodilation, vessel permeability, and pain. Preclinical evidence implicates the activity of plasma kallikrein in diabetic retinopathy, which is a leading cause of visual loss in patients suffering from diabetes mellitus. Employing a technology based on phage-display combined with chemical cyclization, we have identified highly selective bicyclic peptide inhibitors with nano- and picomolar potencies toward plasma kallikrein. Stability in biological matrices was either intrinsic to the peptide or engineered via the introduction of non-natural amino acids and nonpeptidic bonds. The peptides prevented bradykinin release in vitro, and in vivo efficacy was demonstrated in both a rat paw edema model and in rodent models of diabetes-induced retinal permeability. With a highly extended half-life of ∼40 h in rabbit eyes following intravitreal administration, the bicyclic peptides are promising novel agents for the treatment of diabetic retinopathy and diabetic macular edema.

Topics: Animals; Bradykinin; Bridged Bicyclo Compounds; Diabetes Complications; Diabetic Retinopathy; Edema; Eye; Foot; Half-Life; Intravitreal Injections; Macular Edema; Male; Mice; Mice, Inbred C57BL; Permeability; Plasma Kallikrein; Protease Inhibitors; Rabbits; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Substrate Specificity; Vitreous Body

Recent proteomic studies have identified components of the kallikrein kinin system, including plasma kallikrein, factor XII, and kininogen, in vitreous obtained from individuals with advanced diabetic retinopathy. In rodent models, activation of plasma kallikrein in vitreous increases retinal vascular permeability; whereas inhibition of the kallikrein kinin system reduces retinal leakage induced by diabetes and hypertension. These findings suggest that intraocular activation of the plasma kallikrein pathway may contribute to excessive retinal vascular permeability that can lead to diabetic macular edema. The kallikrein kinin system contains two separate and independently regulated serine proteases that generate bradykinin peptides: plasma kallikrein and tissue kallikrein. Tissue kallikrein is expressed in the retina and ciliary body, where it has been implicated in exerting autocrine or paracrine effects via bradykinin receptors that are colocalized in these tissues. Emerging evidence suggests that plasma kallikrein inhibitors may provide a new therapeutic opportunity to reduce retinal vascular permeability.

Topics: Animals; Bradykinin; Diabetic Retinopathy; Humans; Kallikrein-Kinin System; Macular Edema; Plasma Kallikrein