Targeting Plasma Kallikrein With a Novel Bicyclic Peptide Inhibitor (THR-149) Reduces Retinal Thickening in a Diabetic Rat Model

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 inject...

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Bibliographic Details
Published in:Investigative ophthalmology & visual science 2021-10, Vol.62 (13), p.18-18
Main Authors: Van Bergen, Tine, Hu, Tjing-Tjing, Little, Karis, De Groef, Lies, Moons, Lieve, Stitt, Alan W, Vermassen, Elke, Feyen, Jean H M
Format: Article
Language:English
Subjects:
Animals
Anticoagulants - administration & dosage
Biomarkers - blood
Diabetes Mellitus, Experimental
Diabetic Retinopathy - blood
Diabetic Retinopathy - pathology
Intravitreal Injections
Male
Plasma Kallikrein - antagonists & inhibitors
Plasma Kallikrein - metabolism
Rats
Rats, Inbred BN
Retina
Retina - metabolism
Retina - pathology
Tomography, Optical Coherence - methods
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Summary: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.
ISSN:1552-5783
0146-0404
1552-5783
DOI:10.1167/iovs.62.13.18