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

Abstract

Purpose:

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.

Methods:

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.

Results:

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.

Conclusions:

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.

• Authors: Tine Van Bergen, Tjing-Tjing Hu, Karis Little, Lies De Groef, Lieve Moons, Alan W Stitt, Elke Vermassen, Jean H M Feyen
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 62 Issue 13 Pg. 18 (10 04 2021) ISSN: 1552-5783 [Electronic] United States
• PMID: 34677569 (Publication Type: Journal Article)

Chemical References

• Anticoagulants
• Biomarkers
• Plasma Kallikrein

Topics

• Animals
• Anticoagulants (administration & dosage)
• Biomarkers (blood)
• Diabetes Mellitus, Experimental
• Diabetic Retinopathy (blood, pathology)
• Intravitreal Injections
• Male
• Plasma Kallikrein (antagonists & inhibitors, metabolism)
• Rats
• Rats, Inbred BN
• Retina (metabolism, pathology)
• Tomography, Optical Coherence (methods)