Evaluation of an Intravitreal Rho-Associated Kinase Inhibitor Depot Formulation in a Rat Model of Diabetic Retinopathy.

Cecile Lebon,Marianne Berdugo,Francine Behar-Cohen,Holger Fuchs,Jürgen Prestle,Kolja Becker,Remko A Bakker,Elke Markert,Heike Neubauer,Katja S Baum-Kroker,Kimberley Delaunay

doi:10.3390/pharmaceutics13081105

Abstract

Rho-associated kinase (ROCK) activation was shown to contribute to microvascular closure, retinal hypoxia, and to retinal pigment epithelium (RPE) barrier disruption in a rat model of diabetic retinopathy. Fasudil, a clinically approved ROCK inhibitor, improved retinal perfusion and reduced edema in this model, indicating that ROCK inhibition could be a promising new therapeutic approach for the treatment of diabetic retinopathy. However, due to its short intravitreal half-life, fasudil is not suitable for long-term treatment. In this study, we evaluated a very potent ROCK1/2 inhibitor (BIRKI) in a depot formulation administered as a single intravitreal injection providing a slow release for at least four weeks. Following BIRKI intravitreal injection in old Goto-Kakizaki (GK) type 2 diabetic rats, we observed a significant reduction in ROCK1 activity in the retinal pigment epithelium/choroid complex after 8 days and relocation of ROCK1 to the cytoplasm and nucleus in retinal pigment epithelium cells after 28 days. The chronic ROCK inhibition by the BIRKI depot formulation restored retinal pigment epithelial cell morphology and distribution, favored retinal capillaries dilation, and reduced hypoxia and inner blood barrier leakage observed in the diabetic retina. No functional or morphological negative effects were observed, indicating suitable tolerability of BIRKI after intravitreous injection. In conclusion, our data suggest that sustained ROCK inhibition, provided by BIRKI slow-release formulation, could be a valuable treatment option for diabetic retinopathy, especially with regard to the improvement of retinal vascular infusion and protection of the outer retinal barrier.

Highlights

With increasing prevalence and a projected 629 million affected patients by 2045, diabetes presents a major public health concern [1]
We have evaluated the potential of BIRKI (Boehringer Ingelheim Rho kinase inhibitor), a novel and potent inhibitor of ROCK1/2 in the GK diabetic retinopathy model
ROCK1 is activated by high glucose cose in human retinal capillary endothelial cells, inducing their proliferation [21], while in ina rhesus humanmacaque retinal capillary endothelial cells, cell inducing proliferation

Summary

Introduction

With increasing prevalence and a projected 629 million affected patients by 2045, diabetes presents a major public health concern [1]. More than one-third of diabetic patients develop some degree of diabetic retinopathy [2], and this represents a growing cause of blindness worldwide. Pharmaceutics 2021, 13, 1105 in capillary flow, and neurodegeneration precede detectable retinal microangiopathy [3,4]. Current treatments target stages of diabetic retinopathy when vision has already been affected [5], including laser photocoagulation of the peripheral ischemic retina or intraocular injection of anti-VEGF (vascular endothelial growth factor) and corticosteroids to reduce macular edema [6]. Macular edema and macular ischemia remain major causes of visual impairment, prompting the identification of potential additional molecular regulatory targets to enable the development of adequate treatment options for diabetic retinopathy

Methods

Results

Conclusion