Quantitative assessment of retinal permeability in the diabetic Akimba mouse: validation of a promising animal model for diabetic retinopathy

Abstract

PurposeUnravelling the pathogenesis of diabetic retinopathy (DR) remains largely elusive, mainly due to lack of reliable diabetic animal models. The Akimba mouse (Ins2AkitaVEGF+/−) was generated by crossing Akita (T1D) with hVEGF‐overexpressing Kimba mice. The aim of this study was to validate this innovative diabetic model as a quantitative in vivo screening tool for anti‐leakage therapeutics in the context of DR.MethodsFluorescein angiography (FA) and OCT were implemented to assess retinal permeability and edema in Akimba compared to WT. FITC‐BSA perfusion and immunohistochemistry (IHC) were performed as well. Metamorph software (Leica) was used for quantitative analysis. The efficacy of anti‐VEGF therapy was investigated in Akimba mice via intravitreal injection of anti‐VEGF or vehicle.ResultsWe report for the first time that quantitative analysis of FA images and FITC‐BSA perfused flatmounts revealed a significant increase of vascular leakage in the Akimba eye compared to WT. Analogous to the clinical DR situation, edema can be discerned in OCT scans of Akimba eyes. The effect of anti‐VEGF was monitored via longitudinal FA follow‐up before and 2–4 weeks after treatment. Anti‐VEGF treatment induced a significant decrease in vascular leakage (approx. 35%). IHC stainings confirmed that Akimba also exhibits other DR hallmarks such as inflammation, angiogenesis and fibrosis.ConclusionsCurrent study demonstrated that the Akimba mouse is a powerful model for screening therapeutics against sight‐threatening retinal edema. This diabetic model also exhibits other main DR‐related processes, signifying the relevance of the Akimba model for DR research. Further validation will be crucial to strengthen the toolbox of in vivo DR models and ultimately to address the unmet need for effective next generation therapies for DR.