Multiomic analysis of human diabetic retinal disease reveals severity and region-specific impairment of the retinal neurovascular unit

Diabetic retinal disease (DRD) is the leading cause of preventable blindness worldwide, but current therapeutic options only target vascular components in late-stage vision-threatening disease because the molecular mechanisms underlying early disease and affecting the whole retina are poorly understood. This study aimed to uncover disease-driving events of DRD using a multiomic approach to compare peripheral and central retinal tissue from human donors with diabetes without retinopathy or varying severity of diabetic retinal disease to their demographically matched non-diabetic counterparts. Integrative proteo-transcriptomic analysis combined with targeted validation reveals stage and region-specific disease drivers affecting the whole neurovascular unit defined by dysfunction in neuronal signaling, retinal metabolism, and neuroinflammation through activation of complement signaling. Further, our study reveals evidence of correlation of a subset of these retinal changes in the vitreous space in early disease, pointing to the specific role of this ocular fluid for DRD diagnosis and management. These findings are critical for the development of targeted therapeutic approaches to treat or prevent progression of DRD to vision threatening disease.