Project Summary/Abstract Diabetic retinopathy (DR) is a major co-morbidity for patients with Type 1 and Type 2 diabetes. The incidence and severity of DR increase with duration of diabetes and approximately 30 percent will experience vision-threatening deficits. Work over the past decade has shown that the neural deficits observed in DR occur early in the natural history of the disease and likely precede vascular pathology, shifting a focus of research and drug discovery toward restoring function of retinal neurons. The overall goal of this Phase I STTR grant proposal is to establish proof-of-concept efficacy of a TrkB agonist antibody, ZEB85, in experimental DR and to provide a path for preclinical development, clinical trials and ultimately commercialization of these novel therapeutics for the treatment of DR, a critical medical need. In Specific Aim (SA) 1 we will determine Localization and target engagement of TrkB agonist antibodies delivered to the eye. Upon intravitreal (ivt) delivery of TrkB agonist antibody, ZEB85, we will determine its localization to TrkB-expressing retinal ganglion cells (RGCs), and establish target engagement by measuring phospho-TrkB, both by immuinohistological methds. We will also determine whether repeated ivt injections of TrkB agonist antibody induce desensitization of TrkB signaling in the retina. These localization and target engagement validation studies are critical for interpretation of ZEB85 efficacy studies in a rat model of DR, planned in SA2. In SA2 we will determine the ability of TrkB agonist antibody ZEB85 to ameliorate the antomical and functional deficits in streptozotocin (STZ)-induced DR. We will assess dose-dependent restoration of pattern ERG deficits, retinal neuron apoptosis and RGC synaptic markers after 12 weeks of ZEB85 treatment in rats with DR. These studies will demonstrate dose-dependent efficacy of TrkB agonist antibody treatment for DR. Successful achievement of these Milestones will provide a foundation to examine ZEB85 distribution and target engagement in a larger mammalian eye (e.g., rabbit, monkey, human), and assess its pharmacology and safety in anticipation of IND-enabling studies, eventual clinical trials and commercialization. Long term, we propose that ivt treatment with TrkB agonist antibodies is a novel approach that can complement current standard-of-care therapy for DR, allowing eventual clinical trials to be run concurrently with anti-VEGF therapy, with the goal of identifying additive or synergistic efficacy for DR patients.