Therapeutic Intervention of p75^NTR With LM11A-31 Protects Against Systemic and Retinal Inflammation And Visual Impairment In A Model of Diabetic Retinopathy

Abstract

Purpose : Over the past decade, our work established the critical contribution of proNGF, proform of the nerve growth factor and its receptor p75^NTR in mediating diabetic retinopathy. Deletion of p75^NTR preserved the barrier function, prevented inflammatory mediators and microvascular degeneration in diabetic retinas. This study aims to examine the therapeutic efficacy of LM11A-31, a small-molecule p75^NTR modulator and proNGF antagonist, in preventing diabetes-associated systemic and retinal inflammation as well as visual activity in a model of acute ischemia/reperfusion.

Methods : Male C57BL/6 J (WT) mice were rendered diabetic by streptozotocin, then after 4-weeks mice were randomized to receive LM11A-31 (50 mg/Kg/2days) or saline for an additional 12-weeks. Additional group of mice underwent ischemia/reperfusion (IR) injury by increasing intraocular pressure for 40 min, followed by reperfusion. 2 days post IR injury, mice were randomized to receive received oral gavage of LM11A-31 (50 mg/Kg/2days) or saline for an additional 12-days. Urine, serum, and tissues were harvested for biochemical analyses. Visual function was assessed using visual clue-water maize. The visual test was performed after 1, 3, 6, 9, 12 and 15 days post-ischemic injury.

Results : Diabetes induced significant increases in systemic inflammation evident by significant increases in the Urinary Albumin excretion to Creatinine (UAC) ratio and enhanced level of IL-1β in serum and urine and in both retina and kidney compared to controls (P<0.05, n=5-6). Intervention with LM11A-31 did not alter body weight or glycemic level in control or diabetic mice. Intervention with LM11A-31 significantly reduced diabetes-induced inflammation and UAC ratio (P<0.05, n=5-6). Using the ischemia/reperfusion model, vehicle-treated IR mice exhibited visual dysfunction evident by significantly delayed time to reach the platform compared to shams (P<0.05, n=7-9). Intervention with LM11A-31 significantly improved visual function in IR-mice compared to vehicle-treated mice after 6-days of initial insult and persisted till day-15.

Conclusions : Therapeutic intervention of p75^NTR signaling using LM11A-31, an orally bioavailable receptor modulator, offers an effective, safe and non-invasive strategy for treating diabetes-associated inflammation and visual impairment, a major cause of blindness in diabetes.

This is a 2020 ARVO Annual Meeting abstract.