MECHANISMS OF NEUROPROTECTION OF SUBCONJUNTIVAL DELIVERY OF SMALL MOLECULE ANTAGONIST OF P75NTR IN DIABETIC RETINOPATHY

PABLO F. BARCELONA; JIAN Y; ALBA GALAN; SARUNIC MV; NEDEV, H; SARAGOVI, HU

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE

ASSOC RESEARCH VISION OPHTHALMOLOGY INC

Lugar: Rockville, MD 20852; Año: 2017 vol. 58 p. 2852 - 2862

0146-0404

PURPOSE. The p75NTR is a novel therapeutic target validated in a streptozotocin mouse modelof diabetic retinopathy. Intravitreal (IVT) injection of small molecule p75NTR antagonist THX-Bwas therapeutic and resolved the inflammatory, vascular, and neurodegenerative phases of theretinal pathology. To simplify clinical translation, we sought a superior drug delivery methodthat circumvents risks associated with IVT injections.METHODS. We compared the pharmacokinetics of a single 40 lg subconjunctival (SCJ) depot tothe reported effective 5 lg IVT injections of THX-B. We quantified therapeutic efficacy, withendpoints of inflammation, edema, and neuronal death.RESULTS. The subconjunctival depot affords retinal exposure equal to IVT injection, withoutresulting in detectable drug in circulation. At week 2 of diabetic retinopathy, the SCJ depotprovided therapeutic efficacy similar to IVT injections, with reduced inflammation, reducededema, reduced neuronal death, and a long-lasting protection of the retinal structure.CONCLUSIONS. Subconjunctival injections are a safe and effective route for retinal delivery ofp75NTR antagonists. The subconjunctival route offers an advantageous, less-invasive, morecompliant, and nonsystemic method to deliver p75NTR antagonists for the treatment of retinaldiseases.