Galan Alba, Barcelona Pablo F, Nedev Hinyu, Sarunic Marinko V, Jian Yifan, Saragovi H Uri
Lady Davis Institute - Jewish General Hospital, Center for Translational Research, McGill University, Montreal, Quebec, Canada.
Lady Davis Institute - Jewish General Hospital, Center for Translational Research, McGill University, Montreal, Quebec, Canada 2Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Invest Ophthalmol Vis Sci. 2017 Jun 1;58(7):2852-2862. doi: 10.1167/iovs.16-20988.
The p75NTR is a novel therapeutic target validated in a streptozotocin mouse model of diabetic retinopathy. Intravitreal (IVT) injection of small molecule p75NTR antagonist THX-B was therapeutic and resolved the inflammatory, vascular, and neurodegenerative phases of the retinal pathology. To simplify clinical translation, we sought a superior drug delivery method that circumvents risks associated with IVT injections.
We compared the pharmacokinetics of a single 40 μg subconjunctival (SCJ) depot to the reported effective 5 μg IVT injections of THX-B. We quantified therapeutic efficacy, with endpoints of inflammation, edema, and neuronal death.
The subconjunctival depot affords retinal exposure equal to IVT injection, without resulting in detectable drug in circulation. At week 2 of diabetic retinopathy, the SCJ depot provided therapeutic efficacy similar to IVT injections, with reduced inflammation, reduced edema, reduced neuronal death, and a long-lasting protection of the retinal structure.
Subconjunctival injections are a safe and effective route for retinal delivery of p75NTR antagonists. The subconjunctival route offers an advantageous, less-invasive, more compliant, and nonsystemic method to deliver p75NTR antagonists for the treatment of retinal diseases.
p75神经营养因子受体（p75NTR）是在糖尿病性视网膜病变的链脲佐菌素小鼠模型中得到验证的新型治疗靶点。玻璃体内（IVT）注射小分子p75NTR拮抗剂THX-B具有治疗作用，并可解决视网膜病变的炎症、血管和神经退行性病变阶段。为简化临床转化，我们寻求一种能规避与IVT注射相关风险的更优给药方法。
我们将单次40μg结膜下（SCJ）长效注射剂的药代动力学与已报道的有效剂量5μg THX-B的IVT注射进行了比较。我们以炎症、水肿和神经元死亡为终点，对治疗效果进行了量化。
结膜下长效注射剂使视网膜暴露程度与IVT注射相当，且不会导致循环中出现可检测到的药物。在糖尿病性视网膜病变的第2周，SCJ长效注射剂的治疗效果与IVT注射相似，炎症减轻、水肿减轻、神经元死亡减少，并且对视网膜结构有持久的保护作用。
结膜下注射是视网膜递送p75NTR拮抗剂的一种安全有效的途径。结膜下途径为递送p75NTR拮抗剂以治疗视网膜疾病提供了一种有利、侵入性较小、更顺应性且非全身性的方法。
