Alba Galan1, Pablo F Barcelona2, Hinyu Nedev1, Marinko V Sarunic3, Yifan Jian3, H Uri Saragovi4. 1. Lady Davis Institute - Jewish General Hospital, Center for Translational Research, McGill University, Montreal, Quebec, Canada. 2. 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. 3. School of Engineering Science, Simon Fraser University, British Columbia, Canada. 4. 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 4McGill Cancer Center, McGill University, Montreal, Quebec, Canada.
Abstract
Purpose: 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. Methods: 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. Results: 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. Conclusions: 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.
Purpose: The p75NTR is a novel therapeutic target validated in a streptozotocinmouse 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. Methods: 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. Results: 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. Conclusions: 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.
Authors: Sally L Elshaer; Abdulrahman Alwhaibi; Riyaz Mohamed; Tahira Lemtalsi; Maha Coucha; Frank M Longo; Azza B El-Remessy Journal: Diabetologia Date: 2019-05-09 Impact factor: 10.122
Authors: María Platón-Corchado; Pablo F Barcelona; Sean Jmaeff; Miguel Marchena; Alberto M Hernández-Pinto; Catalina Hernández-Sánchez; H Uri Saragovi; Enrique J de la Rosa Journal: Cell Death Dis Date: 2017-07-13 Impact factor: 8.469
Authors: Pablo F Barcelona; Alba Galan; Hinyu Nedev; Yifan Jian; Marinko V Sarunic; H Uri Saragovi Journal: PLoS One Date: 2018-06-21 Impact factor: 3.240
Authors: Alba Galán; Sean Jmaeff; Pablo F Barcelona; Fouad Brahimi; Marinko V Sarunic; H Uri Saragovi Journal: Cell Death Dis Date: 2017-12-14 Impact factor: 8.469