Subconjunctival delivery of p75NTR antagonists reduces the inflammatory, vascular, and neurodegenerative pathologies of diabetic retinopathy

Alba Galan, Pablo F. Barcelona, Hinyu Nedev, Marinko V. Sarunic, Yifan Jian, H. Uri Saragovi

Research output: Contribution to journalArticle

5 Scopus citations

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 lg subconjunctival (SCJ) depot to the reported effective 5 lg 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.

Original languageEnglish (US)
Pages (from-to)2852-2862
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Volume58
Issue number7
DOIs
Publication statusPublished - Jun 1 2017
Externally publishedYes

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Keywords

  • Antagonist
  • Diabetic retinopathy
  • p75 receptor
  • Subconjunctival
  • Target

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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