Thursday, March 13, 2025
3/13/2025
Sjögren's syndrome (SS) is an autoimmune disease manifesting with severe inflammation and loss of function of lacrimal (LG) and/or salivary (SG) glands, leading to severe dry eye and dry mouth. SS patients also exhibit extraglandular systemic symptoms including development of autoantibodies, inflammation of visceral organs and increased risk of B-cell lymphoma. Pathogenesis is complex and involves interplay between the activated immune system and exocrine epithelia; thus, SS therapies should ideally achieve both local glandular and systemic immunomodulation to fully treat the disease. Our initial focus is developing an effective treatment regimen for SS-associated dry eye disease (DED) and systemic symptoms, using the male NOD mouse which exhibits these disease manifestations of SS. We later explore efficacy in a model of autoimmune sialoadenitis and systemic symptoms, the female NOR mouse. Topical treatments are currently used clinically to manage symptoms of SS-associated DED, but these approaches are insufficient to suppress LG inflammation. Systemic symptoms are also treated to limited success with general immunomodulatory agents which also lack sufficient bioavailability to treat glandular inflammation. We hypothesize and test that a combined approach of optimized local glandular plus systemic delivery of therapeutics is necessary to effectively treat both glandular and extraglandular symptoms of SS. To achieve this, we use a versatile protein-polymer platform comprised of elastin-like polypeptides (ELPs) that can be genetically fused to peptides/proteins in ways that optimize their pharmacokinetics and bioactivity. Three Aims are proposed. Aim 1. Local LG immunosuppression using Supra-LG Rapa ELP depots and Molecular targeting to ICAM-1. The immunosuppressant, Rapamycin (Rapa), will be complexed to a depot-forming FKBP12-ELP fusion protein that sequesters Rapa; this carrier will be further modified to target intracellular adhesion molecule 1 (ICAM-1) increased in diseased LG in SS. In male NOD mice, efficacy will be assessed when delivered supra-LG towards SS-associated DED and systemic disease. Aim 2. Th17 immunosuppression using systemic delivery of extracellular IL-17 receptor ELPs. Elevated IL-17A is linked to SS pathogenesis. We develop soluble and depot-ELP fusions expressing the extracellular domain of the IL-17 receptor (eIL17R) to form multivalent IL-17A- sequestering nanoparticles for systemic delivery using subcutaneous (SC, flank) administration. In male NOD mice, efficacy will be assessed in SS-associated DED and systemic symptoms. Aim 3: Efficacy of local and systemic combination therapies in glandular and extraglandular symptoms of SS. Efficacy of combination local + systemic treatments will be assessed using formulations delivered by supra-LG (5FV-Rapa) and SC (soluble eIL17R-A192). Efficacy will be assessed both in male NOD mice (autoimmune dacryoadenitis/systemic symptoms) and in female NOR mice (autoimmune sialoadenitis/systemic symptoms).
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