Uveitis is an inflammatory disease of the eye that if inadequately treated can lead to vision impairment and blindness. Since the 1950's corticosteroids have been used as the main treatment option despite side effects from prolonged usage in severe and chronic uveitis. Research into uveitis has uncovered its underlying autoimmune mechanisms as facilitated by pathogenic lymphocytes and cytokines. We propose using a novel endogenous transcriptional activation technology to drive specific upregulation of the regulatory cytokine IL-10 to create a tolerogenic immune environment within the eye. The therapeutic development strategy leverages this emerging oligonucleotide-based technology coupled with the proven ameliorating properties of IL-10 in uveitis. Our first aim seeks to refine human and mouse IL-10 transcriptional activators to select for the best candidates. Our second aim builds upon the first by measuring in situ expression of IL-10 as upregulated by our therapeutic in the eyes of mice. Our third aim seeks to demonstrate in vivo efficacy in a mouse model of uveitis by decreasing disease upon treatment by our therapeutics candidates. The overall goal of these studies is to provide proof-of-concept and show efficacy by our novel IL-10 transcriptional activator therapeutic in this Phase I proposal and prepare the project for additional research and pre-clinical studies in Phase II.
Public Health Relevance Statement: Public Health Relevance: Uveitis refers to inflammation of the eye uvea regions that if inadequately treated can lead to vision impairment and blindness. Our proposal seeks to develop a novel therapeutic for the benefit of patients suffering from uveitis and treating physicians. The goal of developing novel therapeutics for ophthalmic disease is consistent with the mission of the NIH SBIR Program and NIH institutes including primarily the National Eye Institute - NEI and also the National Institute of Allergy and Infectious Diseases - NIAID.
Project Terms: Acute; Adrenal Cortex Hormones; Adverse effects; Anterior uveitis; Anti-inflammatory; Anti-Inflammatory Agents; Aqueous Humor; Autoimmune Process; base; Blindness; Cataract; Cell Line; Cells; Chronic; Coupled; cytokine; Developed Countries; Disease; Dose; efficacy testing; Environment; Eye; Eye diseases; Future; Gene Expression; Gene Targeting; Genomic DNA; Glaucoma; Goals; Histology; Human; Immune; Immunohistochemistry; Impairment; In Situ; in vitro Assay; in vivo; Infiltration; Inflammation; Inflammatory; Institutes; Interferons; Interleukin-10; Interleukin-17; Lead; Lymphocyte; Measures; Mediating; Messenger RNA; Mission; Modeling; Modification; mouse model; Mus; National Eye Institute; National Institute of Allergy and Infectious Disease; novel; novel therapeutics; Oligonucleotides; Patients; Phase; Physicians; preclinical study; programs; Property; Protein Biosynthesis; protein expression; public health relevance; Research; Risk; Site; Small Business Innovation Research Grant; Steroids; Technology; Therapeutic; therapeutic development; therapeutic target; Tissues; Transcription Coactivator; Transcriptional Activation; United States National Institutes of Health; Up-Regulation (Physiology); Uvea; Uveitis; uveoretinitis; Viral; Vision
