Protein-polymer nanomedicine for Sjogren's Syndrome

用于治疗干燥综合症的蛋白质聚合物纳米药物

• 批准号: 10662981
• 负责人: Sarah F Hamm-Alvarez
• 金额: $ 59.23万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662981
• 关键词: Affect; Affinity; American; Antibodies; Artificial Tears; Autoantibodies; Autoimmune; Autoimmune Diseases; B-Cell Lymphomas; Binding; Biodegradation; Biodistribution; Biological; Biological Availability; Biological Products; Cell Adhesion Molecules; Cells; Chimeric Proteins; Clinical; Combined Modality Therapy; Complex; Cornea; Cyclosporine; Development; Disease; Disease model; Dose; Drug Carriers; Drug Kinetics; Dry Eye Syndromes; Elastin; Engineering; Epithelial Cells; Epithelium; Exhibits; Extracellular Domain; Eye; Fatigue; Female; Flow Cytometry; Fluorescein; Formulation; Histologic; Histology; Hydroxychloroquine; IL17 gene; Immune system; Immunosuppression; Immunosuppressive Agents; Inbred NOD Mice; Individual; Infiltration; Inflammation; Injections; Intuition; Lacrimal gland structure; Link; Liquid substance; Local Therapy; Localized Disease; Measurement; Measures; Methotrexate; Modeling; Molecular Target; NOR Mouse; Non obese; Oral; Organ; Pathogenesis; Patients; Peptides; Pharmaceutical Preparations; Polymers; Production; Property; Proteins; Regimen; Risk; Saliva; Salivary; Salivary Glands; Serum; Sialadenitis; Sirolimus; Site; Sjogren' s Syndrome; Stains; Submandibular gland; Symptoms; Systemic Therapy; Systemic disease; Tacrolimus Binding Protein 1A; Tacrolimus Binding Proteins; Technology; Testing; Therapeutic; Time; Tissue imaging; Topical application; Toxic effect; Transition Temperature; Treatment Efficacy; Treatment Protocols; Visceral; Xerostomia; belimumab; clinically relevant; cytokine; design; diabetic; effective therapy; efficacy evaluation; elastin-binding protein; extracellular; eye dryness; immune modulating agents; immunoregulation; improved; in vitro activity; innovation; loss of function; male; mouse model; nanomedicine; nanoparticle; nanopolymer; novel; novel strategies; novel therapeutics; ocular surface; polypeptide; receptor; rituximab; sex; subcutaneous; success; symptom management; systemic inflammatory response; tocilizumab

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).

干燥综合征（SS）是一种以严重炎症和功能丧失为主要表现的自身免疫性疾病 泪腺（LG）和/或唾液腺（SG）的炎症，导致严重的干眼症和口干。SS患者也表现出 腺外系统症状，包括自身抗体的产生、内脏器官炎症和 B细胞淋巴瘤风险增加发病机制是复杂的，涉及激活的 因此，SS治疗应该理想地实现局部腺体和 全身免疫调节以充分治疗疾病。我们最初的重点是开发有效的治疗方法 使用雄性NOD小鼠， 表现出SS的这些疾病表现。我们稍后将探讨自身免疫性涎腺炎模型的疗效 和全身症状，雌性NOR小鼠。局部治疗目前用于临床管理 这些方法可以治疗SS相关DED的症状，但这些方法不足以抑制LG炎症。系统性 用一般的免疫调节剂治疗这些症状也只能获得有限的成功 治疗腺体炎症的生物利用度。我们假设和测试， 为了有效地治疗这两种疾病， SS的腺和腺外症状。为了实现这一目标，我们使用了一个多功能的蛋白质聚合物平台， 包括弹性蛋白样多肽（ELP），所述ELP可以以 优化其药代动力学和生物活性。提出了三个目标。目标1.当地LG 使用Supra-LG Rapa ELP库和分子靶向ICAM-1的免疫抑制。的 免疫抑制剂雷帕霉素（Rapa）将与形成贮库FKBP 12-ELP融合蛋白复合， 螯合Rapa;该载体将进一步修饰以靶向细胞内粘附分子1（ICAM-1） SS组患病LG增加。在雄性NOD小鼠中，将评估当将超-LG递送至 SS相关DED和全身性疾病。目标二。Th 17免疫抑制，使用全身性递送 细胞外IL-17受体ELP。IL-17 A升高与SS发病机制有关。我们开发可溶性和 表达IL-17受体的胞外结构域（eIL 17 R）以形成多价IL-17 A-ELP融合物的库-ELP融合物 用于使用皮下（SC，侧腹）施用的全身递送的螯合纳米颗粒。男性NOD 在小鼠中，将在SS相关的DED和全身症状中评估功效。目标3：局部和局部 SS的腺和腺外症状的全身联合治疗。的疗效观察 将使用supra-LG（5 FV-Rapa）和SC递送的制剂评估局部+全身治疗 （可溶性eIL 17 R-A192）。将在雄性NOD小鼠（自身免疫性泪腺炎/全身性 症状）和雌性NOR小鼠（自身免疫性涎腺炎/全身症状）。