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

基本信息

  • 批准号:
    10662981
  • 负责人:
  • 金额:
    $ 59.23万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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).
Sjögren综合征(SS)是一种自身免疫性疾病,表现为严重的炎症和功能丧失

项目成果

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Sarah F Hamm-Alvarez其他文献

Sarah F Hamm-Alvarez的其他文献

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{{ truncateString('Sarah F Hamm-Alvarez', 18)}}的其他基金

Development of a novel tear-based biomarker assay for diagnosis of Parkinson's disease using RT-QuIC
使用 RT-QuIC 开发一种新型基于泪液的生物标志物检测方法来诊断帕金森病
  • 批准号:
    10227242
  • 财政年份:
    2020
  • 资助金额:
    $ 59.23万
  • 项目类别:
Development of a novel tear-based biomarker assay for diagnosis of Parkinson's disease using RT-QuIC
使用 RT-QuIC 开发一种新型基于泪液的生物标志物检测方法来诊断帕金森病
  • 批准号:
    10057848
  • 财政年份:
    2020
  • 资助金额:
    $ 59.23万
  • 项目类别:
Cell and Tissue Imaging Core
细胞和组织成像核心
  • 批准号:
    10178037
  • 财政年份:
    2018
  • 资助金额:
    $ 59.23万
  • 项目类别:
Cell and Tissue Imaging Core
细胞和组织成像核心
  • 批准号:
    10413123
  • 财政年份:
    2018
  • 资助金额:
    $ 59.23万
  • 项目类别:
Cell & Tissue Imaging and Data Science Core
细胞
  • 批准号:
    10714515
  • 财政年份:
    2018
  • 资助金额:
    $ 59.23万
  • 项目类别:
CELL TISSUE AND IMAGING CORE
细胞组织和成像核心
  • 批准号:
    7778740
  • 财政年份:
    2010
  • 资助金额:
    $ 59.23万
  • 项目类别:
Ad5 Fiber Entry and Trafficking in Lacrimal Acini
Ad5 纤维在泪腺泡中的进入和运输
  • 批准号:
    7394357
  • 财政年份:
    2006
  • 资助金额:
    $ 59.23万
  • 项目类别:
Ad5 Fiber Entry and Trafficking in Lacrimal Acini
Ad5 纤维在泪腺泡中的进入和运输
  • 批准号:
    7447508
  • 财政年份:
    2006
  • 资助金额:
    $ 59.23万
  • 项目类别:
Ad5 Fiber Entry and Trafficking in Lacrimal Acini
Ad5 纤维在泪腺泡中的进入和运输
  • 批准号:
    7797328
  • 财政年份:
    2006
  • 资助金额:
    $ 59.23万
  • 项目类别:
Ad5 Fiber Entry and Trafficking in Lacrimal Acini
Ad5 纤维在泪腺泡中的进入和运输
  • 批准号:
    7075776
  • 财政年份:
    2006
  • 资助金额:
    $ 59.23万
  • 项目类别:

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