Protein Conjugation For Antigen-Specific Treatment Of Thyroid Autoimmune Diseases

用于甲状腺自身免疫性疾病抗原特异性治疗的蛋白质缀合

基本信息

批准号：
10385632
负责人：
Marco Jackson Lobba
金额：
$ 29.94万
依托单位：
CATENA BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-17 至 2023-09-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10385632
关键词：
Ablation Address Adenoviruses Age American Amino Acids Antibodies Antibody Formation Antigens Anxiety Autoimmune Autoimmune Diseases Binding Biological Biological Assay Biotin Blindness Body Weight decreased Cell Therapy Cell surface Cells Chemistry Chinese Hamster Ovary Cell Chronic Coupled Couples Coupling Cysteine Dependence Detection Development Disease Disease Progression Disease model Dose Enzyme-Linked Immunosorbent Assay Enzymes Erythrocytes Fatigue Fc Receptor Fibroblasts Fibrosis Flow Cytometry Fluorescence G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Genetic Goals Graves&apos Disease Healthcare Systems Heart Hemolysis Homeostasis Hormones Hyperthyroidism Hypothyroidism I131 isotope Immune Immune System Diseases Immune Targeting Immune Tolerance Immune system Immunologics Inflammatory Injections Intravenous Kidney Label Lead Luciferases Malignant neoplasm of thyroid Measures Mediation Methimazole Methods Modernization Modification Monophenol Monooxygenase Mus Optics Osteoporosis Outcome Pathway interactions Patients Peptides Peroxidases Persons Phase Plant Roots Population Positioning Attribute Production Proteins Protocols documentation Quality of life Radioactive Iodine Recovery Relapse Reporting Reproducibility Rest Serum Site Small Business Innovation Research Grant Stains Steroid therapy Sulfhydryl Compounds Surface Symptoms T-Lymphocyte Techniques Technology Testing Therapeutic Thyroid Function Tests Thyroid Gland Thyroid Hormones Thyroid stimulating immunoglobulins Thyrotropin Receptor Thyroxine Time Training Tyrosine Underserved Population Variant Woman Work autoimmune thyroid disease cell type comorbidity cost extracellular hormone therapy immunogenic improved inhibitor/antagonist men mouse model nanoparticle novel prevent radioiodine therapy receptor reduce symptoms response small molecule symptom management treatment group treatment strategy

项目摘要

Abstract Autoimmune disorders effect 1 in 6 Americans and cost the American Healthcare system over $100 billion annually. One of the most common autoimmune disorders is Graves’ disease, which effects 3% of women and 0.5% of men. The primary cause of Graves’ disease is the formation of antibodies against the Thyroid Stimulating Hormone Receptor (TSHR). The TSHR is a G-protein coupled receptor with a soluble extracellular A-subunit. It is understood that this A-subunit is the trigger for autoimmune recognition of the TSHR and resultant production of antibodies. These Thyroid Stimulating Antibodies (TSAb) cause over activation of the thyroid by mimicking the effect of thyroid hormones on the TSHR. Overstimulation of the thyroid leads to hyperthyroidism, or an overproduction of the thyroid hormone thyroxine which results in anxiety, weight loss, and ultimately osteoporosis and thyroid cancer. A common co-morbidity of Graves’ disease is Graves’ opthalmopathy (GO) which is caused by immunological attack on optical fibroblasts and can lead to optical fibrosis and eventually loss of vision. As with most autoimmune disorders, there is not treatment available to address the root cause of Graves’ disease –the immune recognition of the TSHR. Instead, modern approaches to treatment of Graves’ disease rely on symptom management, primarily through a combination of radioactive iodine (RAI) and thyroid inhibitors such as methimazole. In RAI therapy, iodine 131 is given to the patient with the goal of ablating thyroid function, thus diminishing hyperthyroid symptoms. Unfortunately, RAI often results in complete thyroid ablation, triggering chronic hypothyroidism and necessitation lifelong dependence on thyroxine supplements. RAI is also associated with a 20% increase in severe GO, a highly problematic outcome for a putative therapy. Thyroid inhibitors such as methimazole in contrast can be given for years at a time as a daily treatment, but often lead to relapse. Analysis of Graves’ patients across treatment strategies has shown significant decrease in quality of life, suggesting that improved therapeutic strategies are required. What is needed is a therapeutic strategy that addresses the fundamental cause of autoimmune disorders, in this case the recognition and targeting of the TSHR. Recent work has shown that antigen specific immune tolerance is possible when antigens can be coupled to certain tolerogenic receptors, nanoparticles, and proteins. However, as with most protein antigens, the TSHR is challenging to produce as a genetic fusion. We have developed a novel protein coupling technique capable of fusing intact proteins together using only native amino acids. We propose to apply this technique to the creation of antigen specific therapeutics by fusing the TSHR to tolerogenic cariers and delivering these to mouse models of Graves’ to assess the impact on serum thyroxine and TSAb levels.

抽象的自身免疫性疾病效果1中有6个美国人，使美国医疗保健系统超过1000亿美元最常见的自身免疫性疾病之一是Graves的疾病，其影响3％的女性和男性的0.5％。坟墓疾病的主要原因是形成抗甲状腺的抗体刺激激素受体（TSHR）。 TSHR是G蛋白偶联受体，细胞外固体 a-subunit。据了解，这种a-亚基是自身免疫性识别TSHR的触发因素和由此产生的抗体产生。这些甲状腺刺激抗体（TSAB）导致激活通过模仿甲状腺激素对TSHR的影响，甲状腺。甲状腺的过度刺激导致甲状腺功能亢进或甲状腺甲状腺素的过度生产，导致焦虑，体重减轻，最终骨质疏松和甲状腺癌。坟墓病的一个常见合并症是坟墓” 由对光学成纤维细胞的免疫攻击引起的眼科（GO），可能导致光学纤维化，有时失去视力。与大多数自身免疫性疾病一样，没有治疗解决了坟墓疾病的根本原因 - TSHR的免疫识别。相反，现代的方法治疗坟墓疾病的依赖于症状管理，主要是通过放射性的组合碘（RAI）和甲状腺抑制剂，例如甲胺唑。在RAI治疗中，碘131被给予患者消融甲状腺功能的目的，从而减轻甲状腺功能亢进症的症状。不幸的是，Rai经常结果在完整的甲状腺消融中，触发慢性甲状腺功能减退症和必要性终身依赖甲状腺素补充剂。 RAI也与严重的GO增长20％有关，这是一个非常有问题的假定疗法的结果。相反，甲状腺抑制剂（例如甲基咪唑）可以在A时给予多年时间是日常治疗，但通常会导致退休。分析坟墓跨治疗策略的患者已经显示出生活质量的显着降低，表明需要改善治疗策略。需要的是一种治疗策略，该策略解决了自身免疫性疾病的基本原因这种情况是TSHR的识别和靶向。最近的工作表明抗原特异性免疫当抗原可以与某些耐受性受体，纳米颗粒和蛋白质。但是，与大多数蛋白质抗原一样，TSHR被挑战以作为遗传融合。我们已经开发了一种新型的蛋白质偶联技术，能够仅使用天然才能将完整蛋白融合在一起氨基酸。我们建议将此技术应用于抗原特定疗法的创建 TSHR到耐受性载体并将这些交付给坟墓的小鼠模型，以评估对串行的影响甲状腺素和TSAB水平。