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

• 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
• 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' 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

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.

摘要 自身免疫性疾病影响六分之一的美国人，花费美国医疗保健系统超过1000亿美元 每年。最常见的自身免疫性疾病之一是格雷夫斯病，其影响3%的女性， 0.5%的男性。格雷夫斯病的主要原因是形成针对甲状腺的抗体 刺激激素受体（TSHR）。TSHR是一种G蛋白偶联受体，具有可溶性细胞外受体， A亚单位应当理解，该A亚单位是TSHR的自身免疫识别的触发物， 产生抗体。这些甲状腺刺激抗体（TSAb）引起过度激活的 通过模拟甲状腺激素对TSHR的作用，过度刺激甲状腺会导致 甲状腺功能亢进，或甲状腺激素甲状腺素的过度产生，导致焦虑，体重减轻， 最终导致骨质疏松和甲状腺癌。Graves病的一种常见合并症是Graves' 眼病（GO），其由对光学成纤维细胞的免疫攻击引起，并可导致光学损伤。 纤维化并最终丧失视力。与大多数自身免疫性疾病一样， 解决格雷夫斯病的根本原因-TSHR的免疫识别。相反，现代方法 Graves病的治疗依赖于症状管理，主要是通过放射性 碘（RAI）和甲状腺抑制剂，如甲巯咪唑。在RAI治疗中，碘131被给予患者， 目的是消除甲状腺功能，从而减少甲状腺功能亢进症状。不幸的是，RAI经常导致 在完全甲状腺消融中，引发慢性甲状腺功能减退症，并需要终身依赖 甲状腺素补充剂RAI还与严重GO增加20%相关，严重GO是一个高度问题。 一种假定疗法的结果。甲状腺抑制剂，如甲巯咪唑，相反，可以给予多年，在一个 时间作为日常治疗，但往往导致复发。不同治疗策略的Graves病患者分析 已经显示出生活质量的显著下降，这表明需要改进的治疗策略。 我们需要的是一种解决自身免疫性疾病根本原因的治疗策略， 这种情况下的识别和目标TSHR。最近的研究表明，抗原特异性免疫 当抗原可以偶联到某些致耐受性受体、纳米颗粒和免疫球蛋白时，耐受是可能的。 proteins.然而，与大多数蛋白质抗原一样，TSHR作为遗传融合体产生具有挑战性。我们 已经开发了一种新的蛋白质偶联技术， 个氨基酸我们建议将这种技术应用于通过融合 TSHR致耐受性携带者，并将其递送至Graves'小鼠模型以评估对血清 甲状腺素和TSAb水平。