Development of a Novel Therapeutic for Hyperthyroidism

Graves病(GD)是甲状腺机能亢进症的最常见原因，由甲状腺受体刺激性抗体(TSAbs)刺激促甲状腺激素受体(TSHR)引起。GD的治疗包括抗甲状腺药物治疗、放射性碘治疗和手术。目前，治疗GD的替代疗法很少，或正在开发中。阻断TSHR活动的能力也可能对其他疾病有利，包括Graves；眼眶病(GO)和分化性甲状腺癌。因此，有相当大的兴趣开发新的治疗方法来阻断TSHR的作用。重组腺相关病毒(RAAV)治疗已成为基因治疗的病毒载体。其中几项临床试验已经在佛罗里达大学(UF)进行，该大学是基于AAV的基因疗法研究的主要中心。在现有的不同血清型的rAAV中，rAAV8是啮齿动物模型载体介导免疫治疗研究的首选载体。虽然基于载体的免疫疗法已经被提出用于传染病，但我们认为这种针对抗体介导的条件的方法是有限的。在初步研究中，我们鉴定了一种商业上可用的单抗，它可以阻断TSAb和促甲状腺激素(TSH)的作用。我们还开发了一种表达这种功能性抗体的rAAV8载体。因此，我们假设我们生成的rAAV9-TBAb载体将靶向并阻断TSHR的激活。在这个第一阶段的STTR方案中，我们将评估我们的新疗法在阻断TSH受体激活方面的效用。在SA 1中，我们将在单剂量和多剂量研究中测试我们的治疗方法阻断TSH作用的能力。在SA 2中，我们将测试我们的载体阻断给予TSAb的活性的能力，以及一个经过验证的GD小鼠模型。为了实现这些目标，我们的团队将包括甲状腺学和rAAV生物学方面的专家，并将涉及佛罗里达大学和Medosome Biotec LLC的合作努力。我们预计，这种抑制甲状腺分泌和阻断TSAb的新治疗方法的发现将具有相当大的临床重要性和商业潜力。

Graves’ disease (GD) is the most common cause of hyperthyroidism and is caused by stimulation of the thyroid-stimulating hormone receptor (TSHR) by thyroid receptor stimulating antibodies (TSAbs). Treatment of GD involves antithyroid medication therapy, radioactive iodine, and surgery. At the present, few alternative forms of therapy for GD are available or are in development. The ability to block TSHR action may also be of benefit to other conditions, including Graves; orbitopathy (GO) and differentiated thyroid cancer. Thus, there is considerable interest in developing novel treatments to block TSHR action. Recombinant adeno- associated virus (rAAV) therapy has been developed as a viral vector for gene therapy. Several of these clinical trials have taken place at the University of Florida (UF), which is a major center for the study of AAV- based gene therapy. Of the different rAAV that the serotypes that are available, rAAV8 is the preferred vector for vector-mediated immunotherapy studies in rodent models. Although vector-based immunotherapy has been proposed for infectious diseases, we such approaches that target antibody-mediated conditions are limited. In preliminary studies, we identified a commercially available monoclonal antibody that blocks TSAb and thyroid-stimulating hormone (TSH) action. We also developed a rAAV8 construct that expresses this functional antibody. Thus, we hypothesize that the rAAV9-TBAb vector we generated will target and block TSHR activation. In this Phase 1 STTR proposal, we will evaluate the utility of our new therapeutic in blocking TSH receptor activation. In SA 1, we will test the ability of our therapeutic to block the action of TSH in single dose and multidose studies. In SA 2, we will test the ability of our vector to block the activity of administered TSAbs and a validated murine model of GD. To achieve these goals, our team will include experts in thyroidology and rAAV biology and will involve collaborative efforts of the University of Florida and Medosome Biotec LLC. We anticipate that the discovery of this novel therapeutic approach to inhibit thyroid production and block TSAbs will be of considerable clinical importance and commercial potential.