Development of a Novel Therapeutic for Hyperthyroidism

格雷夫斯病（GD）是甲状腺功能亢进症最常见的原因，是由甲状腺受体刺激抗体（TSAb）刺激甲状腺刺激激素受体（TSHR）引起的。GD的治疗包括抗甲状腺药物治疗、放射性碘和手术。目前，GD的替代治疗形式很少可用或正在开发中。阻断TSHR作用的能力也可能对其他疾病有益，包括Graves病、眼眶病（GO）和分化型甲状腺癌。因此，人们对开发阻断TSHR作用的新治疗方法非常感兴趣。重组腺相关病毒（rAAV）疗法已被开发为用于基因治疗的病毒载体。这些临床试验中的几个已经在佛罗里达大学（UF）进行，该大学是基于AAV的基因治疗研究的主要中心。在可用的不同血清型rAAV中，rAAV 8是啮齿动物模型中载体介导的免疫治疗研究的首选载体。尽管已经提出了基于载体的免疫疗法用于感染性疾病，但是我们这样的靶向抗体介导的病症的方法是有限的。在初步研究中，我们确定了一种商业上可获得的单克隆抗体，阻断TSAb和促甲状腺激素（TSH）的作用。我们还开发了表达这种功能性抗体的rAAV 8构建体。因此，我们假设我们产生的rAAV 9-TBAb载体将靶向并阻断TSHR激活。在这个1期STTR提案中，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剂阻断TSH作用的能力。在SA 2中，我们将测试我们的载体阻断施用的TSAb和经验证的GD鼠模型的活性的能力。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，这种新的治疗方法，以抑制甲状腺生产和阻断TSA抗体的发现将具有相当大的临床意义和商业潜力。

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.