A novel product for tendinopathy treatment

项目摘要 肌腱病是一种肌腱疾病，其特征是肌腱退化，经常导致肌腱断裂，以及 与疼痛、肿胀和表现受损有关。目前还没有治愈肌腱病的方法。 因此，迫切需要对肌腱病进行有效的治疗。外显体是专门化的 膜性纳米大小的细胞外小泡来自于许多释放的胞内隔室 单元类型。我们的初步发现是肌腱来源的干/祖细胞(TSPC)分泌的外体 在一种新型支架上培养，当注射到肌腱病变肌腱中时，减轻了大鼠的病理和疼痛 肌腱病模型。因此，我们将培养在这种新型支架上的骨髓间充质干细胞来源的外体命名为 并建立了一个项目，将TenoGen开发为FDA批准的肌腱病生物制剂 治疗。在我们的第一阶段研究中，我们发现外体来自人类脂肪来源的干细胞 (ADSCs)对肌腱病的疗效与TSPC相当，并揭示了 TSPC或ADSCs从老年供者体内产生TenoGen对肌腱病有治疗作用。 此外，我们检查了TenoGen治疗的大鼠，没有发现一般的毒性迹象。这些 第一阶段研究中令人兴奋的结果鼓励我们进一步测试我们的假设，即TenoGen对 减轻肌腱病病理及缓解肌腱病相关疼痛和症状的疗效观察 没有或几乎没有不良影响。第二阶段研究将侧重于提供进一步的关键证据，以 开发TenoGen作为FDA批准的用于自体或同种异体肌腱病治疗的生物制剂。 我们将首先在肌腱病模型中确定来源于人ADSCs的TenoGen的有效性和安全性 裸鼠(目标1)。具体来说，我们将首先确定TenoGen和TenoGen的最佳剂量和给药时间表 确定TenoGen对肌腱病病理的疗效。通过使用所选择的最优剂量和最优 给药计划。我们将进一步确定TenoGen在改善关节力学性能方面的效果 肌腱病变，以及缓解与肌腱病相关的疼痛和行为。此外，为了与 对TenoGen的监管要求作为一种新的生物，TenoGen对人类的安全性将在 这种免疫缺陷的动物模型。在目标2中，我们将确定TenoGen对 兔肌腱病模型中的自体和同种异体治疗，这允许评估 TenoGen关于肌腱病的中型动物模型，该模型与未来的治疗方案非常相似 人类。这些研究的成功完成将提供关键的临床前证据来支持疗效 TenoGen作为同种异体肌腱病生物治疗的安全性。这些数据将是有用的 用于FDA IND应用，以及未来在人体上启动临床试验的研发。 1

Project Summary Tendinopathy is a tendon disorder characterized by tendon deterioration that often leads to tendon rupture, and is associated with pain, swelling and impaired performance. There is currently no cure for tendinopathy. Therefore, there is an urgent need for effective treatments for tendinopathy. Exosomes are specialized membranous nano-sized extracellular vesicles derived from endocytic compartments that are released by many cell types. Our initial discovery was that exosomes secreted from tendon derived stem/progenitor cells (TSPCs) cultured on a novel scaffold, when injected into a tendinopathic tendon, mitigated pathology and pain in a rat tendinopathy model. We therefore designated the exosomes derived from MSCs cultured on this novel scaffold as “TenoGen,” and established a project to develop TenoGen as an FDA-approved biologic for tendinopathy treatment. In our Phase I study, we found that the exosomes derived from human adipose-derived stem cells (ADSCs) exert an efficacy on tendinopathy that was comparable to that derived from TSPCs, and revealed that TenoGen produced by TSPCs or ADSCs from aged donors exerts a therapeutic effect on tendinopathy. Furthermore, we examined and found no general signs of toxicity in the rats treated with TenoGen. These exciting results in the Phase I study encouraged us to further test our hypothesis that TenoGen exerts a therapeutic effect in mitigating tendinopathy pathology and relieving tendinopathy-related pain and symptoms with no or minimal adverse effects. The Phase II study will focus on providing further critical evidence towards developing TenoGen as an FDA-approved biologic for the autologous or allogeneic treatment of tendinopathy. We will first determine the efficacy and safety of TenoGen derived from human ADSCs in a tendinopathy model in nude rats (Aim 1). Specifically, we will first determine the optimal dose and dosing schedule of TenoGen and determine the efficacy of TenoGen on pathology of tendinopathy. By using the selected optimal dose and optimal dosing schedule. We will further determine efficacies of TenoGen on improving the mechanical properties of the diseased tendon, and on relieving pain and behaviors related to tendinopathy. Furthermore, in alignment with the regulatory requirements for TenoGen as a novel biologic, the safety of human TenoGen will be evaluated in this immunodeficient animal model. In Aim 2, we will determine the efficacy and safety of TenoGen for autologous and allogeneic treatment in a tendinopathy model in rabbits, which allows for the evaluation of TenoGen on tendinopathy in a mid-sized animal model that closely mimics the future treatment protocol in humans. Successful completion of these studies will provide critical preclinical evidence to support the efficacy and safety of TenoGen as a biologic for the allogeneic treatment of tendinopathy. The data will be instrumental for a FDA IND application, and the future R&D towards initiating clinical trials in humans. 1