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， 与疼痛、肿胀和表现受损有关。目前还没有治愈肌腱病。 因此，迫切需要有效的治疗肌腱病。外来体是专门的 膜纳米大小的细胞外囊泡来源于内吞隔室， 细胞类型。我们最初的发现是肌腱源性干/祖细胞（TSPC）分泌的外泌体， 在一种新的支架上培养，当注射到一个肌腱病变的肌腱时，减轻了大鼠的病理和疼痛。 肌腱病模型。因此，我们将来源于在这种新型支架上培养的MSC的外泌体命名为 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I期研究中，我们发现来自人类脂肪干细胞的外泌体 脂肪干细胞（ADSC）对肌腱病的疗效与来源于TSPC的疗效相当，并显示， 由来自老年供体的TSPC或ADSC产生的TenoGen对肌腱病发挥治疗作用。 此外，我们检查并发现接受TenoGen治疗的大鼠没有出现一般毒性体征。这些 第一阶段研究中令人兴奋的结果鼓励我们进一步验证我们的假设，即TenoGen发挥了 减轻肌腱病病理和缓解肌腱病相关疼痛和症状的治疗效果 没有或只有最小的副作用。第二阶段研究将重点提供进一步的关键证据， 开发TenoGen作为FDA批准的生物制品，用于肌腱病的自体或同种异体治疗。 我们将首先在肌腱病模型中确定来自人类ADSC的TenoGen的有效性和安全性 在裸大鼠中（目标1）。具体而言，我们将首先确定TenoGen的最佳剂量和给药方案， 确定TenoGen对肌腱病病理学的疗效。通过使用所选择的最佳剂量和最佳 给药方案。我们将进一步确定TenoGen在改善机械性能方面的功效。 患病肌腱，并缓解疼痛和肌腱病相关的行为。此外，根据 根据TenoGen作为一种新型生物制品的监管要求，将在 这个免疫缺陷的动物模型在目标2中，我们将确定TenoGen用于以下目的的有效性和安全性： 兔肌腱病模型中的自体和同种异体治疗，这允许评价 TenoGen在中等大小的动物模型中用于肌腱病，该模型密切模拟了未来的治疗方案， 人类这些研究的成功完成将为支持疗效提供关键的临床前证据 TenoGen作为肌腱病同种异体治疗生物制剂的安全性。这些数据将是有用的 用于FDA IND申请，以及未来的研发，以启动人体临床试验。 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