Engineered Biotherapeutic Agent for Treatment of Post-Traumatic Osteoarthritis

项目摘要/摘要 创伤后骨关节炎(PTOA)是一种由创伤引起的软骨退行性疾病。 关节关节。急性关节损伤之后是严重的关节疼痛和炎症。这导致了很多 软骨的退化比其他形式的骨关节炎更快，原因是关节不稳定 创伤以及加速退变的促炎细胞因子的增加。PTOA影响5.6 100万美国人，估计有117.9亿美元与其治疗的直接治疗费用有关。 目前还没有得到批准的治疗方法来阻止或改变疾病的进展，并完全退化。 关节软骨的损伤可能需要进行关节置换手术。这可能需要手术治疗 大约10年，对于预期寿命更长的年轻患者来说，这是一个特别不好的结果。 ProViZiGen开发了一种新的蛋白质工程可注射治疗水凝胶系统，氢 当注射到关节间隙时形成凝胶，并提供持续的抗炎和 软骨保护性治疗分子。我们最近对兔前十字交叉韧带的临床前研究 韧带(ACL)横断模型表明，立即输送氢气显著阻止了 关节损伤后发生PTOA并在损伤点8周后分娩具有治疗作用 促进内源性软骨修复。在这一阶段，我们的目标是确定稳定性和无毒性 用于建立功能性凝胶和安全剂量的氢气。在目标一中，我们将确定稳定性 通过评估蛋白质的微观结构和宏观结构以及它的 作为温度和时间的函数的流变性，以确定其作为原位凝胶的功能 注射疗法。在目标2中，我们将确定氢的无毒性和选择性生物分布。 在大鼠关节腔内注射的模型中。成功完成这些目标将为ProViZiGen提交 BLA与FDA合作，进行了大型动物PTOA模型研究(第二阶段)，导致了人类试验的第一次。

PROJECT SUMMARY/ABSTRACT Post-traumatic osteoarthritis (PTOA) is a degenerative disease of cartilage brought on by traumatic injury to the articular joints. Acute joint injury is followed by severe joint pain and inflammation. This results in much more rapid degeneration of cartilage than in other forms of osteoarthritis, due to the joint instability caused by trauma as well as the increase in proinflammatory cytokines that accelerate degeneration. PTOA affects 5.6 million Americans, with an estimated $11.79 billion associated with direct treatment costs for its treatment. There are no approved treatments that stop or alter the progression of the disease, and complete degeneration of the articular cartilage can necessitate joint replacement surgery. This may require surgical revision in approximately 10 years, a particularly undesirable outcome in younger patients with longer life expectancies. ProViZiGen has developed a novel protein-engineered injectable therapeutic hydrogel system, HydroGEN that forms a gel when injected into the joint space and provides sustained delivery of an anti-inflammatory and chondroprotective therapeutic molecule. Our recent preclinical investigation in a rabbit anterior cruciate ligament (ACL) transection model has shown that immediate delivery of HydroGEN significantly prevents the development of PTOA after joint injury and delivery 8 weeks after the point of injury has therapeutic effects promoting endogenous cartilage repair. In this Phase I STTR, we aim to determine stability and lack of toxicity of HydroGEN to establish functional gelation and establish safe dosing. In Aim I, we will determine the stability and mechanics of HydroGEN by assessing the protein’s microstructure and macrostructure, as well as its rheologic properties as a function of temperature and time to determine its functionality as an in situ gelling injectable therapeutic. In Aim II, we will establish the lack of toxicity and selective biodistribution of HydroGEN in a rat model of intraarticular injection. Successful completion of these aims will prepare ProViZiGen for filing a BLA with the FDA, with large animal PTOA model investigation (Phase II) leading to first in human trials.