Engineered Biotherapeutic Agent for Treatment of Post-Traumatic Osteoarthritis

用于治疗创伤后骨关节炎的工程生物治疗剂

• 批准号: 10821518
• 负责人: Jui Shivaji Chaugule
• 金额: $ 13.73万
• 依托单位: PROVIZIGEN LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-25 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10821518
• 关键词: Acceleration; Acute; Address; Adverse effects; Adverse event; Affect; American; Animal Model; Animals; Anterior Cruciate Ligament; Anti-Inflammatory Agents; Arthralgia; Arthritis; Behavior; Biocompatible Materials; Biodistribution; Biological Products; Biological Response Modifier Therapy; Carrier Proteins; Cartilage; Cartilage Diseases; Circular Dichroism; Degenerative Disorder; Degenerative polyarthritis; Development; Disease Progression; Dose; Engineering; Exhibits; Gait; Gel; Goals; Growth Factor; Hydrogels; Hydrogen; In Situ; Inflammatory; Injectable; Injury; Intra-Articular Injections; Investigation; Joint Instability; Joints; Life Expectancy; Marketing; Mechanics; Micelles; Modeling; Molecular Structure; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; Pain; Patients; Pharmaceutical Preparations; Phase; Physicians; Physiological; Preparation; Prevention; Preventive care; Preventive treatment; Property; Protein Engineering; Proteins; Public Health; Rattus; Reconstructive Surgical Procedures; Replacement Arthroplasty; Reproducibility; Rheology; Saline; Scanning Electron Microscopy; Second Look Surgery; Small Business Technology Transfer Research; Structure; System; TNF gene; Temperature; Therapeutic; Therapeutic Effect; Time; Toxic effect; Toxicology; Trauma; Traumatic Arthropathy; Traumatic injury; Treatment Cost; Weight; anterior cruciate ligament rupture; arthropathies; articular cartilage; biopharmaceutical industry; cartilage degradation; cartilage repair; chondroprotection; commercial application; cytokine; density; disability; experience; experimental group; first-in-human; good laboratory practice; human disease; joint inflammation; joint injury; light scattering; minimally invasive; novel; point of care; point of injury; pre-clinical; preclinical study; preservation; prevent; product development; viscoelasticity

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.

项目概要/摘要 创伤后骨关节炎（PTOA）是一种由创伤性损伤引起的软骨退行性疾病 关节。急性关节损伤后会出现严重的关节疼痛和炎症。这导致很多 由于骨关节炎引起的关节不稳定，软骨退化比其他形式的骨关节炎更快 创伤以及加速退化的促炎细胞因子的增加。 PTOA影响5.6 百万美国人，估计有 117.9 亿美元用于其治疗的直接治疗费用。 没有批准的治疗方法可以阻止或改变疾病的进展以及完全退化 关节软骨的损伤可能需要关节置换手术。这可能需要手术修复 大约10年，对于预期寿命较长的年轻患者来说，这是一个特别不理想的结果。 ProViZiGen 开发了一种新型蛋白质工程可注射治疗水凝胶系统 HydroGEN， 当注射到关节间隙时形成凝胶，并提供持续的抗炎和抗炎作用 软骨保护治疗分子。我们最近对兔子前十字韧带进行的临床前研究 韧带 (ACL) 横断模型表明，立即给予 HydroGEN 可显着防止 关节损伤后发生PTOA并在损伤点后8周分娩具有治疗作用 促进内源性软骨修复。在第一阶段 STTR 中，我们的目标是确定稳定性和无毒性 HydroGEN 建立功能性凝胶并建立安全剂量。在目标 I 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及其 流变特性作为温度和时间的函数，以确定其作为原位胶凝的功能 可注射治疗。在目标 II 中，我们将确定 HydroGEN 没有毒性并具有选择性生物分布 在关节内注射的大鼠模型中。成功完成这些目标将为 ProViZiGen 准备提交 BLA 与 FDA 合作，通过大型动物 PTOA 模型研究（第二阶段）率先进行人体试验。