Treatment of posttraumatic arthritis and prevention of osteoarthritis

创伤后关节炎的治疗和骨关节炎的预防

• 批准号: 7855300
• 负责人: Martin K Lotz
• 金额: $ 64.82万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7855300
• 关键词: Acute; Address; Adsorption; Animal Model; Apoptosis; Arthralgia; Arthritis; Biochemical Markers; Biological Assay; Biological Markers; Cartilage; Cartilage injury; Caspase; Caspase Inhibitor; Cell Death; Cessation of life; Chondrocytes; Chronic; Clinical; Clinical Drug Development; Clinical Research; Clinical Trials; Data; Degenerative polyarthritis; Development; Disease; Drug Formulations; Enzymes; Excretory function; Goals; Human; In Vitro; Inflammation; Inflammation Mediators; Injury; Interleukins; Intervention; Intra-Articular Injections; Ligaments; Liver diseases; Magnetic Resonance Imaging; Measurement; Mechanics; Mediator of activation protein; Meniscus structure of joint; Metabolism; Modeling; Operative Surgical Procedures; Orthopedics; Osteoarthrosis Deformans; Pain; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Prevention; Process; Reconstructive Surgical Procedures; Research; Risk; Safety; Scientist; Severities; Sports; Surgeon; Symptoms; Testing; Time; Toxic effect; Traumatic Arthropathy; arthropathies; base; cartilage cell; clinical application; cytokine; disability; efficacy testing; experience; improved; inhibitor/antagonist; joint injury; novel; patient population; pre-clinical; preclinical safety; preclinical study; prevent; rheumatologist; small molecule; therapeutic target; tissue culture; tissue/cell culture

DESCRIPTION (provided by applicant): Joint trauma as encountered during sports or other types of injury causes acute cartilage damage and joint inflammation and significantly increases long-term risk for the development of osteoarthritis (OA). After acute injury, patients experience severe and disabling joint pain and inflammation. Therapies that address the acute posttraumatic phase or prevent the development of chronic disabling OA are not available. Our previous research identified cartilage cell death as an important process after mechanical joint injury and in OA. Caspases are a class of enzymes that execute cell death and also activate interleukins that are important mediators of joint inflammation. In previous in vitro and animal model studies we established proof-of-concept that caspase inhibitors are effective in inhibiting cartilage cell death and in reducing the severity of experimental OA. The overall objective of the proposed project is to complete preclinical development of caspase inhibitors and enable a Phase I clinical trial in patients with joint trauma. We have access to a caspase inhibitor that has already been in clinical trials for liver disease. The formulation development (Aim 1) will demonstrate that the formulated caspase inhibitor is released in a biologically active form and has extended intraarticular retention time. The animal model studies (Aim 2) will test the formulated caspase inhibitor in comparison to the free drug and a vehicle control. Endpoints are quantitative measurements of cartilage degradation and joint inflammation. Biochemical markers will be included as secondary endpoints and correlated with the biomarkers observed in humans in Aim 4. Preclinical safety information and Phase II clinical safety data already exists on the caspase inhibitor. In aim 3 we will use standard assays that follow FDA guidance to establish safety of the formulated inhibitor following intraarticular injection. In parallel with these preclinical studies we will perform a clinical study (Aim 4) to characterize the patient population with posttraumatic arthritis to identify MRI and biochemical markers that predict and correlate with joint inflammation and cartilage degradation. Together, the preclinical and clinical components in this project will enable initiation of the first Phase I study to specifically address the needs for treatment of the acute symptoms and the prevention of chronic disability in humans with posttraumatic arthritis.

描述（由申请人提供）：运动或其他类型的伤害期间遇到的关节创伤会导致急性软骨损伤和关节炎症，并显着增加骨关节炎（OA）的长期风险。急性损伤后，患者会出现严重而禁用关节疼痛和炎症。无法使用急性创伤后阶段或防止慢性破坏OA的疗法。我们以前的研究将软骨细胞死亡确定为机械关节损伤和OA后的重要过程。胱天蛋白酶是一类酶，可执行细胞死亡，并激活白细胞介素，这些酶是关节炎症的重要介质。在以前的体外和动物模型研究中，我们确定了概念概念，即caspase抑制剂可有效抑制软骨细胞死亡并降低实验性OA的严重程度。拟议项目的总体目标是完成caspase抑制剂的临床前开发，并在关节创伤患者中进行I期临床试验。我们可以使用已经在肝病临床试验中的caspase抑制剂。配方开发（AIM 1）将证明配制的caspase抑制剂以生物活性形式释放，并扩大了关节内保留时间。与自由药物和媒介物控制相比，动物模型研究（AIM 2）将测试配制的caspase抑制剂。终点是软骨降解和关节炎症的定量测量。生化标记将作为次要终点包括在内，与AIM 4中人类观察到的生物标志物相关。临床前安全信息和II期临床安全数据已经存在于caspase抑制剂上。在AIM 3中，我们将使用遵循FDA指南的标准测定法，以确立关节内注射后配方抑制剂的安全性。与这些临床前研究同时，我们将进行临床研究（AIM 4），以表征患有创伤后关节炎的患者人群，以鉴定MRI和生化标志物，这些MRI和生化标志物预测并与关节炎症和软骨降解相关。共同，该项目中的临床前和临床成分将使第一阶段I研究开始，以特别满足治疗急性症状的需求以及预防创伤后关节炎的人类的慢性残疾。