Efficacy of intra-articular SLPI in rat RA

关节内 SLPI 对大鼠 RA 的疗效

• 批准号: 6934792
• 负责人: PATRICK MCCONVILLE
• 金额: $ 10.01万
• 依托单位: MOLECULAR IMAGING RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-03 至 2006-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6934792
• 关键词: alternative medicine; antineoplastics; arthritis therapy; biomarker; cartilage; computed axial tomography; disease /disorder model; drug delivery systems; drug screening /evaluation; folate antagonist; gel; injection /infusion; laboratory rat; magnetic resonance imaging; methotrexate; musculoskeletal imaging /visualization /scanning; nonhuman therapy evaluation; pathologic process; protease inhibitor; rheumatoid arthritis; slow release drug; therapy design /development

DESCRIPTION (provided by applicant): This proposal seeks to apply magnetic resonance imaging (MRI) and micro-computed tomography (micro-CT) in vivo imaging techniques to demonstrate therapeutic efficacy using a novel treatment in a rat model of rheumatoid arthritis (RA). The proposed novel treatment is an intra-articular injection of SLPI-loaded thermo-reversible (TR) gel. After intra-articular injection, the TR gel delivery system will enable local slow release of SLPI, a protease inhibitor which plays a protective role in the normal joint by accumulating in cartilage. It is hypothesized that an SLPI treatment will be effective in neutralizing excess protease activity in the rheumatoid arthritic joint, which, in turn, could inhibit the erosion and destruction of the joint. In the proposed preclinical trial, a streptococcal cell wall-induced (SCW) rat model of rheumatoid arthritis will be used. The SCW-induced disease resembles human arthritis in its clinical course and distribution, and in its radiological and histological features. MRI and micro-CT imaging modalities will initially be validated in the rat SCW RA model, to demonstrate the ability to quantify bone and cartilage modifications with disease progression, including bone erosions, synovial fluid loss and changes in bone mass density. A preclinical trial will then be implemented to measure theraputic efficacy of the intra-articular SLPI-loaded TR gel system, compared with untreated controls, controls treated with direct SLPI injection (both local and systemic injection), and a positive control treated using the current drug of choice for RA treatment, methotrexate. An additional group will be treated with intra-articular SLPI-loaded TR gel, 4 weeks after the onset of chronic disease. Having successfully demonstrated efficacy in Phase I, MIR will further optimize the therapy in Phase II, also seeking to incorporate standard agents for sustained local delivery by the TR gel system, conducting further preclinical trials with a view towards implementing initial clinical trials by the end of Phase II. The goals of this work are (1) to demonstrate complete inhibition of RA disease progression using the SLPI-loaded TR gel system, addressing the current lack of efficacious therapies for RA, and (2) to validate MRI and micro-CT imaging methods for following RA disease biomarkers in this preclinical model.

描述（由申请人提供）： 该提案旨在在体内成像技术中应用磁共振成像（MRI）和微型层析成像（Micro-CT），以在类风湿关节炎（RA）的大鼠模型中使用新的治疗方法来证明治疗功效。拟议的新型治疗方法是对SLPI的热可逆（TR）凝胶的关节内注射。关节内注射后，TR凝胶递送系统将使SLPI的局部慢速释放，SLPI是一种蛋白酶抑制剂，通过在软骨中积聚在正常关节中起保护作用。假设SLPI治疗将有效地中和类风湿关节中的过量蛋白酶活性，进而可以抑制关节的侵蚀和破坏。在拟议的临床前试验中，将使用类风湿关节炎的链球菌细胞诱导的（SCW）大鼠模型。 SCW诱导的疾病在其临床过程和分布以及其放射学和组织学特征上类似于人类关节炎。最初将在大鼠SCW RA模型中验证MRI和MICRO-CT成像方式，以证明随着疾病进展的骨骼和软骨修饰的能力，包括骨骼侵蚀，滑液流体损失以及骨骼质量密度的变化。然后，将实施一项临床前试验，以测量关节内SLPI载荷TR凝胶系统的治疗功效，与未经处理的对照相比，用直接SLPI注射（局部和全身注射）处理的对照（均为局部和全身注射）以及使用当前选择药物治疗RA治疗，甲氧脱氧甲甲甲氧铁治疗的对照。慢性疾病发作4周后，将用关节内SLPI的TR凝胶治疗另外一组。 MIR成功证明了在第一阶段的功效后，将进一步优化II期的治疗，还试图通过TR Gel系统纳入标准的局部局部递送，并进行了进一步的临床前试验，以期在II阶段结束前实施初始临床试验。这项工作的目标是（1）使用SLPI-poaded Tr Gel系统证明对RA疾病进展的完全抑制，以解决当前RA的有效疗法的缺乏，以及（2）验证MRI和MIRR-CT成像方法，用于遵循此临床前模型中遵循RA疾病生物标志物的MRI和MICRO-CT成像。