Utility of AAV Serotypes for Gene Delivery in Treatment of Chronic Joint Disease

AAV 血清型在慢性关节疾病治疗中基因传递的效用

• 批准号: 8125905
• 负责人: Steven C Ghivizzani
• 金额: $ 86.3万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8125905
• 关键词: Address; Affect; American; Animal Model; Arthritis; Arthroscopy; Aspirate substance; Biodistribution; Capsid; Cartilage; Cells; Chronic; Clinical; Clinical Trials; Complementary DNA; Data; Degenerative polyarthritis; Dependovirus; Deterioration; Development; Diagnostic; Digital Radiography; Disease; Disorder by Site; Dose; Drug Kinetics; Equus caballus; Evaluation; Fluorescence; Forelimb; Gene Delivery; Gene Transfer; Genes; Histology; Human; Inflammation; Injection of therapeutic agent; Interleukin-1; Intra-Articular Injections; Joints; Knee; Learning; Magnetic Resonance Imaging; Mediating; Mediator of activation protein; Methods; Modeling; Molecular Profiling; Pain; Pathology; Pattern; Prevalence; Procedures; Production; Proteins; Recombinant Proteins; Recombinant adeno-associated virus (rAAV); Role; Safety; Sclerosis; Serotyping; Site; Societies; Structure of intercarpal joint; Synovial Fluid; Synovial Membrane; System; Technology; Testing; Therapeutic; Time; Tissue Sample; Tissues; Transgenes; Transgenic Organisms; Treatment Efficacy; Viral Genome; Virus; Work; anakinra; arthropathies; articular cartilage; base; bone; clinical application; cost; design; effective therapy; gene delivery system; gene therapy; immunogenicity; improved; indexing; inhibitor/antagonist; joint loading; kinematics; osteochondral tissue; receptor; recombinant viral vector; soft tissue; therapeutic transgene; transgene expression; vector

DESCRIPTION (provided by applicant): Osteoarthritis (OA) is chronic, debilitating condition for which there is no cure. There is strong evidence that interleukin-1 (IL-1) serves as an intra-articular mediator of cartilage loss, pain and inflammation in OA. Its natural inhibitor, the IL-1 receptor antagonist (IL-1Ra), holds promise as an effective treatment, but clinical application is hindered by difficulty achieving and maintaining effective concentrations intra-articularly. We have worked to develop technologies for delivering the cDNA for IL-1Ra to cells in the capsular tissues of joints, such that these tissues become endogenous sites of sustained, elevated IL-1Ra production. This gene-based approach removes the need for repeated application of the recombinant protein while providing the greatest concentration of the gene product specifically at the site of disease. Direct intra- articular injection of certain recombinant viral vectors can provide expression of therapeutic transgenes at levels sufficient to halt arthritis in small animal models. With the use of immunologically compatible vectors and cDNAs, exogenous transgenes can be expressed indefinitely in cells that populate the capsular tissues. Adeno-associated virus (AAV) offers many advantages that favor its use as a gene delivery vehicle for treatment of arthritis. The development of double-stranded (self-complementary [sc]) vectors and alternate capsid serotypes overcomes previous deficiencies such that AAV can be realistically considered as a candidate for human application in OA. The present study will test the hypothesis that scAAV- mediated delivery of the cDNA for IL-1Ra locally to joints with OA will provide sustained therapeutic benefit. Horses provide a unique system in which to study intra-articular gene transfer for joint disease. Their joints are proportional in size to human knees, and they are vulnerable to the onset of OA. In Specific Aims 1 and 2 we will work to determine the utility of scAAV as a gene delivery system to joints of human scale by performing pharmacokinetic studies in equine joints, characterizing biodistribution and transgenic expression patterns following delivery of the cDNA for the homologous equine IL-1Ra (eqIL-1Ra). Lessons learned from this part of the study will be used in Specific Aim 3 to evaluate the capacity of scAAV- mediated delivery of eqIL-1Ra to inhibit the pathologies of an osteochondral fragmentation model of OA in horses. By studying the efficacy of scAAV-IL-1Ra gene therapy in this manner- on an appropriate scale and in a relevant disease context- a clear representation of its therapeutic capacity will emerge. If successful these studies will provide the necessary pharmacokinetic, safety and efficacy data to support the implementation of human trials. PUBLIC HEALTH RELEVANCE: This study is designed to explore the usefulness of a local gene therapy for osteoarthritis. It involves the injection into the joint of recombinant viral vectors containing genes, whose products protect the cartilage from degeneration. To examine the usefulness of this procedure on a human scale, we will perform safety and efficacy studies in the forelimb joints of horses. These joints are proportional in size to human knees, and they naturally develop osteoarthritis. Information from these studies will be used to support clinical trials in humans.

描述（由申请人提供）：骨关节炎（OA）是一种慢性、使人衰弱的疾病，无法治愈。有强有力的证据表明白介素-1 (IL-1) 是 OA 中软骨损失、疼痛和炎症的关节内介质。其天然抑制剂 IL-1 受体拮抗剂 (IL-1Ra) 有望成为一种有效的治疗方法，但由于难以在关节内达到和维持有效浓度而阻碍了临床应用。我们致力于开发将 IL-1Ra 的 cDNA 递送至关节囊组织细胞的技术，使这些组织成为持续、升高 IL-1Ra 产量的内源位点。这种基于基因的方法消除了重复应用重组蛋白的需要，同时在疾病部位提供了最大浓度的基因产物。直接关节内注射某些重组病毒载体可以提供治疗性转基因的表达，其水平足以阻止小动物模型中的关节炎。通过使用免疫相容的载体和 cDNA，外源转基因可以在荚膜组织中的细胞中无限表达。腺相关病毒（AAV）具有许多优势，有利于其用作治疗关节炎的基因递送载体。双链（自互补 [sc]）载体和替代衣壳血清型的开发克服了先前的缺陷，使得 AAV 可以真正被视为人类应用 OA 的候选者。本研究将检验以下假设：scAAV 介导的 IL-1Ra cDNA 局部递送至骨关节炎关节将提供持续的治疗益处。马提供了一个独特的系统来研究关节疾病的关节内基因转移。它们的关节大小与人类膝盖成正比，因此很容易患骨关节炎。在具体目标 1 和 2 中，我们将通过在马关节中进行药代动力学研究，确定 scAAV 作为人类关节基因传递系统的效用，表征同源马 IL-1Ra (eqIL-1Ra) cDNA 传递后的生物分布和转基因表达模式。从这部分研究中获得的经验教训将用于具体目标 3，以评估 scAAV 介导的 eqIL-1Ra 递送抑制马 OA 骨软骨碎裂模型病理的能力。通过以这种方式在适当的规模和相关疾病背景下研究 scAAV-IL-1Ra 基因治疗的功效，将清楚地体现其治疗能力。如果成功，这些研究将提供必要的药代动力学、安全性和功效数据，以支持人体试验的实施。 公共卫生相关性：本研究旨在探索局部基因疗法对骨关节炎的有效性。它涉及将含有基因的重组病毒载体注射到关节中，其产物可以保护软骨免于退化。为了检验该程序在人体范围内的有效性，我们将对马的前肢关节进行安全性和有效性研究。这些关节的大小与人类膝盖成正比，它们自然会发展成骨关节炎。这些研究的信息将用于支持人体临床试验。