Recombinant FIV vectors for the delivery of siRNA therapy to joints

用于向关节递送 siRNA 治疗的重组 FIV 载体

• 批准号: 7296138
• 负责人: Stephanos Kyrkanides
• 金额: $ 16.45万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-25 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7296138
• 关键词: Address; Adult; Adverse effects; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Arthralgia; Arthritis; Autoimmune Diseases; Binding; Chronic; Clinical; Degenerative polyarthritis; Development; Dose; Elderly; Endosomes; Family Felidae; Functional disorder; Gene Silencing; Genes; Hip region structure; Human; Immune; Immune response; Immune system; Immunologic Deficiency Syndromes; In Vitro; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Intra-Articular Injections; Invasive; Joint Capsule; Joints; Knee; Knee joint; Laboratories; Ligands; Mediating; Methods; Modeling; Mono-S; Mus; Nerve Degeneration; Operative Surgical Procedures; Oral; PTGS2 gene; Pain; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacia brand of valdecoxib; Procedures; Property; Prostaglandin-Endoperoxide Synthase; Purpose; RNA; RNA Interference; RNA-Induced Silencing Complex; Reaction; Recombinants; Relative (related person); Research Personnel; Rofecoxib; Signal Transduction; Specificity; Support of Research; Temporomandibular Joint; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Toxic effect; Transgenic Mice; Transgenic Organisms; Translating; Viral Cancer; Viral Vector; base; cyclooxygenase 1; cyclooxygenase 2; disability; human TLR7 protein; improved; in vivo; inhibitor/antagonist; mRNA Transcript Degradation; member; mouse PGE synthase 1; mouse model; novel; polycation; programs; research study; response; soft tissue; success; vector

DESCRIPTION (provided by applicant): Osteoarthritis (OA) is the most common form of arthritis and a major cause of activity limitation and physical disability in the elderly: 80%-90% of humans over the age of 65 suffer from OA. Available treatments for OA are mostly palliative with limited specificity. In fact, the recently identified serious side effects of some intra- oral COX-2 selective inhibitors (i.e. Vioxx, Bextra) underscore the need for the development of novel anti- inflammatory therapies for OA. The purpose of this Exploratory/Developmental R21 grant application is to develop a novel, simple and highly efficient method for the intra-articular delivery of siRNA to joints for the management of arthritis. Our model aims at significantly improving the transduction efficacy of siRNA to soft and hard tissues of joints via a non-invasive, one-time application that will result in sustainable therapeutic siRNA titers over prolonged periods of time (several months). Our strategy is based on combining the unique properties of the feline immunodeficiency viral vector (FIV) with the therapeutic properties of siRNA targeting key inflammatory genes. Specifically, our laboratory has demonstrated that VSV-G pseudo typed FIV vectors can successfully be used in stably transducing hard and soft tissues of joints in adult mice following a single intra-articular injection while evading the elicitation of an innate immune response. This method of direct intra-articular administration also confines the therapeutic effects within the joint capsule (thus minimizing any off-target side effects) following a simple, straight forward injection that can be readily performed clinically in an ambulatory setting without the need of open joint surgery or other invasive procedure. We hypothesize that FIV-mediated intra-articular delivery of siRNA constructs targeting the inducible COX-2 and/or mPGES-1 genes will ameliorate the development of joint pathology, pain and dysfunction in the Col1- IL1beta(XAT) transgenic mouse model of mono-arthritis. We have initially selected to focus on these inflammatory factors because the cyclooxygenase pathway appears to serve as a node of convergence in arthritis as supported by research studies as well as the extensive use and relative clinical success of non-steroidal anti- inflammatory drugs. Based on our strategy, we will develop FIV(siRNA) vectors for the transfer of the aforementioned siRNA constructs to joints (knee and tempromandibular joint) of adult mice suffering from arthritis. We evaluate the efficacy of these FIV(siRNA) vectors in ameliorating joint pathology, pain and dysfunction will be assessed in the Col1-IL1beta(XAT) arthritis model following intra-articular injection into the joints (knee and/or tempromandibular joint) of adult mice. Emphasis will be given in evaluating COX-2 and/or mPGES-1 expression as they are targets of our FIV(siRNA) therapy over time as well as assessing potential inflammatory responses elicited by this siRNA therapy.

描述（由申请人提供）： 骨关节炎 (OA) 是最常见的关节炎形式，也是老年人活动受限和身体残疾的主要原因：65 岁以上的人中 80%-90% 患有 OA。 OA 的现有治疗方法大多是姑息治疗，特异性有限。事实上，最近发现的一些口腔内 COX-2 选择性抑制剂（即 Vioxx、Bextra）的严重副作用强调了开发新型 OA 抗炎疗法的必要性。本次探索性/开发性 R21 拨款申请的目的是开发一种新颖、简单且高效的方法，用于将 siRNA 关节内递送至关节以治疗关节炎。我们的模型旨在通过非侵入性的一次性应用显着提高 siRNA 向关节软组织和硬组织的转导效率，从而在较长时间内（几个月）产生可持续的治疗 siRNA 滴度。我们的策略基于将猫免疫缺陷病毒载体 (FIV) 的独特特性与针对关键炎症基因的 siRNA 的治疗特性相结合。具体来说，我们的实验室已经证明，VSV-G 伪型 FIV 载体可以成功地用于在单次关节内注射后稳定转导成年小鼠的关节硬组织和软组织，同时避免引发先天免疫反应。这种直接关节内给药的方法还将治疗效果限制在关节囊内（从而最大限度地减少任何脱靶副作用），通过简单、直接的注射，可以在临床上轻松地在门诊环境中进行，无需开放关节手术或其他侵入性手术。我们假设，FIV 介导的针对可诱导 COX-2 和/或 mPGES-1 基因的 siRNA 构建体的关节内递送将改善单关节炎 Col1-IL1beta(XAT) 转基因小鼠模型中关节病理、疼痛和功能障碍的发展。我们最初选择关注这些炎症因子，因为环氧合酶途径似乎是关节炎的汇聚节点，这一点得到了研究以及非甾体抗炎药的广泛使用和相对临床成功的支持。根据我们的策略，我们将开发 FIV(siRNA) 载体，用于将上述 siRNA 构建体转移到患有关节炎的成年小鼠的关节（膝关节和颞下颌关节）。我们评估这些 FIV(siRNA) 载体在改善关节病理、疼痛和功能障碍方面的功效，并将在关节内注射到成年小鼠的关节（膝关节和/或颞下颌关节）后，在 Col1-IL1beta(XAT) 关节炎模型中进行评估。将重点评估 COX-2 和/或 mPGES-1 表达，因为它们是我们的 FIV(siRNA) 治疗随时间推移的目标，并评估该 siRNA 治疗引起的潜在炎症反应。