Predevelopment of VV8321, a Novel CRAC Channel Therapeutic for the Treatment of Osteoarthritis

VV8321 的预开发，一种用于治疗骨关节炎的新型 CRAC 通道疗法

基本信息

批准号：
10383630
负责人：
Milton L Greenberg
金额：
$ 25.2万
依托单位：
VIVREON BIOSCIENCES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-22 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10383630
关键词：
Address Adult Affect Age-Years Ames Assay Animal Model Arthralgia Arthritis Behavior Biochemical Biological Sciences Cardiovascular system Cartilage Cells Chemicals Chronic Clinical Trials Cytochrome P450 Degenerative polyarthritis Development Disease Disease Progression Documentation Dosage Forms Drug Interactions Drug Kinetics Drug Targeting Emulsions Enzymes Event Excretory function Exhibits Family Funding Gene Expression Genes Genetic Genetic Polymorphism Goals Grant Homeostasis Immune Immunity Inflammation Inflammatory Injections Intra-Articular Injections Iodoacetates Joints Knee Knee joint Lead Leukocytes Macrophage Activation Medial meniscus structure Mediating Messenger RNA Metabolism Minor Mission Modeling Morbidity - disease rate National Institute of Arthritis and Musculoskeletal and Skin Diseases Normal tissue morphology Nuclear Pain Pain management Pathogenesis Pathogenicity Pathway interactions Patient risk Patients Persons Pharmaceutical Preparations Pharmacologic Substance Pharmacology Pharmacotherapy Phase Plasma Positioning Attribute Predisposition Privatization Production Program Appropriateness Program Development Property Proteins Rattus Regimen Role Safety Signal Transduction Small Business Innovation Research Grant Symptoms Synovial Membrane Synovitis Testing Therapeutic Therapeutic Index Tissues Treatment Efficacy Up-Regulation Western Ontario and McMaster Universities Arthritis Index absorption bone candidate validation channel blockers chronic inflammatory disease clinical candidate clinical development cytokine cytotoxicity drug candidate drug development efficacy study efficacy validation first-in-human genotoxicity immunoregulation in vitro Assay in vivo indexing inhibitor/antagonist interest joint destruction joint inflammation joint stiffness leukocyte activation macrophage novel osteoarthritis pain patient population prevent programs promoter receptor repaired research clinical testing response screening senescence side effect small molecule therapeutic candidate transcription factor treatment duration

项目摘要

Vivreon Biosciences, LLC 4940 Carroll Canyon Rd., Ste. 110 San Diego, CA 92121 milton@vivreonbiosciences.com NIAMS PA-20-260 Project Summary Osteoarthritis (OA) is a progressive arthritic condition and the most common form of painful and disabling arthritis, affecting over 10% of adults over 60 years of age. Destruction of joint cartilage and bone occurs with significant chronic inflammation of the synovium tissue that normally nourishes and supports the joint. There is no available Disease Modifying Osteoarthritis Drug (DMOAD), and the need is great. Joint destructive synovitis is driven largely by inflammatory and destructive innate immune cell responses to signals from damaged tissues and senescent joint cells. An ideal therapeutic to control synovitis and modify OA progression would be safe and able to reduce damaging macrophage overactivity in the synovium while maintaining the repair activities of beneficial macrophage activation. The Ca2+ Release Activated Ca2+ Channel (CRAC), the topic of this SBIR Phase I project, is supported as a drug target by genetic evidence of a causative role for CRAC pathway components and by upregulation of the CRAC channel protein in OA tissues. The CRAC channel is activated by multiple proinflammatory receptors on macrophages, and signaling events downstream of CRAC activation drive a multiplicity of biochemical and gene expression events driven by NF-B and NFAT promoters typical of chronic inflammation. Vivreon Biosciences seeks to control synovitis and reduce OA-associated morbidity by advancing a lead CRAC blocker compound, VV8321, into the drug development pipeline. We propose that VV8321 exhibits properties that make it suitable for intra-articular injection and the likelihood of a prolonged retention in the joint to provide sustained inhibition of synovial macrophage inflammation. In this project we will further characterize VV8321 to advance it into a full drug development program appropriate for external funding support. In Aim 1 we will perform in vitro assays to characterize VV8321 ADME behaviors, cytochrome P450 enzyme family liabilities (CYP mRNA induction), cytotoxicity screening, cardiovascular hERG channel liability and genotoxic liabilities (Ames test). Aim 1 will also investigate the joint and plasma pharmacokinetic behavior of VV8321 upon intra-articular injection into rat knees. In Aim 2 VV8321 efficacy will be tested in two rat models of OA – a destabilization of the medial meniscus model and a chemical induction model (monosodium iodoacetate injection into the knee joint). Successful completion of the program will position Vivreon to advance VV8321 into a full drug development program with sufficient documentation to attract additional Phase II and external funding support.

Vivreon 生物科学有限公司 4940 卡罗尔峡谷路，Ste 110 圣地亚哥, CA 92121 milton@vivreonbiosciences.com 尼亚姆斯 PA-20-260 项目概要骨关节炎 (OA) 是一种进行性关节炎，是最常见的疼痛和致残形式关节炎影响超过 10% 的 60 岁以上成年人，伴随着关节软骨和骨骼的破坏。通常滋养和支持关节的滑膜组织存在明显的慢性炎症。没有可用的疾病修饰骨关节炎药物（DMOAD），并且对关节破坏性滑膜炎的需求很大。主要是由炎症和破坏性先天免疫细胞对受损组织信号的反应驱动的控制滑膜炎和改变 OA 进展的理想治疗方法是安全且有效的。能够减少滑膜中破坏性巨噬细胞的过度活跃，同时维持滑膜的修复活性有益的巨噬细胞激活。Ca2+ 释放激活的 Ca2+ 通道 (CRAC)，这是本 SBIR 的主题。 I 期项目作为药物靶点得到了 CRAC 通路致病作用的遗传证据的支持 OA 组织中 CRAC 通道蛋白的上调可激活 CRAC 通道。巨噬细胞上的多种促炎受体以及 CRAC 激活驱动下游的信号事件由慢性病典型的 NF-κB 和 NFAT 启动子驱动的多种生化和基因表达事件炎。 Vivreon Biosciences 寻求通过推进领先的 CRAC 来控制滑膜炎并降低 OA 相关发病率阻断剂化合物 VV8321 进入药物开发管道我们建议 VV8321 表现出特性。这使得它适合关节内注射，并有可能长期保留在关节中，以提供持续抑制滑膜巨噬细胞炎症在本项目中，我们将进一步表征 VV8321 在目标 1 中，我们将把它纳入适合外部资金支持的完整药物开发计划中。体外测定来表征 VV8321 ADME 行为、细胞色素 P450 酶家族负债（CYP mRNA 诱导）、细胞毒性筛查、心血管 hERG 通道责任和基因毒性责任（Ames 测试）。 1还将研究VV8321关节内注射后的关节和血浆药代动力学行为目标 2 将在两种 OA 大鼠模型（内侧不稳定）中测试 VV8321 的功效。半月板模型和化学诱导模型（碘乙酸钠注射到膝关节）。该计划的成功完成将使 Vivreon 推动 VV8321 进入全面药物开发阶段计划有足够的文件来吸引额外的第二阶段和外部资金支持。