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 Biosciences，LLC 4940 Carroll Canyon Rd。，Ste。 110 圣地亚哥，加利福尼亚州92121 milton@vivreonbiosciences.com Niams PA-20-260 项目摘要骨关节炎（OA）是一种进行性关节炎状况，是最常见的痛苦和残疾的形式关节炎，影响60岁以上的成年人中超过10％。关节软骨和骨骼的破坏发生通常滋养和支持关节的滑膜组织的明显慢性炎症。有没有可用的疾病改变骨关节炎药物（DMOAD），需求很大。关节破坏性滑膜炎主要由对受损组织受损的信号的炎症和破坏性的先天免疫细胞反应驱动和感觉关节细胞。控制滑膜炎和修改OA进展的理想疗法将是安全的，并且可以减少滑膜中的破坏性巨噬细胞过度活动，同时维护修复活动有益的巨噬细胞激活。 CA2+释放激活的Ca2+通道（CRAC），该SBIR的主题第一阶段项目通过CRAC途径的病因作用的遗传证据来支持药物目标成分和通过OA组织中CRAC通道蛋白的上调。 CRAC通道被激活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NF-B和NFAT启动子驱动的多种生化和基因表达事件炎。 Vivreon Biosciences试图通过推进铅CRAC来控制滑膜炎并降低与OA相关的发病率阻断器化合物VV8321进入药物开发管道。我们建议VV8321具有特性这使其适合于关节内注射和关节长时间保留的可能性持续抑制滑膜巨噬细胞注射。在这个项目中，我们将进一步将VV8321描述为将其推向适合外部资金支持的完整药物开发计划。在AIM 1中，我们将表演体外测定的特征VV8321 ADVAD行为，细胞色素P450酶家族责任（CYP mRNA）诱导），细胞毒性筛查，心血管HERG通道责任和遗传毒性负债（AMES检测）。目的 1还将研究关节内注射中VV8321的关节和血浆药代动力学行为老鼠膝盖。在AIM 2 VV8321中，将在两种大鼠模型中测试效率 - 培养基的不稳定半月板模型和化学诱导模型（碘乙酸酯注射到膝关节中）。该计划的成功完成将使Vivreon将VV8321推向完整的药物开发提供足够文档的计划，以吸引额外的II阶段和外部资金支持。