Development of Nicotinamide-Riboside plus Pterostilbene as a Disease Modifying Osteoarthritis Therapeutic

开发烟酰胺核苷加紫檀芪作为骨关节炎疾病缓解疗法

基本信息

批准号：
10699600
负责人：
RU BRYAN
金额：
$ 28.31万
依托单位：
ELYSIUM HEALTH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10699600
关键词：
Adverse event Affect Age Agreement American Animal Model Animals Autophagocytosis Biochemistry Biodistribution Biology Blood Bone Growth Brain Businesses Caring Cartilage Chondrocytes Chronic Complement DNA Methylation Data Degenerative polyarthritis Development Disease Dose Drug or chemical Tissue Distribution Economic Burden Gene Expression Goals Health Heart Hematology Histology Human Hypersensitivity Immunology In Vitro Individual Inflammation Inflammatory Response Intake Interleukin-1 beta Investigation Isotope Labeling Joints Kidney Knee Knee joint Laboratories Legal patent Licensing Light Liver Mass Spectrum Analysis Meniscus structure of joint Metabolic Methylation Mitochondria Modeling NAD+ Nucleosidase New York Niacinamide Non-Steroidal Anti-Inflammatory Agents Obesity Oral Organ Outcome Oxidation-Reduction Pain Pain management Pathology Persons Phase Play Prevalence Rattus Reaction Recording of previous events Replacement Arthroplasty Research Research Personnel Rheumatology Rights Role SIRT1 gene Safety Serum Sirtuins Small Business Technology Transfer Research Synovitis Testing Therapeutic Tissues Trauma Whole Blood age related aging population arthropathies cofactor disability efficacy evaluation innovation joint injury mitochondrial dysfunction mouse model nicotinamide-beta-riboside oxidative damage pain reduction pain score phase 2 study primary outcome response response biomarker safety assessment treatment response

项目摘要

Osteoarthritis is a progressive joint disease that affects more than 32 million Americans and over 655 million worldwide. OA is the leading cause for pain and disability in individuals over 65. Estimates place the annual US economic burden of OA at $136.4 billion. OA care continues to rely on NSAIDS for symptomatic pain management and joint replacement as a last-resort. Disease modifying OA therapies are currently unavailable. Prevalence of OA is predicted to rapidly increase due to population aging and rise of obesity therefore innovative approaches that slow or reverse OA progression and are a dire unmet need. OA is a whole-joint disease featuring progressive loss of cartilage, dysregulated bone growth and chronic synovial inflammation. Redox imbalance-induced oxidative damage and mitochondrial dysfunction instrumental to OA pathology. NAD+, a Vitamin B3 metabolite occupies a pivotal role in cellular redox reactions, mitochondrial function and is a required cofactor for sirtuins1-7. The Sirt1/Sirt3 axis has been shown to play a protective role in OA on account of their ability to promote chondrocyte autophagy and survival. Both NAD+ levels and activity of Sirt1/3 decrease during chronic inflammation and decline with age, leading us to hypothesize that concomitant elevation of NAD+ and Sirt1/3 activation may be a promising approach for developing a disease-modifying OA treatment. With the overall goal to develop EH302 as a disease-modifying treatment, this Phase 1 STTR application is a joint effort from Elysium Health and the laboratory of Dr. Ru Liu Bryan in the Division of Rheumatology, Allergy and Immunology at UCSD. Elysium Health, co-founded by Dr. Leonard Guarente, a pioneering researcher in the field of sirtuin biology, is a New York-based small business with a core focus on NAD+ boosting and sirtuin activating products. The immediate objectives of this Phase 1 STTR are to demonstrate proof-of-concept and feasibility of oral EH302 as OA treatment. In Aim 1 we will determine efficacy and safety of EH302 in a rat model of trauma-induced Osteoarthritis. Major milestones will be reduction of pain and protection from joint damage. Aim 2 will investigate tissue distribution of NR and PT metabolites after oral EH302 intake using isotope-labeling and mass spectrometry. Based on promising pilot data we expect that oral EH-302 will meet primary outcome milestones for reduction of pain and joint protection demonstrating proof-of-concept and feasibility of development as an OA therapeutic.

骨关节炎是一种进行性关节疾病，影响超过 3200 万美国人和超过 6.55 亿人全世界。 OA 是 65 岁以上老年人疼痛和残疾的主要原因。据估计，美国每年 OA 的经济负担为 1,364 亿美元。骨关节炎护理继续依赖非甾体抗炎药来缓解症状性疼痛管理和关节置换作为最后的手段。目前尚无缓解 OA 疾病的疗法。由于人口老龄化和肥胖症的增加，预计 OA 的患病率将迅速增加减缓或逆转 OA 进展的创新方法是一个亟待满足的需求。 OA 是一种全关节疾病，其特征是软骨进行性丧失、骨生长失调和慢性滑膜炎症。氧化还原失衡引起的氧化损伤和线粒体功能障碍 OA 病理学。 NAD+ 是一种维生素 B3 代谢物，在细胞氧化还原反应中发挥着关键作用，线粒体功能，是 Sirtuins1-7 必需的辅助因子。 Sirt1/Sirt3 轴已被证明可以发挥作用由于它们能够促进软骨细胞自噬和存活，因此在 OA 中发挥保护作用。两者均为 NAD+ Sirt1/3 的水平和活性在慢性炎症期间下降，并随着年龄的增长而下降，导致我们假设 NAD+ 和 Sirt1/3 激活同时升高可能是一种有前途的方法开发一种缓解疾病的 OA 治疗方法。总体目标是将 EH302 开发为疾病缓解疗法，该 1 期 STTR 该应用是 Elysium Health 和该部门 Ru Liu Bryan 博士实验室的共同努力加州大学圣地亚哥分校的风湿病学、过敏学和免疫学。 Elysium Health，由 Leonard Guarente 博士共同创立， Sirtuin 生物学领域的先驱研究员，是一家总部位于纽约的小型企业，其核心重点是 NAD+ 增强剂和 Sirtuin 激活产品。第一阶段 STTR 的近期目标是证明口服 EH302 作为 OA 治疗的概念验证和可行性。在目标 1 中，我们将确定 EH302 在创伤性骨关节炎大鼠模型中的功效和安全性。主要里程碑将是减轻疼痛并保护关节免受损伤。目标 2 将研究 NR 和 PT 的组织分布使用同位素标记和质谱分析口服 EH302 后的代谢物。基于有希望的试点根据数据，我们预计口服 EH-302 将达到减轻疼痛和保护关节的主要结果里程碑展示作为 OA 治疗方法的概念验证和开发可行性。