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

• 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
• 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

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 国际吧OA是65岁以上人群疼痛和残疾的主要原因。据估计， OA的经济负担为1364亿美元。OA护理继续依赖NSAIDS治疗症状性疼痛 管理和关节置换作为最后手段。目前尚无法获得改善疾病的OA疗法。 由于人口老龄化和肥胖的增加，预计OA的患病率将迅速增加， 创新方法，减缓或逆转OA进展，是一个迫切的未满足的需求。 OA是一种全关节疾病，其特征在于软骨的进行性损失、骨生长失调和慢性炎症。 滑膜炎症氧化还原失衡诱导的氧化损伤和线粒体功能障碍 到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起关键作用， 线粒体功能，并且是sirtuins 1 -7所需的辅因子。Sirt 1/Sirt 3轴已被证明发挥了 由于它们能够促进软骨细胞自噬和存活，因此在OA中具有保护作用。两种NAD+ Sirt 1/3的水平和活性在慢性炎症过程中降低，并随年龄增长而下降，导致我们 假设伴随NAD+和Sirt 1/3激活升高可能是一种有希望的方法， 开发一种缓解疾病的OA治疗方法 总体目标是开发EH 302作为一种疾病缓解治疗，该1期STTR 该应用程序是Elysium Health和Ru Liu Bryan博士实验室的共同努力， 流变学，过敏和免疫学。Elysium Health，由伦纳德瓜伦特博士共同创立， 在sirtuin生物学领域的先驱研究员，是一家总部设在纽约的小企业，核心重点是 NAD+增强和sirtuin激活产品。本第1阶段STTR的近期目标是 证明口服EH 302作为OA治疗的概念验证和可行性。在目标1中，我们将确定 EH 302在创伤性骨关节炎大鼠模型中有效性和安全性。主要里程碑将是 减轻疼痛和保护关节免受损伤。目的2将研究NR和PT的组织分布 使用同位素标记和质谱法测定口服EH 302摄入后的代谢物。基于有前途的试点 我们预计口服EH-302将达到减轻疼痛和保护关节的主要结局里程碑 证明了作为OA治疗剂开发的概念验证和可行性。