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

点击翻译按钮获取中文摘要

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.