Osteoarthritis is a progressive joint disease that affects more than 32 million Americans and over 655 millionworldwide. OA is the leading cause for pain and disability in individuals over 65. Estimates place the annual USeconomic burden of OA at $136.4 billion. OA care continues to rely on NSAIDS for symptomatic painmanagement 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 thereforeinnovative 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 chronicsynovial inflammation. Redox imbalance-induced oxidative damage and mitochondrial dysfunction instrumentalto 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 aprotective 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 tohypothesize that concomitant elevation of NAD+ and Sirt1/3 activation may be a promising approach fordeveloping a disease-modifying OA treatment. With the overall goal to develop EH302 as a disease-modifying treatment, this Phase 1 STTRapplication is a joint effort from Elysium Health and the laboratory of Dr. Ru Liu Bryan in the Division ofRheumatology, Allergy and Immunology at UCSD. Elysium Health, co-founded by Dr. Leonard Guarente, apioneering researcher in the field of sirtuin biology, is a New York-based small business with a core focus onNAD+ boosting and sirtuin activating products. The immediate objectives of this Phase 1 STTR are todemonstrate proof-of-concept and feasibility of oral EH302 as OA treatment. In Aim 1 we will determineefficacy and safety of EH302 in a rat model of trauma-induced Osteoarthritis. Major milestones will bereduction of pain and protection from joint damage. Aim 2 will investigate tissue distribution of NR and PTmetabolites after oral EH302 intake using isotope-labeling and mass spectrometry. Based on promising pilotdata we expect that oral EH-302 will meet primary outcome milestones for reduction of pain and joint protectiondemonstrating proof-of-concept and feasibility of development as an OA therapeutic.
Public Health Relevance Statement: Osteoarthritis (OA) is a progressive joint disease affecting more than 32 million Americans and over 527 million
people worldwide and is the leading cause of pain and disability in individuals over 65. The prevalence of OA is
predicted to grow rapidly due to population aging and the rise of obesity, yet disease-modifying therapies for
OA do not currently exist. Sirtuin activation and elevated NAD+ levels have been shown to protect against
inflammation and promote healthy cartilage, and therefore the research goal of this Phase 1 STTR application
from Elysium Health and UCSD is to assess the efficacy of nicotinamide riboside (an NAD+ booster) combined
with pterostilbene (a sirtuin activator) as a potential disease-modifying therapeutic for OA.
Project Terms: <3-Pyridinecarboxamide> 