Metabolically Reprogrammed Mesenchymal Stem Cells for Treating Osteoporosis

ABSTRACT Primary osteoporosis and low bone density are bone formation deficits associated with aging and decline in sex hormonesaffecting an estimatedmillion adults agedand over in the United Statesand resulting in more thanmillion fragility fractures per year and over $billion in related costswhich are expected to increase as the population agesNo current treatment is able to safely increase bone formation long termThusnovelsafe and effective treatments for low bone mineral density and osteoporosis are urgently neededOsteoporosis is hypothesized to arise from the shift of MSC differentiation from osteogenesis to adipogenesiswhich comes with the loss of MSC self renewal differentiation capacityDifferentiation into adipocytes is triggered by the production of reactive oxygen speciesROSwhereas differentiation to osteoblasts takes place under low ROS conditionsAging of MSCs results in higher levels of ROSdue to lowered resistance to oxidative stressOSand increasing use of oxidative phosphorylationOxPhosfor metabolismleading to high levels of adipogenesisIn contrastMSCs with high differentiation capacityyouthfulMSCsare characterized by a primarily glycolytic metabolic state with low OxPhos levelshigh resistance to OSand low ROSresulting in high osteogenesisIn this Phase I SBIRAgeX TherapeuticsIncproposes to study repression of COX Aan electron transport chain subunit critical to OxPhosas a potential therapeutic approach to treating osteoporosisWe identified COX Aas a marker of the highly regenerative embryonic state and glycolytic metabolismIn our preliminary studies in COX Aknockout mice and COX Aknockdown human umbilical cord MSCswe showed that COX Arepression in MSCs increases glycolysisimproves resistance to oxidative stress and gene expression analysis indicates a shift in lineage commitment away from adipogenesisIn Specific Aimwe will perform in vitro experiments to test whether knock outKOof COX Aexpression in MSCs from post menopausal womenageusing CRISPR Caswill rejuvenate the cellsproliferativeregenerativeand differentiation capacity to at leastof values for MSCs from normal young female donorsageIn Specific Aimwe will test whether Cox AKO in mouse MSCs in vivo can confer resistance to bone mineral density loss in the ovariectomizedOVXmouse model of estrogen deficient bone loss and normal early age associated bone loss in miceAfter having demonstrated that Cox AKO in bone marrow MSCs can restore function in vitro and reduce bone loss in vivowe will be able to progress to Phase II and transplant human MSC COX AKO into the mouse OVX model of osteoporosisOur long term goal is to commercialize an autologous osteoporosis therapy using COX Arepression NARRATIVE Osteoporosis and low bone densitywhich are associated with menopause and agingaffect an estimatedmillion adults in the United Statesand result in more than two million fragility fractures per year and over $billion in related costsNo current treatment is capable of safely increasing bone formation long termand novelsafe and effective treatments for low bone mineral density and osteoporosis are urgently neededAgeX TherapeuticsIncproposes to develop a potential therapy for osteoporosis by rejuvenating the bone forming potential of bone marrow stem cells