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Metabolically Reprogrammed Mesenchymal Stem Cells for Treating Osteoporosis

Award Number: R43AR074351
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2020

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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 hormones, affecting an estimated 55 million adults aged 50 and over in the United States, and resulting in more than 2 million fragility fractures per year and over $20 billion in related costs, which are expected to increase as the population ages. No current treatment is able to safely increase bone formation long-term. Thus, novel, safe and effective treatments for low bone mineral density and osteoporosis are urgently needed. Osteoporosis is hypothesized to arise from the shift of MSC differentiation from osteogenesis to adipogenesis, which comes with the loss of MSC self-renewal/differentiation capacity. Differentiation into adipocytes is triggered by the production of reactive oxygen species (ROS), whereas differentiation to osteoblasts takes place under low ROS conditions. Aging of MSCs results in higher levels of ROS, due to lowered resistance to oxidative stress (OS) and increasing use of oxidative phosphorylation (OxPhos) for metabolism, leading to high levels of adipogenesis. In contrast, MSCs with high differentiation capacity (“youthful” MSCs) are characterized by a primarily glycolytic metabolic state with low OxPhos levels, high resistance to OS, and low ROS, resulting in high osteogenesis. In this Phase I SBIR, AgeX Therapeutics, Inc. proposes to study repression of COX7A1, an electron transport chain subunit critical to OxPhos, as a potential therapeutic approach to treating osteoporosis. We identified COX7A1 as a marker of the highly regenerative embryonic state and glycolytic metabolism. In our preliminary studies in COX7A1-knockout mice and COX7A1-knockdown human umbilical cord MSCs, we showed that COX7A1 repression in MSCs increases glycolysis, improves resistance to oxidative stress and gene expression analysis indicates a shift in lineage commitment away from adipogenesis. In Specific Aim #1, we will perform in vitro experiments to test whether knock out (KO) of COX7A1 expression in MSCs from post-menopausal women (age 55-60) using CRISPR/Cas9 will rejuvenate the cells’ proliferative, regenerative, and differentiation capacity to at least 70% of values for MSCs from normal young female donors (age 20-25). In Specific Aim #2, we will test whether Cox7A1-KO in mouse MSCs in vivo can confer resistance to bone mineral density loss in the ovariectomized (OVX) mouse model of estrogen-deficient bone loss and normal early age-associated bone loss in mice. After having demonstrated that Cox7A1 KO in bone marrow MSCs can restore function in vitro and reduce bone loss in vivo, we will be able to progress to Phase II and transplant human MSC-COX7A1-KO into the mouse OVX model of osteoporosis. Our long-term goal is to commercialize an autologous osteoporosis therapy using COX7A1 repression.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2018	AGEX THERAPEUTICS, INC.	1101 MARINA VILLAGE PKWY STE 201	ALAMEDA	CA	94501	ALAMEDA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	11/9/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $224,973 )
2018	2018	AGEX THERAPEUTICS, INC.	1010 ATLANTIC AVE STE 102	ALAMEDA	CA	94501	ALAMEDA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/20/2018	NEW	$224,973
														Subtotal = $224,973

Grand Total All Awards = $224,973

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Metabolically Reprogrammed Mesenchymal Stem Cells for Treating Osteoporosis

Award Number: R43AR074351

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/20/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2020

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