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.
