Repair of Bone Defects with Human Autologous Pluripotent Very Small Embryonic lik

DESCRIPTION (provided by applicant): Bone loss due to fractures and disease is a serious medical condition in the US affecting millions of Americans. It is particularly a problem with oral craniofacial disorders were the costs of treating damage exceeds60 billion annually. Furthermore, periodontitis is associated with systemic disorders such as diabetes mellitus, preterm low birth weight, and cardiovascular disease. While major efforts have been made to understand mechanisms of healing of large bones andto develop therapeutics to treat overall bone loss, very little information is available on bone remodeling in the human craniofacial skeleton, nor the mechanisms involved in osteonecrosis of the jaw and there are few effective treatments. The results ofour phase 1 SBIR showed that a unique population of human, adult, pluripotent, Very Small Embryonic like (VSEL) stem cells, have important bone regenerative properties and could be useful in treating oral-craniofacial disorders. Human VSELs are pluripotentstem cells involved in the normal turnover and regeneration of tissues and their circulating levels greatly increase in response to injury. They are able to repair injured tissues such as the heart after myocardial infarct. Adult human VSELs, are SSEA-4+/Oct-4+/CD133+/CXCR4+/Lin-/CD45-, express pluripotency markers (Oct-4 and Nanog) and are capable of differentiation into cells from all three germ lineages. With our collaborator, Dr. Russell Taichman of the University of Michigan we showed that VSELs differentiate to osteoblastic lineage after intra-marrow transplant. Importantly, VSELs from adult humans repaired a calvarial defect in SCID mice. The human VSELs formed new bone when applied in the injured area as measured by u-CT scan, and histological analysis demonstrated osteogeneis, significant new bone formation, dense thickening of the trabeculae and bone marrow formation. Most importantly, new bone tissue was derived from the human VSELs. These studies show that VSELs can generate new bone and have thepotential to repair bone injuries. In this phase 2 SBIR, we propose to further test the effectiveness of human VSELs to regenerate bone in human patients. Specifically, we will test the ability of VSELs to promote bone remodeling in the human craniofacialskeleton. For our studies, we will test the efficacy of human VSELs to generate bone in humans in a tooth extraction model in which individuals requiring tooth extraction due to caries or periodontal disease will be the subjects. In these individuals, theunderlying jaw bone tissue is injured and depleted and while there is some healing overtime after tooth extraction, the process is slow. We will test whether VSELs isolated from the patient expedite bone growth in the oral cavity after tooth removal. TheVSELs are autologous and will not cause rejection and do not form tumors or cause other health risks. This is not a clinical trial but a focused patient based study intended to move forward the development of VSELs as a therapeutic for bone repair. It successful, these studies will provide the basis for the rapid clinical development of VSELs for craniofacial osseous regeneration and treatment of a number of other skeletal based disorders. PUBLIC HEALTH RELEVANCE: It is a goal of NeoStem to develop the therapeutic capabilities of Human VSELs to treat a host of diseases and disorders. Studies in this proposal are focused on establishing the utility of VSELs to repair bone and treat oral-craniofacial disorders. If the results of these studies in humans show safety and efficacy of adult autologous VSELs in bone repair, then we will attempt to further develop this cell therapy in clinical studies in the futureto establish the cells as a standard of care for the treatment of bone disease and loss.