Synthesis of bone-selective osteogenic oxysterols

Summary

Principal Investigator: Frank Stappenbeck
Abstract: DESCRIPTION (provided by applicant): Osteoporosis affects 10 million Americans and another 34 million are osteopenic and at risk for developing osteoporosis. Bone fractures, the most important complication of the disease, cause substantial morbidity and mortality in the aging population as well as significant socio-economic cost. Since the 1960's, bisphosphonate drug therapy has produced clinical benefits such as improved bone density and reduced fracture risk by slowing osteoclastic bone resorption. The existing anti-resorptive drugs are plagued with untoward side effects and limited duration of clinical benefits. New and improved strategies for therapeutic intervention in osteoporosis are needed, particularly in the area of new medicines that safely promote anabolic bone growth. Presently, there is only one FDA approved bone anabolic agent, Forteo (teriparatide) that confers significant clinical benefits in osteoporosis, but its use is severely restricted due to safety concerns. Multipotent mesenchymal stem cells (MSCs) are precursors of a variety of cell types, including osteoblasts and adipocytes. Formation of new bone is driven by osteoblastic differentiation of MSCs, a process that can be disrupted by age and other factors in favor of adipogenesis. Parhami et al. discovered that specific naturally- occurring oxysterols induce osteogenesis when applied to MSCs while inhibiting their adipogenesis. Recently, we have characterized a new series of semi-synthetic analogues of the natural oxysterols with improved properties. Our most advanced compound, OXY133, displays increased potency for osteogenic differentiation in vitro, including in mouse and human primary MSCs, and it stimulates robust localized bone formation in vivo in a rat spine fusion model. Here we propose to begin evaluating Oxy133 as a bone anabolic agent in the context of systemic administration and bone targeting. Our strategy involves conjugation of OXY133 to a known bone-targeting agent (BTA) derived from tetracycline. We predict that systemic dosing of such conjugates will result in their selective deposition in bone followed by enzymatic linker hydrolysis and release of the osteogenic agent, OXY133, at controlled rates into the bone tissue. We have produced the first example of such a conjugate, OXY149, and determined that it retains significant osteogenic activity in C3H10T1/2 cells. Expanding on this proof of principle study, we propose to conjugate the BTA-linker to OXY133 through tunable succinate and aspartate ester linkages in different positions of the molecule, likely to result in variable degrees of linker hydrolysis and bone affinity thus allowing for optimization of these properties. We propose to perform studies as part of three Specific Aims: 1) Synthesis of Oxy133-BTA conjugated analogues, 2) Examination of the hydroxyapatite binding capacity of Oxy133-BTA conjugated analogues, and 3) Examination of the osteogenic activity of Oxy133-BTA conjugated analogues. Information obtained from these studies will provide the rationale for future investigation of the therapeutic effects of Oxy133-BTA analogues in animal models of osteoporosis that may ultimately lead to the development of new bone anabolic agents fit for use in humans.
Funding Period: 2013-09-16 - 2014-08-31
more information: NIH RePORT

Detail Information

Research Grants31

  1. Development of Osteogenic Oxysterols for Local Bone Formation
    Farhad Parhami; Fiscal Year: 2013
    ....
  2. PKC delta as a central mediator of osteogenic signaling
    ATUM BUO; Fiscal Year: 2013
    ....
  3. Regulation of PTH-induced Osteoanabolism by Inflammatory Lipids
    Yin Tintut; Fiscal Year: 2013
    ..abstract_text> ..
  4. Economics of Health, Wealth, and Well-Being
    DAVID A WISE; Fiscal Year: 2013
    ..Subproject 8 explores ways of Improving Health and Health Care for Minority and Aging Populations. ..
  5. STUDIES OF ORGAN TRANSPLANTATION IN ANIMALS AND MAN
    Arthur J Matas; Fiscal Year: 2013
    ..2. To maximize rehabilitation. The focus here is on minimizing complications and maximizing quality of life. ..
  6. Intracellular trafficking of Bisphosphonates in bone mesenchymal Stem Cells
    Sunday O Akintoye; Fiscal Year: 2013
    ..The goal is to formulate preventive measures for ONJ. ..
  7. Enhancement of Fracture Repair by Hematopoietic Stem Cells
    Amanda C LaRue; Fiscal Year: 2013
    ..Findings from the proposed studies have the potential to impact Veterans Health Care by identifying unique stem cell-based therapies for improving recovery from fracture. ..
  8. NIAMS: CORT Innovations to Assess and Forestall Post-Traumatic Osteoarthritis
    Joseph A Buckwalter; Fiscal Year: 2013
    ..The four projects will be supported by an administrative-biostatistics core, a biomechanics-imaging core, and a tissue and experimental modeling core. ..
  9. Repair of Bone Defects with Human Autologous Pluripotent Very Small Embryonic lik
    Russell S Taichman; Fiscal Year: 2013
    ..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. ..
  10. Injectable and Strong Nano-Apatite/Stem Cell Scaffolds for Bone Regeneration
    HUAKUN XU; Fiscal Year: 2013
    ..abstract_text> ..
  11. Impact of Amyloid on the Aging Brain
    Reisa A Sperling; Fiscal Year: 2013
    ..This PPG brings together an exceptional multidisciplinary team of clinical, statistical, cognitive neuroscience, imaging, and laboratory investigators dedicated to exploring the impact of amyloid on the aging brain. ..
  12. PDGF D AND PROSTATE CANCER BONE METASTASIS
    Hyeong Reh Choi Kim; Fiscal Year: 2013
    ....
  13. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  14. Defining a myofibroblast/pericyte as a mesenchymal progenitor cell
    Ivo Kalajzic; Fiscal Year: 2013
    ..The knowledge developed in this grant will provide the foundation for future studies aimed at use of mesenchymal progenitor cells as therapeutic tools for osteoporosis and genetic disorders of bone. ..
  15. Regulation of osteoblast number by PTH
    Robert L Jilka; Fiscal Year: 2013
    ....
  16. Mechanisms by which LMP-1 Regulates Lineage Commitment in Mesenchymal Stem Cells
    FRANCES LOUISA TITUS; Fiscal Year: 2013
    ..abstract_text> ..
  17. Connection of Mineral and Energy Metabolism by the Nuclear Receptor PPAR-gamma
    Yihong Wan; Fiscal Year: 2013
    ..Therefore, this investigation will significantly impact the broader scientific, clinical, and patient community. ..
  18. Mitochondrial Dysfunction in Neurodegeneration of Aging
    Gary E Gibson; Fiscal Year: 2013
    ..Successful completion of the goals of these projects can be expected to provide new insights into neurodegenerative processes and contribute to novel approaches to ameliorating age-related neurodegenerations. ..
  19. DETECTION AND MODELS OF TOXICANT EXPOSURE
    Robert H Tukey; Fiscal Year: 2013
    ..Our combined efforts are anticipated to provide new insights into the molecular mechanisms that lead to environmental illness, and improve our understanding of the consequences of exposure to Superfund site contaminants. ..
  20. Cellular Senescence and Aging
    James L Kirkland; Fiscal Year: 2013
    ..Our approach will provide timely, innovative, and clinically relevant interventional results based on addressing the fundamental question of the role of cellular senescence that has remained unanswered for many years. ..
  21. mTOR Signaling and Bone Formation in Aging Skeleton
    John C Lee; Fiscal Year: 2013
    ..These outcomes will provide the necessary basis for the development of future therapeutics for the treatment of osteoporosis aimed at reducing lipotoxicity. ..
  22. PTH Effects of Craniofacial Allografts
    Edward M Schwarz; Fiscal Year: 2013
    ..abstract_text> ..
  23. Osteoporosis treatment response assessed by micromechanical modeling of MRI data.
    Felix W Wehrli; Fiscal Year: 2013
    ..The successful completion of the project will provide new insight into the potential for image-based computational biomechanics for monitoring prophylactic intervention. ..