| Budget Amount *help |
¥13,800,000 (Direct Cost: ¥13,800,000)
Fiscal Year 2004: ¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2003: ¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2002: ¥5,800,000 (Direct Cost: ¥5,800,000)
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| Research Abstract |
We are developing a novel protein vaccine targeting the self-protein Receptor Activator of NFκB Ligand (RANKL) aberrantly expressed in metabolic bone disorders. RANKL (also know as OPGL, TRANCE, or ODF) is a key regulator of bone resorption and a therapeutic target for diseases associated with bone destruction. RANKL, a member of the TNF-family, is a 317 amino acid type II transmembrane protein expressed both as a membrane bound and secreted protein. Activated T cells, osteoblasts and some stromal cells express RANKL and many compounds that induce bone resorption (1α,25 (OH)_2 vitamin D_3, PTH, PGE_2, IL-1α, TNFα, IL-11, and glucocorticoids) act by enhancing RANKL expression. RANKL stimulates osteoclast differentiation and activation, as well as prolongs survival of mature osteoclasts. Osteoprotegerin (OPG), a soluble decoy receptor, can neutralize RANKL and helps to maintain the balance of bone resorption and formation. Disruption of the RANKL -OPG ratio is associated with pathologica
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l bone destruction as seen in osteoporosis, rheumatoid arthritis and metastatic bone cancer. Neutralizing RANKL is effective at reducing bone destruction in animal models of postmenopausal osteoporosis, rheumatoid arthritis, bone metastasis, periodontal disease and reducing markers of bone turnover in phase I clinical trials of postmenopausal women and bone metastases. The ability of the murine RANKL vaccine to suppress bone resorption were previously tested in mouse models of pathological bone disease. The first study was conducted in a model of post-menopausal osteoporosis. Mice were pre-vaccinated with a murine RANKL protein vaccine prior to ovariectomy (OVX) surgery to induce bone resorption. After OVX surgery control vaccinated mice had 16% lower bone mineral density (BMD) compared to sham-operated littermates. In contrast mice vaccinated with the murine RANKL vaccine did not lose trabecular bone after OVX-surgery compared to sham-operated littermates. The next animal study was conducted in a model of rheumatoid arthritis. The SKG mouse is a spontaneous mutant of Balb/c mouse that develops rheumatoid arthritis-like symptoms by 8 weeks of age. RANKL vaccinations ameliorated the recruitment of activated osteoblasts to the affected joints by 90% and the accompanying bone destruction by 80%. Surprisingly, the synovial inflammation was on average reduced by 40%, and completely ablated in some of the mice. Less
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