Black Bear Parathyroid Hormone as an Anabolic Agent for Bone

描述(申请人提供)：项目摘要/摘要。由于只有一种合成代谢疗法(截短的重组人甲状旁腺激素1-34，Teriparatide/Forteo(R))在商业上可用，因此临床上需要更好的骨质疏松症治疗方法。熊具有独特的能力，通过维持平衡的骨重建来防止在身体不活动(冬眠)期间的骨丢失；这种现象背后的生物过程可能由内源性甲状旁腺激素(PTH)控制，因为在冬眠和活跃的熊中，血清PTH水平与骨形成标记物骨钙素相关。因此，我们的目标是研究黑熊(BB)-PTH1-84的合成代谢作用，以帮助开发一种更有效的合成代谢疗法来治疗骨质疏松症。通过改变甲状旁腺激素的氨基酸序列，可以上调骨细胞的合成代谢途径。BB-PTH 1-84的氨基酸序列与全长的人PTH相比有9个差异。因此，BB-PTH1-84可能通过改变基因表达，减少成骨细胞的凋亡，增加骨基质的产生，从而促进骨的合成代谢反应。在第一阶段的工作中，我们重组生产了BB-PTH 1-84，并发现它在增加健康雄性小鼠的骨量和强度方面明显更有效。在第二阶段的工作中，我们将在去卵巢的小鼠身上进行剂量-反应研究，以评估Bear PTH1-84在逆转去卵巢所致的骨丢失方面的效果。我们还将用人甲状旁腺素1-84和BB-甲状旁腺素1-84处理人成骨细胞，比较它们通过激活人甲状旁腺素受体来激活合成代谢骨细胞反应的能力。重要的是，非GLP和GLP病理学/毒理学研究将在第二阶段STTR资助下进行，以便使公司能够向FDA提交IND，以启动未来对有文件记载的骨质疏松症患者的第一/第二阶段临床研究。 公共卫生相关性：项目叙述：需要改进药物疗法来治疗大约4400万受骨质疏松症影响的美国人。熊通过甲状旁腺激素(PTH)调节的生物过程，独特地预防身体不活动(冬眠)时的骨质疏松症。注射人甲状旁腺激素目前用于严重骨质疏松患者的骨重建，但由于其氨基酸序列不同，BB-PTH 1-84可能比人甲状旁腺素诱导更多的骨形成，因此可能是一种更有效的治疗人类骨质疏松症的方法。

DESCRIPTION (provided by applicant): Project Summary/Abstract. A clinical need exists for better osteoporosis treatments since only one anabolic therapy (truncated recombinant human parathyroid hormone 1-34, teriparatide/Forteo(R)) is commercially available. Bears possess the unique ability to prevent bone loss during physical inactivity (hibernation) by maintaining balanced bone remodeling; the biological processes behind this phenomenon are likely governed by endogenous parathyroid hormone (PTH), since serum PTH levels are correlated with the bone formation marker osteocalcin in hibernating and active bears. Thus, our goal is to investigate the anabolic effects of Black Bear (BB)- PTH 1-84 to aid in the development of a more effective anabolic treatment for osteoporosis. It is possible to up-regulate anabolic pathways in bone cells by altering the amino acid sequence of PTH. BB-PTH 1-84 has nine differences in its amino acid sequence compared to full length human PTH. Thus, BB-PTH 1-84 may promote a greater anabolic response in bone than human PTH by decreasing osteoblast apoptosis and increasing bone matrix production by altering gene expression. In Phase I work we recombinantly produced BB-PTH 1-84 and found it is significantly more potent at increasing bone mass and strength in healthy male mice. In the Phase II work we will perform a dose-response study in ovariectomized mice to evaluate the efficacy of bear PTH 1-84 at reversing ovariectomy induced bone loss. We will also treat human osteoblastic cells with human PTH 1-84 and BB-PTH 1-84 to compare their abilities to activate anabolic bone cell responses by activating the human PTH receptor. Importantly, non-GLP and GLP pathology/toxicology studies will be performed with Phase II STTR funding in order to enable the Company to file an IND with the FDA to initiate future Phase I/II clinical studies in patients with documented osteoporosis. PUBLIC HEALTH RELEVANCE: Project Narrative: Improved drug therapies are needed to treat the approximately 44 million Americans affected by osteoporosis. Bears uniquely prevent osteoporosis during physical inactivity (hibernation) through biological processes regulated by parathyroid hormone (PTH). Injections of human PTH are currently used to rebuild bone in severely osteoporotic patients, but due to its different amino acid sequence, BB-PTH 1-84 may elicit greater bone formation than human PTH, and therefore may be a more effective treatment for human osteoporosis.