NELL-1 Systemic Therapy for Osteoporosis

描述（由申请人提供）：骨质疏松症影响全球2亿多人。骨质疏松性骨丢失的治疗方法主要集中在合成代谢或抗吸收药物上。然而，迫切需要开发新的药剂。NELL-1是一种有效的促成骨蛋白，研究最多的是其局部骨形成作用。初步研究表明，NELL-1也发挥了系统的，对骨质疏松性骨丢失的保护功能。此外，NELL-1最近被鉴定为具有抗骨坏死作用，其大部分通过激活Wnt/β-连环蛋白信号传导而发生。这符合我们的中心假设，即NELL-1是一种有前途的骨质疏松症全身治疗剂，能够（1）有效逆转骨质疏松性骨丢失，和（2）通过Wnt/β-连环蛋白信号传导调节成骨细胞（OB）和破骨细胞（OC）分化和活性来调节骨稳态。我们将在三个具体目标中测试这些假设：目的1：优化全身重组（r）NELL-1递送以逆转小鼠中OVX诱导的骨质疏松症。我们的初步数据显示，全身rNELL-1逆转OVX诱导的小鼠骨丢失。AIM 1将测试rNELL-1的聚乙二醇化以优化OVX诱导的肥大小鼠模型中的全身递送。同时，我们将评估全身性rNELL-1对干细胞含量、OB和OC数量和活性以及Wnt/β-连环蛋白信号传导的影响。目的2：确定系统性rNELL-1是否能增强Wnt/β-catenin信号通路的合成代谢和抗骨质疏松作用。AIM 2将进一步探索系统性rNELL-1介导的效应被失调的Wnt/β-catenin信号改变的程度。特别是，这一目标将确定rNELL-1是否能够进一步增强Wnt信号在遗传和治疗上升高时所见的合成代谢作用。将采用Wnt上调的两种方法：通过使用Axin 2-/-小鼠在所有细胞中对Wnt信号传导进行遗传去抑制，以及通过使用中和抗体抑制Wnt抑制剂Dickkopf 1（DKK 1）对Wnt信号传导进行药物去抑制。目的3：确定优化的全身rNELL-1逆转绵羊OVX诱导的骨质疏松症的疗效。我们已经显示了局部递送rNELL-1在逆转绵羊骨质疏松性骨丢失中的功效。在AIM 3中，我们将评估系统性rNELL-1治疗在绵羊癫痫模型中的转化潜力。基于rNELL-1的新疗法可以改善目前治疗骨质疏松症的护理标准，并预防每年花费250亿美元的骨质疏松性骨折。同样，对rNELL-1调节Wnt信号传导的基础生物学理解的提高可能导致未来对以Wnt信号传导失调为特征的其他疾病实体的治疗。

DESCRIPTION (provided by applicant): Osteoporosis affects more than 200 million people worldwide. Therapeutic approaches to osteoporotic bone loss have focused on either anabolic or antiresorptive agents. However, there is a pressing need to develop new agents. NELL-1 is a potent pro-osteogenic protein most studied for its local bone forming effects. Preliminary studies have suggested that NELL-1 also exerts a systemic, protective function against osteoporotic bone loss. Additionally, NELL-1 has recently been identified to have anti-osteoclastic effects, occurring in large part via activation of Wnt/β-catenin signaling. This has ld to our central hypothesis that NELL-1 is a promising systemic therapeutic agent for osteoporosis with ability to (1) effectively reverse osteoporotic bone loss, and (2) regulate bone homeostasis by regulating osteoblast (OB) and osteoclast (OC) differentiation and activity via Wnt/β-catenin signaling. We will test these hypotheses in three specific aims: AIM 1: Optimize systemic recombinant (r)NELL-1 delivery for the reversal of OVX-induced osteoporosis in mice. Our preliminary data show that systemic rNELL-1 reverses OVX-induced bone loss in mice. AIM 1 will test PEGylation of rNELL-1 to optimize systemic delivery in an OVX-induced osteoporotic mouse model. In parallel, we will evaluate the effects of systemic rNELL-1 on stem cell content, OB and OC number and activity, and Wnt/β-catenin signaling. AIM 2: Determine if systemic rNELL-1 can augment anabolic and anti- osteoclastic effects of Wnt/β-catenin signaling. AIM 2 will further explore the extent to which systemic rNELL-1 mediated effects are altered by dysregulated Wnt/β-catenin signaling. In particular, this aim will determine whether rNELL-1 is capable of further enhancing the anabolic effects seen when Wnt signaling is elevated genetically and therapeutically. Two methods of Wnt upregulation will be employed: genetic de- repression of Wnt signaling in all cells via the use of Axin2-/- mice, and pharmaceutical de-repression of Wnt signaling via inhibition of Wnt inhibitor, Dickkopf 1 (DKK1), using neutralizing antibodies. AIM 3: Determine the efficacy of optimized, systemic rNELL-1 for the reversal of OVX-induced osteoporosis in sheep. We have already shown the efficacy of local delivery of rNELL-1 in reversing osteoporotic bone loss in sheep. In AIM 3, we will assess the translational potential of systemic rNELL-1 therapy in an osteoporotic sheep model. Novel rNELL-1 based therapies can improve the current standard of care for the treatment of osteoporosis, and the prevention of osteoporotic fractures that cost $25 billion annually. As well, improved basic biological understanding of rNELL-1 regulation of Wnt signaling may lead to future therapies for other disease entities characterized by deregulated Wnt signaling.