NELL-1 Systemic Therapy for Osteoporosis

描述（由申请人提供）：骨质疏松症影响全球超过2亿人。骨质疏松性骨质流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物。NELL-1是一种有效的促骨蛋白，主要研究其局部骨形成作用。初步研究表明，NELL-1还对骨质疏松性骨质流失具有系统性的保护作用。此外，NELL-1最近被发现具有抗破骨作用，这在很大程度上是通过激活Wnt/ -catenin信号传导而发生的。这证实了我们的中心假设，即NELL-1是一种很有前景的骨质疏松系统性治疗剂，它能够(1)有效逆转骨质疏松性骨质流失，(2)通过Wnt/ -catenin信号通路调节成骨细胞（OB）和破骨细胞（OC）的分化和活性，从而调节骨稳态。我们将在三个特定目标中验证这些假设：目标1：优化系统重组(r)NELL-1递送，以逆转ovx诱导的小鼠骨质疏松症。我们的初步数据显示，全身rNELL-1逆转ovx诱导的小鼠骨质流失。AIM 1将测试rNELL-1的PEGylation，以优化ovx诱导的骨质疏松小鼠模型的全身递送。同时，我们将评估系统性rNELL-1对干细胞含量、OB和OC数量和活性以及Wnt/ β -catenin信号传导的影响。目的2：确定全身rNELL-1是否能增强Wnt/ -catenin信号的合成代谢和抗破骨作用。AIM 2将进一步探讨系统性rNELL-1介导的效应在多大程度上被失调的Wnt/ -catenin信号通路所改变。特别是，该目的将确定当Wnt信号在遗传和治疗上升高时，rNELL-1是否能够进一步增强合成代谢作用。将采用两种上调Wnt的方法：通过使用Axin2-/-小鼠在所有细胞中对Wnt信号进行遗传去抑制，以及使用中和抗体通过抑制Wnt抑制剂Dickkopf 1 （DKK1）对Wnt信号进行药物去抑制。目的3：确定优化的全身rNELL-1逆转ovx诱导的绵羊骨质疏松症的疗效。我们已经证明了局部递送rNELL-1在逆转绵羊骨质疏松性骨质流失方面的功效。在AIM 3中，我们将评估系统性rNELL-1治疗在骨质疏松羊模型中的转化潜力。基于rNELL-1的新型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。此外，提高对rNELL-1调控Wnt信号的基本生物学理解，可能会导致未来治疗其他以Wnt信号失调为特征的疾病实体。

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/�-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/�-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/�-catenin signaling. AIM 2: Determine if systemic rNELL-1 can augment anabolic and anti- osteoclastic effects of Wnt/�-catenin signaling. AIM 2 will further explore the extent to which systemic rNELL-1 mediated effects are altered by dysregulated Wnt/�-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.