I-Corps: Bone healing using a small-molecule therapeutic

这个i-Corps项目的更广泛的影响/商业潜力是开发一种抗癌药物的替代应用，以促进骨骼愈合。虽然大多数骨折和骨损伤愈合良好，但在某些情况下，如骨质疏松症、糖尿病和高龄，骨愈合机制受阻，导致骨愈合受损。这项拟议的技术将专注于重新使用一种当前的抗癌药物，以促进骨再生和/或防止骨丢失。这种药物能够通过增加骨体积和骨密度来促进骨愈合。该机制还显示出在绝经患者失去雌激素导致的骨质疏松症环境中预防骨质丢失的潜力。目前，市场上所有用于骨愈合的药物都以骨细胞为靶点，以增加骨形成或减少骨吸收，但效果有限。建议的药物通过增加间充质干细胞的成骨能力来靶向它们。这些结果将是非常有意义的，因为传统的抗癌药物在杀死肿瘤细胞的同时也会导致骨丢失，但拟议的药物具有相反的效果，因为它保护骨骼。这个I-Corps项目是基于一种促进骨骼愈合的小分子疗法的开发。抗癌药物UC2288将被重新用于这一应用。骨骼通常在骨折后完全愈合，但在高龄等情况下，这一过程会发生实质性变化，导致骨骼愈合受阻和延迟或骨不愈合。这可能会导致骨骼的生物力学变化，导致其他并发症，并最终影响生活质量。已经证实，间充质干细胞(MSCs)在骨愈合过程中起着至关重要的作用，在像高龄这样的病例中，MSCs会降低成骨能力。目前的治疗策略主要集中在下游成骨因子上，往往显示出有限的成功。以前的研究已经证明了细胞周期调节因子p21和骨愈合之间的联系，其中p21的表达减少与损伤后骨形成的增加有关。为了将这些发现转化为临床，测试了UC2288在降低p21表达方面的有效性。结果表明，UC2288可降低人和小鼠骨髓间充质干细胞中p21的表达，增加成骨基因的表达。此外，UC2288的体内疗效显示，注射UC2288增加了小鼠横形骨折后的骨体积和表面积。在骨折部位使用建议的药物，可能会改善骨骼愈合和患者结果。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this I-Corps project is the development of alternate applications for an anti-cancer drug to promote bone healing. While most fractures and bone injuries heal well, in some cases such as osteoporosis, diabetes, and advanced age, the bone healing mechanism is hampered leading to compromised bone healing. The proposed technology will focus on repurposing a current anti-cancer drug for improving bone regeneration and/or preventing bone loss. This drug is able to enhance bone healing by increasing bone volume and bone mineral density. The mechanism also has shown potential to prevent the loss of bone in an osteoporotic environment induced by loss of estrogen in patients with menopause. Currently, all drugs for bone healing on the market target bone cells to increase bone formation or reduce bone resorption with limited success. The proposed drug targets mesenchymal stem cells by increasing their osteogenic capacity. These results would be of significant interest as conventional anti-cancer drugs also induce bone loss while killing tumor cells, but the proposed drug has the opposite effect in that it protects bone.This I-Corps project is based on the development of a small molecule therapeutic to promote bone healing. The anti-cancer drug, UC2288, will be repurposed for this application. Bones typically heal completely after fracture, but in cases such as advanced age, this process is substantially altered resulting in hampered and delayed healing or non-union of bone. This may result in changes in biomechanics of the bone leading to other complications and ultimately affect quality of life. It has been established that mesenchymal stem cells (MSCs) play a vital role in the bone healing process, and in cases like advanced age, MSCs have reduced bone forming capacity. Current treatment strategies focus on downstream osteogenic factors, often showing limited success. Previous research has demonstrated a link between the cell cycle regulator p21 and bone healing where reduced expression of p21 has been linked to increased bone formation after injury. To translate these findings to the clinic, efficacy of UC2288 was tested in reducing p21 expression. It was shown that UC2288 may reduce p21 expression and increase expression of osteogenic genes in both human and murine mesenchymal stem cells. In addition, in vivo efficacy of UC2288 was shown where injections of UC2288 increased bone volume and surface area in mice after a transverse fracture. Using the proposed drug at the site of fracture, it may be possible to improve bone healing and patient outcomes.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.