Simvastatin to Retard Degenerative Disc Disease

描述（由申请人提供）：目前对退行性椎间盘疾病的医学治疗是有限的，在稳定新脊柱结构的同时切除受干扰的椎间盘的手术治疗是昂贵的，具有侵入性，并伴有发病风险。领先的研究集中在微创方法来逆转或预防椎间盘退变。大多数依靠昂贵的新药和设备。然而，新的植入物与移动假体甚至工程组织带来了新的并发症和障碍需要解决。随着重组治疗蛋白的最新进展，椎间盘的生物修复或再生已被提倡。包括骨形态发生蛋白（bone morphogenetic protein， BMP）在内的许多生长因子在生物修复方面的研究已经得到初步证实，它们对椎间盘细胞具有合成代谢作用。尽管如此，对这些重组人生长因子的担忧仍然存在，因为它们要么参与不希望的椎间盘血管长入，要么其给药剂量通常远远超过获得有效性的生理水平。此外，使用这些生物因子的成本尚未达到可负担的水平。拟议的研究将探讨一种治疗椎间盘退变的潜在低成本方法。我们之前的研究表明，常见的降胆固醇药物辛伐他汀刺激内源性BMP-2的表达，进而增加体外培养的椎间盘细胞的软骨表型表达，并且在我们的大鼠模型中，将辛伐他汀以热敏的、可生物降解的聚合物的形式注射到受干扰的椎间盘髓核中，可以完全逆转由刺伤引起的椎间盘退变。在这项研究中，我们希望将我们的研究扩展到具有IVD退变的动物模型，以进一步表征辛伐他汀作为他汀类药物说明书外适应症专门用于治疗退行性椎间盘疾病的安全性和有效性。我们假设辛伐他汀从可注射的、可降解的聚合物中有控制地释放将延缓椎间盘退变的进展，并可能进一步再生椎间盘内组织。我们将在Sprague-Dawley大鼠尾椎的预定水平上使用刺伤（环切术）扰动椎间盘来发展每种类型的椎间盘退变，并根据影像学、形态学和组织学评估进行分级。纤维环结构完整的等级将显示在聚合物中装载辛伐他汀的注射剂。药物的剂量将以递增的方式施用，并将持续到预定的牺牲时间点，以表征最佳剂量和有效持续时间。最后，将利用尤卡坦迷你猪模型进一步评估扰动椎间盘在接受辛伐他汀治疗后能否恢复其固有的生物力学功能和椎间空间解剖特征，为未来临床试验的制定和实施提供参考。

DESCRIPTION (provided by applicant): Current medical treatments for degenerative disc disease are limited and the available surgical treatments to remove the perturbed discs while stabilizing the new spinal construct are costly and invasive with associated risks of morbidity. Leading research is focused on less invasive methods to reverse or prevent intervertebral disc degeneration. Most rely on costly new drugs and devices. However, new implantations with mobile prostheses or even engineered tissues have brought a new spectrum of complications and hurdles to be addressed. Biological repair or regeneration of the intervertebral disc has been advocated with recent advances in recombinant therapeutic proteins. Many growth factors including bone morphogenetic protein (BMP) have been investigated on the aspect of biological repair and have been proved preliminarily with their anabolic effects on the intervertebral disc cells. Nonetheless, concerns still remain with these recombinant human growth factors since they either participate in undesired blood vessel ingrowth at the intervertebral disc or their given doses are normally much over the physiological levels to obtain effectiveness. In addition, costs for using these biofactors have not yet reached affordable. The proposed study will investigate a treatment for disc degeneration with the potential for substantially lower cost. Our previous work indicated that the common cholesterol-lowing drug simvastatin stimulated endogenous BMP-2 expression and in turn increased the chondrogenic phenotype expression of intervertebral disc cells cultured in vitro, and also the disc degeneration induced by a stab injury was fully reversed when injecting simvastatin that was loaded in a thermosensative, biodegradable polymer into nucleus pulposus of the perturbed discs in our rat model. In this study, we would like to extend our investigation to the defined animal models with IVD degeneration to further characterize the safety and effectiveness of using simvastatin specifically for the treatment of degenerative disc disease as an off-label indication of statins. We hypothesize that controlled release of simvastain from an injectable, degradable polymer will retard the progress of disc degeneration and may further regenerate intradiscal tissues. We will use stab injury (annulotomy) perturbation on intervertebral discs at predetermined levels of Sprague-Dawley rat's caudal spine to develop each category of disc degeneration that will be graded according to imaging, morphological and histological assessments. Grades with intact structure of annulus fibrosus will be indicated to the injection with simvastatin loaded in the polymer. Doses of the drug will be administered in an escalating manner and will be last until predetermined sacrifice time points to characterize the optimal dosage as well as the effective duration. Finally, a Yucatan minipig model will be utilized to further evaluate whether perturbed discs can restore the inherent biomechanical functions and anatomical features of interbody space after being treated with simvastatin to provide an insight in the development and implementation of future clinical trials. PUBLIC HEALTH RELEVANCE: A prevalent cholesterol-lowing drug simvastatin has recently been investigated to stimulate bone cells to secrete a growth factor that can augment bone tissue growth. This mechanism is thought to be critical as well for cells in the intervertebral disc to regenerate tissue substances. It is then proposed in this study to observe the potential to inject simvastatin into degenerative disc to retard the progression of degenerative disc disease and also help repair the aberrant tissues.