Simvastatin to Retard Degenerative Disc Disease

辛伐他汀可延缓退行性椎间盘疾病

• 批准号: 7885153
• 负责人: Chia-Ying James Lin
• 金额: $ 31.29万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-11 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7885153
• 关键词: Address; Advocate; Affect; Anabolism; Animal Model; Animals; Arthroplasty; Behavior; Biochemical; Biological; Biological Assay; Biomechanics; Blood Vessels; Body Temperature; Bone Morphogenetic Proteins; Bone Tissue; Catabolism; Categories; Cell Culture Techniques; Cell Death; Cells; Cellularity; Characteristics; Cholesterol; Chondrogenesis; Choristoma; Clinical; Clinical Trials; Coenzyme A; Collagen; Collagen Gene; Collagen Type II; Defect; Development; Devices; Disease; Dose; Effectiveness; Ensure; Equilibrium; Ethylene Glycols; Evaluation; Excision; Exhibits; Exposure to; Extracellular Matrix; Family suidae; Future; Gel; Gene Expression; Genetic; Goals; Growth; Growth Factor; Harvest; High temperature of physical object; Human; Hydrogels; Image; In Situ; In Vitro; Individual; Injectable; Injection of therapeutic agent; Injury; Instruction; Intervertebral disc structure; Investigation; Label; Lead; Light; Marketing; Measures; Mediating; Medical; Metabolism; Methods; Microdialysis; Miniature Swine; Modality; Modeling; Monitor; Morbidity - disease rate; Motion; Natural regeneration; Operative Surgical Procedures; Oxidoreductase; Pathway interactions; Pharmaceutical Preparations; Phase; Phase Transition; Phenotype; Physiological; Placebos; Polymers; Pre-Clinical Model; Preparation; Prevention; Primates; Procedures; Prosthesis; Protein Family; Proteins; Proteoglycan; Protocols documentation; Ptosis; Rattus; Recombinant Proteins; Recombinants; Recovery; Recovery of Function; Reporting; Research; Risk; Safety; Scheme; Simvastatin; Site; Solutions; Specificity; Specimen; Spinal; Sprague-Dawley Rats; Staging; Structure; System; Techniques; Temperature; Testing; Therapeutic; Therapeutic Agents; Time; Tissue Engineering; Tissues; Toxic effect; Translating; Translational Research; Treatment Efficacy; Use Effectiveness; Vertebral column; Work; aggrecan; aqueous; base; biodegradable polymer; bone cell; bone morphogenetic protein 2; cell type; clinical application; clinically significant; controlled release; cost; cytokine; design; dosage; ethylene glycol; implantation; in vivo; inhibitor/antagonist; insight; intervertebral disk degeneration; mRNA Expression; mevalonate; nucleus pulposus; phase 1 study; poly-L-lactic acid; polysulfated glycosaminoglycan; prevent; public health relevance; reconstitution; reconstruction; repaired; response; safety testing; therapeutic protein; tissue regeneration

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.

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，并且在稳定新的脊柱结构的同时去除受干扰的椎间盘的可用手术治疗成本高昂且具有侵入性，并具有相关的发病风险。领先的研究重点是逆转或预防椎间盘退变的侵入性较小的方法。大多数人依赖昂贵的新药物和设备。然而，新的移动假体甚至工程组织的植入带来了一系列新的并发症和需要解决的障碍。随着重组治疗蛋白的最新进展，椎间盘的生物修复或再生得到了提倡。骨形态发生蛋白（BMP）等多种生长因子在生物修复方面进行了研究，并初步证明了其对椎间盘细胞的合成代谢作用。尽管如此，人们对这些重组人类生长因子的担忧仍然存在，因为它们要么参与椎间盘上不希望的血管向内生长，要么它们的给定剂量通常远远超过生理水平以获得有效性。此外，使用这些生物因子的成本尚未达到可承受的水平。拟议的研究将研究一种治疗椎间盘退变的方法，其成本可能大幅降低。我们前期的工作表明，常用的降胆固醇药物辛伐他汀刺激内源性BMP-2表达，进而增加体外培养的椎间盘细胞的软骨形成表型表达，并且当将载有热敏、可生物降解聚合物的辛伐他汀注射到受干扰的髓核中时，刺伤引起的椎间盘退变得到了完全逆转。 我们的大鼠模型中的圆盘。在这项研究中，我们希望将我们的研究扩展到已定义的 IVD 变性动物模型，以进一步表征使用辛伐他汀作为他汀类药物的标签外适应症专门用于治疗退变性椎间盘疾病的安全性和有效性。我们假设从可注射的可降解聚合物中控制释放辛伐他汀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对椎间盘使用刺伤（纤维环切开术）扰动，以开发每种类型的椎间盘退变，并根据成像、形态学和组织学评估进行分级。纤维环结构完整的等级将通过聚合物中负载辛伐他汀的注射来指示。药物的剂量将以逐步递增的方式施用，并且将持续到预定的牺牲时间点以表征最佳剂量以及有效持续时间。最后，将利用尤卡坦半岛小型猪模型进一步评估扰动椎间盘在辛伐他汀治疗后是否能够恢复椎间盘固有的生物力学功能和解剖学特征，为未来临床试验的开发和实施提供参考。 公共健康相关性：最近研究了一种流行的降胆固醇药物辛伐他汀，它可以刺激骨细胞分泌一种可以促进骨组织生长的生长因子。这种机制被认为对于椎间盘细胞再生组织物质也至关重要。然后，本研究提出观察将辛伐他汀注射到退变椎间盘中以延缓退变椎间盘疾病的进展并帮助修复异常组织的潜力。