Simvastatin to Retard Degenerative Disc Disease

辛伐他汀可延缓退行性椎间盘疾病

• 批准号: 8261128
• 负责人: Chia-Ying James Lin
• 金额: $ 33.59万
• 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/8261128
• 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; 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(申请人提供)：目前退行性腰椎间盘疾病的医学治疗是有限的，在稳定新的脊柱结构的同时移除受干扰的椎间盘的可用的外科治疗是昂贵的和侵入性的，并伴随着相关的发病风险。领先的研究集中在侵入性较小的方法上，以逆转或防止椎间盘退变。大多数人依赖昂贵的新药和设备。然而，使用可移动假体甚至是工程化组织的新植入物带来了一系列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倡导。骨形态发生蛋白(BMP)等多种生长因子已被从生物修复的角度进行了研究，并已初步证实其对椎间盘细胞的合成代谢作用。尽管如此，人们仍然对这些重组人生长因子感到担忧，因为它们要么参与了不受欢迎的血管在椎间盘内的生长，要么它们的给定剂量通常远远超过了获得效果所需的生理水平。此外，使用这些生物因子的成本还没有达到负担得起的水平。这项拟议的研究将探索一种治疗腰椎间盘退变的方法，并有可能大幅降低成本。我们以前的工作表明，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，并且将辛伐他汀负载于热敏感的可生物降解的聚合物中的辛伐他汀注入受干扰的大鼠髓核中，也可以完全逆转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已定义的IVD退变动物模型，以进一步表征辛伐他汀作为他汀类药物的非标签适应症专门用于治疗退行性腰椎间盘疾病的安全性和有效性。我们推测，辛伐他汀从可注射、可降解的聚合物中的受控释放将延缓椎间盘退变的进程，并可能进一步再生椎间盘内组织。我们将在Spraogue-Dawley大鼠的尾部脊柱预定节段对椎间盘进行刺伤(环切术)扰动，以形成每一类椎间盘退变，并根据成像、形态学和组织学评估对其进行分级。纤维环结构完整的等级将指示注射辛伐他汀在聚合物中。药物剂量将以递增的方式给予，并将持续到预定的牺牲时间点，以确定最佳剂量和有效持续时间。最后，将利用尤卡坦小型猪模型进一步评估扰动的椎间盘经辛伐他汀治疗后是否能恢复椎间间隙的固有生物力学功能和解剖特征，为未来临床试验的开发和实施提供依据。 与公共健康相关：一种流行的降胆固醇药物辛伐他汀最近被研究用来刺激骨细胞分泌一种可以促进骨组织生长的生长因子。这一机制被认为对椎间盘细胞再生组织物质也是至关重要的。在这项研究中，建议观察向退变的椎间盘内注射辛伐他汀的可能性，以延缓退变的椎间盘疾病的进展，并帮助修复异常的组织。