Nonsurgical Exogenous Crosslink Therapy for Intervertebral Disc Disease

描述（由申请人提供）：退行性椎间盘疾病和相关的脊柱不稳定是西方文明中慢性腰痛的主要原因。包括人工椎间盘在内的手术选择令人失望，只有很小比例的背痛患者（约1/20）选择手术。该计划的具体目标集中在非手术组织工程解决方案的设计，将成为退变性椎间盘疾病的第一线治疗。Orthopeutics的关键创新是使用无毒的注射剂，增加椎间盘纤维环细胞外基质中的胶原交联，模仿身体自身的努力来稳定老化和机械不稳定的椎间盘。初步的体外研究形成了该I期建议的基础，显示耐久性提高了2至3倍，关节稳定性提高了4倍，椎间盘中心的营养供应/废物清除增加了一倍。体内概念验证研究已经证明了温和的治疗效果，纤维环中没有显著的组织学变化。本I期研究将使用离体牛/猪椎间盘模型表征几种候选试剂的交联效应和扩散转运。交联效果将通过机械测试、热分析和蛋白酶消化进行评估。将通过使用代表性分子量的染料的时间推移可视化研究以及使用热分析对经处理的椎间盘进行绘图来评估扩散转运。对最有前途的制剂进行的II期研究将侧重于优化试剂活性、效果持久性和安全性;并开发适合人体临床试验的产品。 与脊柱退化和不稳定相关的背痛和残疾是最昂贵和最普遍的健康问题之一。每年（1990年）有4.7%（医疗记录）至9.4%（人口调查）的美国人口因腰痛寻求专业医疗保健，预期患者人数超过1500万/年。面对这一巨大的未满足的临床需求，NIAMS认为开发再生医学技术来逆转椎间盘退变过程是一个重要的研究机会。

DESCRIPTION (provided by applicant): Degenerative disc disease and associated spinal instability are the major cause of chronic low back pain in western civilization. Surgical options, including artificial discs, have been disappointing and only a very small percentage of back pain sufferers (~1 in 20) elect to have surgery. The specific aims of this program focus on the design of a nonsurgical tissue engineering solution that would become the first line of therapy for degenerative disc disease. Orthopeutics' key innovation is the use of nontoxic injectable agents that increase collagen crosslinking in the extracellular matrix of the disc annulus fibrosus, mimicking the body's own efforts to stabilize aged and mechanically unstable discs. Preliminary in vitro studies which form the basis of this Phase I proposal show a 2 to 3-fold improvement in durability, a 4-fold improvement in joint stability, and doubled nutritional supply/waste removal to center of the disc. In vivo proof of concept studies have demonstrated a mild treatment effect, with no significant histological changes in the annulus fibrosus. This Phase I study will characterize several candidate reagents with regard to crosslinking effect and diffusive transport using an ex vivo bovine/porcine disc model. Crosslinking effect will be assessed through mechanical testing, thermal analysis, and protease digestion. Diffusive transport will be assessed through time lapse visualization studies using dyes of representative molecular weights, as well as mapping of treated discs using thermal analysis. A Phase II study of the most promising formulation would focus on optimizing reagent activity, durability of effect, and safety; and developing a product suitable for human clinical trials. Back pain and disability associated with spinal degeneration and instability is one of the costliest and most prevalent health problems. Between 4.7 percent (medical records) and 9.4 percent (population surveys) of the US population seeks professional health care annually (1990) for low back pain, a prospective patient population in excess of 15 million/year. In the face of this great unmet clinical need, the development of regenerative medicine techniques to reverse the process of spinal disc degeneration has been recognized as an important research opportunity by NIAMS.