Release Chondroitinase Systems for Spinal Cord Injury

释放软骨素酶系统治疗脊髓损伤

• 批准号: 6689094
• 负责人: ANTHONY O CAGGIANO
• 金额: $ 10.73万
• 依托单位: ACORDA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2004-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6689094
• 关键词: antibody; axon; biotechnology; biotherapeutic agent; cell line; chondroitin sulfates; dendrites; disease /disorder model; drug administration routes; drug design /synthesis /production; enzyme activity; enzyme linked immunosorbent assay; gene deletion mutation; hyaluronidase; immunologic substance development /preparation; laboratory rat; nervous system disorder chemotherapy; protein purification; proteoglycan; recombinant proteins; slow release drug; spinal cord injury; transfection /expression vector

DESCRIPTION (provided by applicant): Spinal cord injury (SCI) inflicts trauma to the cells and tissues of the central nervous system and causes a severe and debilitating condition in the individual. Following SCI, limited regeneration of injured neurons results in permanent disability characterized by some loss of sensation, paralysis and autonomic dysfunction. One reason that neurons fail to regenerate is their inability to traverse the glial scar that develops following SCI. This glial scar contains extra cellular matrix molecules including chondroitin sulfate proteoglycans (CSPGs). In vitro studies show that neurons fail to extend processes over CSPG coated surfaces, while in vivo data correlate failure of regeneration with areas of CSPG expression. Treatment with bacterial chondroitinase (Chase), an enzyme that digests CSPG arbohydrate chains, decreases the CSPG inhibition, both in vitro and in vivo. Chase was recently used to treat spinal cord lesions in a rodent model, resulting in enhanced functional recovery. Several obstacles exist in the development of a Chase-based SCI therapy, including the delivery of a large protein to the central nervous system and the use of an enzyme with a short half-life in solution at body temperature. The aim of this study is to develop a sustained release (SR) formulation of a Chase therapy that can be delivered locally to the site of injury and demonstrate its effectiveness at digesting CSPGs in the rat spinal cord. To accomplish these goals are a repertoire of Chase enzymes will be cloned, expressed and purified. These enzymes will then be tested in vitro in several existing sustained release formulations. These sustained release Chase formulations will then be place in the sub-dural space of rat spinal cords to assess their ability to digest CSPGs in vivo. These studies will provide justification for a Phase II study examining the therapeutic effects of sustained release formulation of chondroitinase in an animal model of spinal cord injury.

描述(由申请人提供)：脊髓损伤(SCI)对中枢神经系统的细胞和组织造成创伤，并导致个人严重和虚弱的情况。脊髓损伤后，损伤神经元的有限再生导致永久性残疾，其特征是一些感觉丧失、瘫痪和自主神经功能障碍。神经元无法再生的一个原因是它们无法穿越脊髓损伤后形成的胶质疤痕。这种胶质瘢痕含有细胞外基质分子，包括硫酸软骨素蛋白多糖(CSPGs)。体外研究表明，神经元无法在CSPG涂层表面延伸突起，而体内数据表明，再生失败与CSPG表达区域相关。细菌软骨素酶(Chase)是一种消化CSPG碳水物链的酶，在体外和体内都能降低CSPG的抑制作用。Chase最近被用于治疗啮齿动物模型的脊髓损伤，从而增强了功能恢复。基于Chase的脊髓损伤疗法的发展存在几个障碍，包括将大蛋白输送到中枢神经系统，以及在体温下使用半衰期较短的酶。本研究的目的是开发一种可局部给药的Chase疗法的缓释(SR)配方，并证明其在大鼠脊髓中消化CSPG的有效性。为了实现这些目标，将克隆、表达和纯化一系列Chase酶。然后，这些酶将在几种现有的缓释制剂中进行体外测试。这些缓释Chase制剂随后将被放置在大鼠脊髓的硬膜下间隙，以评估它们在体内消化CSPG的能力。这些研究将为第二阶段研究提供依据，以检验软骨素酶缓释制剂在脊髓损伤动物模型中的治疗效果。