Chimeric proteins for the treatment of spinal cord injury

用于治疗脊髓损伤的嵌合蛋白

• 批准号: 6991093
• 负责人: ANTHONY O CAGGIANO
• 金额: $ 15.32万
• 依托单位: ACORDA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2006-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6991093
• 关键词: SDS polyacrylamide gel electrophoresis; behavior test; cell migration; chimeric proteins; chondroitin sulfates; combination therapy; disease /disorder model; enzyme activity; enzyme therapy; hyaluronidase; laboratory rat; mass spectrometry; matrix assisted laser desorption ionization; nervous system regeneration; neural plasticity; neurogenesis; neurons; nonhuman therapy evaluation; protein purification; proteoglycan; spinal cord injury

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 extracellular 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. Chondroitinase ABCI is a bacterial enzyme that catalyzes the degradation of chondroitin sulfate carbohydrate chains such as those found on CSPG. Chondroitinase treatment was found to improve functional outcome following surgical lesion of the dorsal column / cortico-spinal pathways in rodents. In addition, Chondroitinase was found to restore a period of plasticity in the visual cortex of rodents. We have recently demonstrated that Chondroitinase ABC I treatment improves open-field locomotor function and autonomic function in a contusion SCI model. Although the effects in animal models are significant, clinically relevant improvements in neurological function following SCI may require combinatorial therapies. For example, Chondroitinase treatment may be combined with an inhibitor of NOGO such as the decoy NOGO receptor (NgR) to promote regeneration. The objective of this grant proposal is to combine Chondroitinase with NgR at the genetic level to create a bi-functional therapeutic protein (Chase-NgR). In addition to providing combinatorial therapy with a single drug the affinity of the NgR for myelin associated inhibitors would confer a targeting mechanism to Chase-NgR wherein Chondroitinase treatment is focused on inhibitor rich regions in the CNS. In addition, we have shown that Chondroitinase facilitates diffusion into the CMS presumably by creating pathways for diffusion via digestion of CSPG. Therefore, Chondroitinase segment of Chase-NgR may promote diffusion of the NgR into the parenchyma of the CNS to a much greater extent than can be achieved without CSPG digestion. These studies will provide justification for a Phase II grant to fund further development of Chase-NgR as a therapeutic for SCI.

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，并导致个体严重和衰弱。脊髓损伤后，受损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。神经元不能再生的一个原因是它们不能穿过脊髓损伤后形成的胶质瘢痕。这种神经胶质瘢痕含有细胞外基质分子，包括硫酸软骨素蛋白聚糖（CSPG）。体外研究表明，神经元不能在CSPG包被的表面上延伸突起，而体内数据将再生失败与CSPG表达区域相关联。软骨素酶ABCI是催化硫酸软骨素碳水化合物链（如在CSPG上发现的那些）降解的细菌酶。研究发现，软骨素酶治疗可改善啮齿动物背柱/皮质脊髓通路手术损伤后的功能结局。此外，发现软骨素酶可恢复啮齿动物视觉皮层的一段可塑性。我们最近证实软骨素酶ABC I治疗可改善挫伤SCI模型的旷场运动功能和自主神经功能。虽然在动物模型中的效果是显著的，但SCI后神经功能的临床相关改善可能需要联合治疗。例如，软骨素酶治疗可以与NOGO的抑制剂如诱饵NOGO受体（NgR）组合以促进再生。该资助提案的目标是在基因水平上将软骨素酶与NgR结合联合收割机，以创建双功能治疗蛋白（Chase-NgR）。除了用单一药物提供组合疗法之外，NgR对髓磷脂相关抑制剂的亲和力将赋予Chase-NgR靶向机制，其中软骨素酶治疗集中于CNS中富含抑制剂的区域。此外，我们已经表明，软骨素酶促进扩散到CMS可能通过创建扩散途径，通过消化CSPG。因此，Chase-NgR的软骨素酶片段可以促进NgR扩散到CNS的实质中，其程度比没有CSPG消化所能达到的程度大得多。这些研究将为第二阶段拨款提供理由，以资助Chase-NgR作为SCI治疗药物的进一步开发。