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了创伤，并在个体中引起严重而令人衰弱的状况。 SCI之后，受伤神经元的再生有限导致永久性残疾，其特征是某些感觉，瘫痪和自主功能障碍。神经元无法再生的原因之一是它们无法穿越SCI后出现的神经胶质疤痕。这种神经胶质疤痕包含包括硫酸软骨蛋白蛋白聚糖（CSPGS）的细胞外基质分子。体外研究表明，神经元无法在CSPG涂层表面上扩展过程，而体内数据将再生与CSPG表达区域的失败相关。软骨素酶ABCI是一种细菌酶，可催化硫酸软骨素碳水化合物链的降解，例如在CSPG上发现的链。在啮齿动物中背侧柱 /皮质脊柱途径手术病变后，发现软骨素酶处理可改善功能结果。此外，发现软骨素酶在啮齿动物的视觉皮层中恢复了一段可塑性。我们最近证明，软骨蛋白酶A的治疗可改善挫伤SCI模型中的开放式运动功能和自主功能。尽管动物模型的影响很大，但是SCI后神经功能的临床相关改善可能需要组合疗法。例如，软骨蛋白酶处理可以与Nogo的抑制剂（例如诱饵Nogo受体（NGR））结合使用，以促进再生。该赠款提案的目的是将软骨素酶与NGR在遗传水平相结合，以创建双功能治疗蛋白（Chase-NGR）。除了提供单一药物提供联合治疗外，NGR对髓磷脂相关抑制剂的亲和力还将赋予Chase-NGR的靶向机制，其中软骨蛋白酶治疗的重点是CNS中的抑制剂富含抑制剂。此外，我们已经表明，软骨素酶通过消化CSPG的扩散途径促进了扩散到CMS中。因此，Chase-NGR的软骨蛋白酶段可能会促进NGR扩散到CNS的实质中，而不是没有CSPG消化而实现的程度要大得多。这些研究将为II期赠款提供理由，以资助Chase-NGR作为SCI治疗的进一步发展。