THERAPEUTIC BENEFIT OF HYDROGEN PEROXIDE REMOVAL IN FALS

去除过氧化氢对 FLS 的治疗效果

• 批准号: 6261417
• 负责人: JOSEPH F PODUSLO
• 金额: $ 35.28万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-15 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6261417
• 关键词: amyotrophic lateral sclerosis; biotechnology; biotherapeutic agent; blood brain barrier; catalase; chemical conjugate; drug administration rate /duration; drug delivery systems; genetic disorder; genetically modified animals; hydrogen peroxide; hydroxyl radical; immunocytochemistry; laboratory mouse; morphometry; neural degeneration; neuromuscular disorder chemotherapy; neuropathology; nitric oxide; nonhuman therapy evaluation; oxidative stress; pharmacokinetics; polyamines; superoxide dismutase; tyrosine analog

DESCRIPTION: (Verbatim from the Applicant's Abstract) Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons primarily of the spinal cord. Dominantly inherited mutations in the gene that encodes human copper/zinc-superoxide dismutase (Cu/Zn-SOS: hSODl), a free radical scavenging enzyme, have been observed in approximately 20-25 percent of patients with FALS Three mutations of hSODl found in FaLS families have caused motor neuronal degeneration similar to that of ALS patients. Free radical-mediated oxidative injury is a critical component in the mechanism of degeneration of motor neurons that results in FALS. The mutated form of hSODl has been suggested to initiate the neuropathological changes associated with FALS by a dominant gain-of-function which results from expression of the mutant protein that confers a neurotoxic property on the enzyme. In this grant application, we summarize the evidence that suggests that hydrogen peroxide-mediated oxidative damage in motor neurons involving hydroxyl radicals and/or nitric oxide is beneficial in the treatment of FALS. We have made the important observation that when catalase is covalently attached to the naturally occurring polyamines, the resultant product has an increased permeability at the blood-brain barrier (*BBB) after systemic administration. We have been able to demonstrate a highly significant increase in survival of FALS mice (G93A) (GlL/+) by 28.9 days after continuous subcutaneous administration with osmotic pumps of polyamine-modified catalase compared to PBX control (p<0.0001). This is the best increase in survival of any treatment protocol in the FALS transgenic mice that has been published to date. This grant proposal, therefore, will further test whether this hypothesis-driven therapy is beneficial in the treatment of FALS transgenic mice, which will have direct implications for the treatment of both familial and sporadic ALS.

描述：(逐字摘自申请人摘要)肌萎缩侧索硬化症 硬化症(ALS)是一种进行性运动神经元退行性疾病。 主要是脊髓。基因中的显性遗传突变 编码人铜/锌超氧化物歧化酶(铜/锌-SOS：hSODl)，一种游离的 自由基清除酶，在大约20%-25%的 FALS患者在FALS家族中发现三种hSOD1突变导致 运动神经元变性与ALS患者相似。免费 自由基介导的氧化损伤是血管紧张素转换酶的重要组成部分。 运动神经元变性，导致FALS。HSOD1的突变形式 已经被建议启动与以下相关的神经病理改变 由突变体的表达所导致的显性功能增益的FALS 赋予这种酶神经毒性的蛋白质。在这笔赠款中 应用中，我们总结了表明氢 过氧化氢介导的涉及羟基自由基的运动神经元氧化损伤 和/或一氧化氮在FAL的治疗中是有益的。我们已经做出了 重要的观察结果是，当过氧化氢酶共价连接到 自然产生的多胺，其产物增加了 全身给药后血脑屏障通透性(*BBB)。 我们已经能够证明人类的存活率有了显著的提高 FALS小鼠(G93A)(Gll/+)连续皮下注射28.9天 多胺修饰过氧化氢酶渗透泵给药的比较 程控交换机(P&lt；0.0001)。这是所有治疗方法中最好的存活率提高。 到目前为止已经发表的关于FALS转基因小鼠的协议。这 因此，格兰特提案将进一步检验这一假设是否驱动了 治疗对FALS转基因小鼠是有益的，它将会有 对家族性和散发性肌萎缩侧索硬化症的治疗有直接意义。