THERAPEUTIC BENEFIT OF HYDROGEN PEROXIDE REMOVAL IN FALS

去除过氧化氢对 FLS 的治疗效果

• 批准号: 6477163
• 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/6477163
• 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）是一种运动神经元的进行性神经退行性疾病 主要是脊髓。显性遗传的基因突变 编码人铜/锌超氧化物歧化酶 (Cu/Zn-SOS: hSODl)，一种游离的 自由基清除酶，已在大约 20-25% 的细胞中观察到 FaLS家族中发现的三种hSOD1突变导致FALS患者 运动神经元变性与 ALS 患者相似。自由的 自由基介导的氧化损伤是其机制的关键组成部分 运动神经元退化导致 FALS。 hSOD1的突变形式 已被建议启动与相关的神经病理学变化 FALS 是由于突变体表达导致的显性功能获得 赋予酶神经毒性的蛋白质。在这笔补助金中 应用中，我们总结了表明氢的证据 过氧化物介导的运动神经元氧化损伤涉及羟基自由基 和/或一氧化氮对于治疗 FALS 是有益的。我们已经做了 重要的观察结果是，当过氧化氢酶共价连接到 天然存在的多胺，所得产品具有增加 全身给药后血脑屏障（*BBB）的通透性。 我们已经能够证明存活率显着提高 连续皮下注射后 28.9 天，FALS 小鼠 (G93A) (GlL/+) 与多胺修饰过氧化氢酶渗透泵给药相比 PBX 控制 (p<0.0001)。这是任何治疗中最能提高生存率的方法 迄今为止已发布的 FALS 转基因小鼠实验方案。这 因此，拨款提案将进一步测试这种假设驱动的 疗法对治疗 FALS 转基因小鼠是有益的，这将有 对家族性和散发性 ALS 的治疗有直接影响。