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：（来自申请人摘要的逐字记录）肌萎缩侧索硬化 硬化症（ALS）是运动神经元的进行性神经变性疾病 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：hSOD 1），一种游离的 自由基清除酶，已经在大约20- 25%的 在FaLS家族中发现的hSODl的三种突变引起了 类似于ALS患者的运动神经元变性。免费 自由基介导的氧化损伤是一个关键组成部分的机制， 运动神经元的退化导致了肌萎缩侧索硬化。hSODl的突变形式 已经被认为是引发与以下疾病相关的神经病理学变化的原因： 通过由突变体表达引起的显性功能获得性而导致的FALS 赋予酶神经毒性的蛋白质。在这份赠款中， 应用，我们总结的证据表明，氢 过氧化氢介导的羟自由基对运动神经元的氧化损伤 和/或一氧化氮在治疗FALS中是有益的。我以黑夜做 重要的观察是，当过氧化氢酶共价连接到 天然存在的多胺，所得产物具有增加的 全身给药后血脑屏障（*BBB）的通透性。 我们已经能够证明， 在连续皮下给药后28.9天，对FALS小鼠（G93 A）（G1 L/+）进行了研究。 用多胺修饰的过氧化氢酶的渗透泵给药， PBX对照（p<0.0001）。这是所有治疗中提高生存率最好的 方案中的FALS转基因小鼠，已公布的日期。这 因此，赠款提案将进一步测试这种假设驱动的 该疗法在治疗FALS转基因小鼠中是有益的， 对家族性和散发性ALS的治疗有直接意义。