MINOCYCLINE IN 400 SUBJECTS WITH ALS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。肌萎缩性侧索硬化症导致随意运动系统退化和平均3年死亡。这个过程是渐进的，随着时间的推移功能会下降。目前还没有治愈或已知的治疗方法可以显著改善功能。流行率为每10万人4-6例，发病率为每10万人0.4至1.8例。大多数ALS病例是散发性的。然而，10-15%是作为常染色体显性性状遗传的，称为家族性ALS （FALS）。其中，25%与编码铜锌超氧化物歧化酶（SOD1）的基因缺陷有关。在FALS中发现突变体SOD1后，利用该基因建立了转基因小鼠模型。SOD1 FALS啮齿动物模型已成为ALS病理研究和治疗药物筛选的重要方法。人类ALS的散发性和家族性形式在临床和病理上是相似的。二甲胺四环素被选择用于这项研究，因为它的作用可能在几个点上抑制运动神经变性。它可能通过阻止促凋亡和促炎酶的激活来抑制细胞死亡途径。它抑制线粒体细胞色素c的释放，抑制p38有丝分裂原活化蛋白（MAP）激酶，从而减少半胱天冬酶、小胶质细胞、细胞因子和氧化物质的周期性激活和产生。它减缓了包括ALS在内的几种神经退行性疾病的恶化。它在实验性缺血中具有神经保护作用，并且已被证明对人类炎症性关节炎有效，除了它的抗生素特性。假设：肌萎缩侧索硬化症的神经元死亡可能包括细胞凋亡。二甲胺四环素在ALS转基因小鼠模型中显示出抗凋亡作用，并减缓了进展速度。具体目标1：二甲胺四环素将减缓ALS的进展速度15%。特异性目标2：米诺环素的耐受性为200mg /BID。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Amyotrophic lateral sclerosis leads to degeneration of the voluntary motor system and death on average in 3 years. The course is progressive with a decline in function with time. There is no cure or known treatment that significantly improves function. The prevalence is 4-6 cases per 100,000 with an incidence of 0.4 to 1.8 per 100,000. The majority of ALS cases are sporadic. However, 10-15% are inherited as an autosomal dominant trait known as familial ALS (FALS). Of these, 25% are associated with a defect in the gene encoding the enzyme copper-zinc superoxide dismutase (SOD1). After discovery of mutant SOD1 in FALS, a transgenic mouse model was developed using the same gene. The SOD1 FALS rodent model has become an important method of pathological study and therapeutic drug screening in ALS. The sporadic and familial forms of human ALS are clinically and pathologically similar. Minocycline was selected for this study because its effects may inhibit motor nerve degeneration at several points. It likely inhibits cell death pathways by preventing both pro-apoptotic and pro-inflammatory enzyme activation. It inhibits release of mitochondrial cytochrome c and inhibits p38 mitogen activated protein (MAP) kinase, thus reducing cyclical activation and production of caspase enzymes, microglia, cytokines and oxidative species. It slows deterioration in several models of neurodegeneration, including ALS. It has neuroprotective benefit in experimental ischemia, and it has proven efficacy in human inflammatory arthritis, separate from its antibiotic properties. Hypothesis: Neuronal death in ALS may include apoptosis. Minocycline has shown anti-apoptotic effects and has slowed the rate of progression in a transgenic mouse model of ALS. Specific Aim 1: Minocycline will slow the rate of progression in ALS by 15%. Specific Aim 2: Minocycline will be tolerated at 200 mg/BID.