USE OF PYRIMETHAMINE IN FAMILIAL ALS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 假设：在家族性肌萎缩侧索硬化症患者中，乙胺嘧啶在100毫克或更少的剂量下会降低淋巴细胞和脑脊液中SOD1的水平。 不幸的是，肌萎缩侧索硬化症(ALS)仍然是一种致命的神经退行性疾病，目前还没有有效的治疗方法。家族性形式(FALS)的临床病程可能特别侵袭性。由于这种基因突变是已知的某些形式的FALS[即编码超氧化物歧化酶(SOD1)的基因突变]，因此导致基因转录或翻译抑制的药物将是潜在的有效治疗剂。到目前为止，针对这种突变或其蛋白表达的小分子还没有被识别出来。已经确定了几个小分子通过不同的机制降低SOD1蛋白水平。其中一种候选药物乙胺嘧啶被FDA批准用于其他适应症，并已上市多年。乙胺嘧啶可显著降低小鼠和细胞中的SOD1水平。 这项研究的主要目的是评估乙胺嘧啶在FALS患者中的安全性和耐受性。次要目标将是确定最大限度地降低SOD1水平的剂量优化。患者将被要求接受淋巴细胞和脑脊液中SOD1水平的测定。

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. Hypothesis: In patients with Familial ALS, pyrimethamine will reduce SOD1 levels in lymphocytes and cerebrospinal fluid at doses of 100 mg of less. Amyotrophic lateral sclerosis (ALS) unfortunately remains a uniformly fatal neurodegenerative disorder for which no effective therapy exists. The clinical course of the familial form (FALS) may be particularly aggressive. Since the gene mutation is known for some forms of FALS [i.e. mutations in the gene coding for the enzyme superoxide dismutase (SOD1)], drugs which cause inhibition of gene transcription or translation would be potential potent therapeutic agents. Until now small molecules targeting this mutation or its protein expression have not been identified. Several small molecules have been identified that reduce SOD1 protein levels through various mechanisms. One candidate, pyrimethamine, is FDA approved for other indications, and has been on the market for many years. Pyrimethamine dramatically reduces SOD1 levels in mice and cells. The study's primary objective is to evaluate the safety and tolerability of pyrimethamine in patients with FALS. Secondary objectives will be to determine dose optimization for maximal SOD1 level reduction. Patients will be asked to undergo SOD1 level determination in lymphocytes and cerebrospinal fluid.