USE OF PYRIMETHAMINE IN FAMILIAL ALS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 假设：在家族性ALS患者中，乙胺嘧啶将降低淋巴细胞和脑脊液中的SOD 1水平，剂量为100 mg或更少。 肌萎缩侧索硬化症（ALS）不幸地仍然是一种一致致命的神经退行性疾病，没有有效的治疗方法。家族性形式（FALS）的临床过程可能特别具有侵略性。由于已知某些形式的FALS的基因突变[即编码酶超氧化物歧化酶（SOD 1）的基因中的突变]，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，尚未鉴定出靶向该突变或其蛋白表达的小分子。已经鉴定出几种小分子通过各种机制降低SOD 1蛋白水平。一种候选药物乙胺嘧啶已被FDA批准用于其他适应症，并已上市多年。乙胺嘧啶显著降低小鼠和细胞中的SOD 1水平。 这项研究的主要目的是评估乙胺嘧啶在ALS患者中的安全性和耐受性。次要目的是确定最大SOD 1水平降低的剂量优化。将要求患者接受淋巴细胞和脑脊液中的SOD 1水平测定。

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.