Cooperative lead development program for treatment of spinal muscular atrophy

描述(申请人提供)：脊髓性肌萎缩症(SMA)是一种常见的肌营养不良症，是导致婴儿死亡的主要遗传原因。这种常染色体隐性遗传病的特征是由于运动神经元功能丧失而导致的进行性肌肉无力。SMA是由于存活运动神经元(SMN)蛋白水平不足引起的，通常是由于SMN1基因的纯合突变引起的。一个几乎相同的复制基因SMN2无法防止SMA的发生，因为它的mRNA经历了外显子7的选择性剪接。大约10%的SMN2RNA转录本包括外显子7，并编码与SMN1相同的SMN蛋白。我们实施了一项新的先导发现计划，以确定增加细胞内SMN蛋白水平的类药物化合物。使用一种新的和改进的基于细胞的报告分析，我们与神经变性药物发现实验室、诺华基金会基因组研究所和NIH化学基因组中心合作，完成了三个大型化学多样性文库的高通量筛选。这些筛查已经确定了药物样的SMN蛋白表达激活剂，这些激活剂已在二次检测中得到确认。这项为期三年的拨款的第一个目标是在我们已经确定的活性支架的基础上设计和合成更有效的化合物。然后，我们将调查出现的铅的药代动力学和急性毒理学。一项药物化学计划将修改这些化合物，以改善吸收和维持适当的组织水平，并准备它们在动物身上给药的配方。第二个目的是在SMA小鼠模型中测试最具活性和药理上合适的化合物在体内提高SMN蛋白水平的有效性，并确定是否可以改善疾病的严重性。这项提议将在SMA拥有分子生物学和临床前药物开发专业知识的六个团队的经验和人才与神经退行性疾病新药设计方面的领导者结合在一起。这项建议的预测结果是识别出药理上合适的类药物化合物，这些化合物可以提高SMN水平并恢复SMA模型小鼠的运动能力，可以迅速进入人体试验。最终目标是开发一种治疗脊髓性肌萎缩症的有效药物。 公共卫生相关性：脊髓性肌萎缩症(SMA)是肌营养不良症的一种，是导致婴儿死亡的主要遗传原因，在破坏性较小的形式下，会导致儿童和成年人出现症状性肌肉无力。所有形式的SMA都是由于一种名为SMN的蛋白质水平不足造成的。对于SMA，没有治疗方法。我们使用了一种策略来测试非常大的化合物集合是否能够提高细胞中SMN蛋白的水平。这项赠款申请要求提供资金，以最大限度地发挥这些化合物的效力和类似药物的特性。然后，我们将在通过基因工程繁殖SMA的小鼠身上测试它们的疗效，并测量它们的SMN水平和效果。发现一种可以提高SMN水平并改善SMA小鼠存活率的药物，将是推进人类临床试验的一个重要里程碑。

DESCRIPTION (provided by applicant): Spinal Muscular Atrophy (SMA) is a common form of muscular dystrophy and the leading genetic cause of infant mortality. This autosomal recessive disorder is characterized by progressive muscle weakness due to loss of motor neuron function. SMA is caused by insufficient levels of the survival motor neuron (SMN) protein, usually from homozygous mutation of the SMN1 gene. A nearly identical copy gene, SMN2, fails to protect from development of SMA because its mRNA undergoes alternative splicing of exon 7. About 10% of SMN2 RNA transcripts include exon 7 and encode the same SMN protein as SMN1. We implemented a novel lead discovery program to identify drug-like compounds that increase intracellular SMN protein levels. Using a new and improved cell-based reporter assay, we completed three high-throughput screens of large chemical diversity libraries in collaborations with the Laboratory of Drug Discovery in Neurodegeneration, the Genomics Institute of Novartis Foundation, and the NIH Chemical Genomics Center. These screens have identified drug-like activators of SMN protein expression that have been confirmed in secondary assays. The first aim of this three-year grant is to design and synthesize more potent compounds based on the active scaffolds we have identified. We will then investigate the pharmacokinetics and acute toxicology of the leads that emerge. A medicinal chemistry program will modify these compounds for improved absorption and maintenance of adequate tissue levels and prepare formulations for their administration in animals. The second aim is to test the most active and pharmacologically suitable compounds in SMA mouse models for efficacy in raising SMN protein levels in vivo and to determine whether the severity of disease can be ameliorated. This proposal unites the experience and talents of six teams with expertise in molecular biology and pre-clinical drug development in SMA with leaders in design of novel medicines for neurodegenerative diseases. The predicted outcome of this proposal is identification of pharmacologically suitable drug-like compounds that increase SMN levels and restore motor activity in SMA model mice that can be rapidly advanced to human trials. The ultimate goal is to develop an effective drug treatment of spinal muscular atrophy. PUBLIC HEALTH RELEVANCE: Spinal muscular atrophy (SMA), a form of muscular dystrophy, is the leading genetic cause of infant death, and in less devastating forms leads to symptomatic muscle weakness in children and adults. All forms of SMA result from insufficient levels of the protein called SMN. There is no treatment for SMA. We used a strategy to test very large collections of chemical compounds for ability to increase SMN protein levels in cells. This grant application requests funds for maximizing the potency and drug-like properties of these compounds. We will then test their efficacy in mice genetically engineered to reproduce SMA and measure their SMN levels and effects. Discovery of a medicine that increases SMN levels and improves SMA mouse survival would represent an important milestone for advancement to human clinical trials.