Cooperative lead development program for treatment of spinal muscular atrophy

描述（由申请人提供）：脊髓性肌萎缩症（SMA）是一种常见的肌肉萎缩症，也是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进行性肌肉无力。SMA是由存活运动神经元（SMN）蛋白水平不足引起的，通常来自SMN1基因的纯合突变。一个几乎相同的复制基因SMN2不能防止SMA的发展，因为它的mRNA经历了外显子7的选择性剪接。大约10%的SMN2 RNA转录本包含外显子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，以鉴定增加细胞内SMN蛋白水平的药物样化合物。我们与神经退行性疾病药物发现实验室、诺华基金会基因组学研究所和美国国立卫生研究院化学基因组学中心合作，使用一种新的、改进的基于细胞的报告基因分析方法，完成了三个大型化学多样性文库的高通量筛选。这些筛选已经确定了SMN蛋白表达的药物样激活剂，并在二次分析中得到证实。这项为期三年的资助的第一个目标是基于我们已经确定的活性支架设计和合成更有效的化合物。然后我们将研究出现的铅的药代动力学和急性毒理学。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，并制备其在动物体内施用的配方。第二个目的是在SMA小鼠模型中测试最有效和药理学上最合适的化合物在体内提高SMN蛋白水平的功效，并确定是否可以改善疾病的严重程度。该提案将具有分子生物学和SMA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的领导者结合起来。该建议的预测结果是确定药理学上合适的药物样化合物，这些化合物可以增加SMA模型小鼠的SMN水平并恢复运动活动，这可以迅速推进到人体试验。最终目标是开发一种有效的药物治疗脊髓性肌萎缩症。

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.