Cooperative lead development program for treatment of spinal muscular atrophy

治疗脊髓性肌萎缩症的合作先导开发项目

基本信息

批准号：
7866212
负责人：
ELLIOT J. ANDROPHY
金额：
$ 71.06万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-07 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7866212
关键词：
Acute Adult Alternative Splicing Animals Applications Grants Biological Assay Blood - brain barrier anatomy Cells Chemicals Chemistry Child Clinical Drug Development Clinical Trials Collaborations Collection Correlative Study Development Disease Diversity Library Drug Formulations Drug Kinetics Exons Foundations Functional disorder Funding Genetic Genetic Transcription Genetically Engineered Mouse Genomics Goals Grant Human Individual Infant Mortality Institutes Laboratories Lead Longevity Maintenance Measures Medicine Messenger RNA Metabolic Molecular Biology Motor Motor Activity Motor Neurons Mus Muscle Weakness Muscular Dystrophies Mutation Nerve Degeneration Neurodegenerative Disorders Outcome Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology and Toxicology Program Development Property Proteins RNA Reporter Request for Applications SMN protein (spinal muscular atrophy)SMN1 gene SMN2 gene Screening procedure Series Severity of illness Spinal Muscular Atrophy Structure-Activity Relationship Talents Testing Therapeutic Tissues Toxic effect Toxicology Transcript Transgenic Mice United States National Institutes of Health absorption animal efficacy base design drug discovery experience high throughput screening improved improved functioning in vivo infant death lead series motor neuron function mouse model novel postnatal pre-clinical prevent programs promoter protein expression public health relevance research study response restoration scaffold treatment program

项目摘要

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.

描述（由申请人提供）：脊柱肌肉萎缩（SMA）是肌肉营养不良的一种常见形式，也是婴儿死亡率的主要遗传原因。这种常染色体隐性疾病的特征是由于运动神经元功能的丧失而导致进行性肌肉无力。 SMA通常是由通常来自SMN1基因的纯合突变的生存运动神经元（SMN）蛋白的水平不足引起的。一个几乎相同的副本基因SMN2无法保护SMA的发育，因为其mRNA经历了外显子7的替代剪接。大约10％的SMN2 RNA转录物包括外显子7，并编码与SMN1相同的SMN蛋白。我们实施了一个新型的铅发现程序，以鉴定增加细胞内SMN蛋白水平的药物样化合物。使用新的和改进的基于细胞的记者测定法，我们在与神经退行性研究中的药物发现实验室，诺华基金会基因组学研究所和NIH化学基因组中心合作完成了三个大型化学多样性库的高通量屏幕。这些筛选已经鉴定出在次级测定中已证实的SMN蛋白表达的药物样活化剂。这项三年赠款的第一个目的是根据我们确定的活跃脚手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。一项药物化学计划将修改这些化合物，以改善吸收和维持足够的组织水平，并为其在动物中施用制定配方。第二个目的是测试SMA小鼠模型中最活跃和药理学上最合适的化合物，以便在体内提高SMN蛋白水平的功效，并确定是否可以改善疾病的严重性。该提案将六支团队的经验和才能与SMA分子生物学和临床前药物开发方面的专业知识结合在一起，并在神经退行性疾病的新型药物设计方面的领导者。该提案的预测结果是鉴定了具有药理上适合的药物样化合物，这些化合物可以提高SMN水平并恢复SMA模型小鼠的运动活性，从而可以快速前进到人类试验中。最终目标是开发有效的脊柱肌肉萎缩药物治疗。公共卫生相关性：脊柱肌肉萎缩（SMA）是一种肌肉营养不良的一种形式，是婴儿死亡的主要遗传原因，并且以较小的毁灭性形式导致儿童和成人的症状性肌肉无力。所有形式的SMA源于称为SMN的蛋白质水平不足。没有SMA的治疗方法。我们使用策略来测试非常大的化合物集合，以增加细胞中SMN蛋白水平的能力。该赠款申请要求资金最大化这些化合物的效力和类似毒品的特性。然后，我们将测试它们在基因工程的小鼠中的功效，以重现SMA并测量其SMN水平和效果。发现增加SMN水平并改善SMA小鼠存活的药物将代表进步人类临床试验的重要里程碑。