Unraveling the therapeutic potential of a new class of splicing modulators

揭示新型剪接调节剂的治疗潜力

• 批准号: 9134913
• 负责人: Susan A Slaugenhaupt
• 金额: $ 21.75万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9134913
• 关键词: ABI2 gene; Affect; Alzheimer' s Disease; Automobile Driving; Biological Assay; Cataloging; Catalogs; Cells; Characteristics; Clinic; Collaborations; Computing Methodologies; Consensus Sequence; Cytokinins; Data; Defect; Development; Disease; Drug Targeting; Elements; Evaluation; Exons; Explosion; Familial Dysautonomia; Frontotemporal Dementia; Funding; Future; Gene Targeting; Genes; Genome; Genomics; Goals; Hand; Health; Hereditary Disease; Human; Institutes; Kinetins; Laboratories; Libraries; Luciferases; Messenger RNA; Modification; Molecular; Mutation; NF1 gene; National Institute of Neurological Disorders and Stroke; Nature; Nervous system structure; Neurodegenerative Disorders; Neurofibromatosis 1; Neurologic; Other Genetics; Parkinson Disease; Patients; Pharmaceutical Preparations; Plants; Protein Isoforms; Proteins; RNA Splicing; Site; Spinal Muscular Atrophy; Spliced Genes; Testing; Therapeutic; Tissue-Specific Splicing; Transcript; Work; analog; arm; autonomic neuropathy; base; disease-causing mutation; drug efficacy; high risk; human disease; improved; in vivo; individual patient; nervous system disorder; novel therapeutics; programs; research study; response; sensory neuropathy; therapy development; transcriptome; transcriptome sequencing

 DESCRIPTION (provided by applicant): The recent explosion of genomic sequence data generated from individual patients highlights the importance of mRNA splicing alterations in human disease. A large proportion of these mutations have been described in genes responsible for neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Frontotemporal Dementia, Spinal Muscular Atrophy and Neurofibromatosis type 1. Our previous work has been focused on Familial Dysautonomia (FD), a congenital sensory and autonomic neuropathy caused by an mRNA splicing defect. Our work has led to the discovery that the plant cytokinin kinetin is a potent modulator of IKBKAP splicing and leads to a dramatic increase in the amount of functional IKAP protein. We also demonstrated that kinetin can modify splicing of NF1-causing mutations, suggesting that an appropriately targeted drug may prove efficacious in other genetic splicing disorders. Based on these findings, our FD program was selected to be part of the NINDS Blueprint Neurotherapeutics Network to develop a new drug for FD that targets disrupted splicing. Through this program, work is currently underway to optimize the potency and efficacy of kinetin and create a drug that can be used in patients. To date, we have created over 400 kinetin analogs and have in hand more than 50 splice modulator compounds (SMCs) with significantly improved potency, efficacy, and drug-like characteristics. The aim of the current R21 application is to determine if this new class of splicing modulators might be useful for other neurologic disorders. We have already shown that kinetin is able to modulate the splicing of human genes including IKBKAP, ABI2, BMP2K and NF1. Development of a drug to specifically target a precise molecular defect would be a major advance and would shift treatment paradigms not only for FD, but potentially for a number of other genetic diseases caused by mutations that alter mRNA splicing. Armed with our new class of splice modulator compounds, we will identify potential target genes and determine if our drugs can drive splicing modification in a gene-specific cell based assay.

 描述(由申请人提供)： 最近从个体患者产生的基因组序列数据的爆炸性增长突显了mRNA剪接改变在人类疾病中的重要性。这些突变中有很大一部分被描述在导致神经退行性疾病的基因上，如阿尔茨海默病、帕金森病、额颞叶痴呆、脊髓性肌萎缩症和1型神经纤维瘤病。我们之前的工作集中在家族性自主障碍(FD)，这是一种由mRNA剪接缺陷引起的先天性感觉和自主神经疾病。我们的工作发现，植物细胞分裂素是IKBKAP剪接的有效调节器，并导致功能性IKAP蛋白数量的急剧增加。我们还证明了激动素可以修改NF1导致的突变的剪接，这表明适当的靶向药物可能对其他基因剪接疾病有效。基于这些发现，我们的FD项目被选为NINDS Blueprint神经治疗网络的一部分，以开发一种针对剪接中断的FD新药。通过这一计划，目前正在进行优化激动素的效力和疗效的工作，并创造一种可用于患者的药物。到目前为止，我们已经创造了400多个激动素类似物，并拥有50多个剪接调节剂化合物(SMC)，它们的效力、有效性和类药物特性都得到了显著改善。目前R21应用的目的是确定这种新的剪接调节剂是否对其他神经疾病有用。我们已经证明激动素能够调节包括IKBKAP、ABI2、BMP2K和NF1在内的人类基因的剪接。开发一种专门针对精确分子缺陷的药物将是一项重大进步，不仅将改变FD的治疗模式，而且可能改变由改变mRNA剪接的突变引起的其他一些遗传病的治疗模式。有了我们的新型剪接调节剂化合物，我们将识别潜在的目标基因，并确定我们的药物是否可以在基于基因特异性细胞的检测中驱动剪接修饰。