Unraveling the therapeutic potential of a new class of splicing modulators

 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突出了mRNA剪接改变在人类疾病中的重要性。这些突变中的大部分已经在负责神经退行性疾病的基因中描述，所述神经退行性疾病例如阿尔茨海默病、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。我们以前的工作一直集中在家族性自主神经功能障碍（FD），一种先天性感觉和自主神经病变引起的mRNA剪接缺陷。我们的研究发现，植物细胞分裂素激动素是IKBKAP剪接的有效调节剂，并导致功能性IKAP蛋白的量急剧增加。我们还证明激动素可以修饰引起NF 1突变的剪接，这表明适当的靶向药物可能在其他遗传剪接疾病中有效。基于这些发现，我们的FD项目被选为NINDS蓝图神经治疗网络的一部分，以开发一种针对断裂剪接的FD新药。通过该计划，目前正在进行工作，以优化激动素的效力和功效，并创造一种可用于患者的药物。迄今为止，我们已经创造了400多种激动素类似物，并拥有50多种剪接调节剂化合物（SMC），具有显着改善的效力，功效和药物样特征。目前R21应用的目的是确定这类新的剪接调节剂是否对其他神经系统疾病有用。我们已经证明激动素能够调节人类基因的剪接，包括IKBKAP，ABI2，BMP 2K和NF 1。开发一种专门针对精确分子缺陷的药物将是一个重大进展，不仅将改变FD的治疗模式，而且可能改变由改变mRNA剪接的突变引起的许多其他遗传疾病的治疗模式。有了我们新的剪接调节剂化合物，我们将确定潜在的靶基因，并确定我们的药物是否可以在基因特异性细胞检测中驱动剪接修饰。

 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.