Optimizing Small Molecule Read-Through Compounds for Treating AtaxiaTelangiectasia

优化小分子通读化合物治疗共济失调毛细血管扩张症

基本信息

批准号：
10434554
负责人：
Paul James Mathews
金额：
$ 50.87万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-19 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10434554
关键词：
APTX gene ATM deficient ATM function ATM gene Address Affect Age Animal Model Animals Ataxia Ataxia Telangiectasia Ataxia Telangiectasia Patients Binding Proteins Biological Assay Blood - brain barrier anatomy Brain Cell Line Cells Cellular Assay Cessation of life Cistrons Clinical DNA Damage DNA Repair Gene Data Development Disease Duchenne muscular dystrophy Exons Fireflies Funding Genetic Hereditary Disease Human Immunofluorescence Immunologic Immunologic Deficiency Syndromes Inherited Knock-out Lead Length Life Luc Gene Luciferases Measures Messenger RNA Modeling Motor Mus Mutation National Institute of Neurological Disorders and Stroke Neurodegenerative Disorders Neurologic Neurologic Symptoms Nonsense Mutation Nuclear Protein Nucleotides Pain Patients Penetrance Persons Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phenotype Phosphorylation Phosphotransferases Preparation Production Property Proteins Publishing Quality of life RNA Reaction Reporter Reporting Research Safety Series Solubility Terminator Codon Testing Therapeutic Toxic effect Translations Validation Work analog assay development ataxia telangiectasia mutated protein ataxia-telangiectasia like disorder blood-brain barrier permeabilization cancer predisposition clinically relevant design effective therapy efficacy study efficacy testing experimental study high throughput screening in vivo innovation lymphoblastoid cell line mouse model nervous system disorder novel novel therapeutics pharmacokinetics and pharmacodynamics preclinical study premature preservation prevent protein function pulmonary arterial hypertension repository screening small molecule small molecule therapeutics success

项目摘要

PROJECT SUMMARY Ataxia-Telangiectasia (A-T) is a rare (~ 1 in every 100,000) but catastrophic and deadly disease that causes progressive loss of motor function and death between the ages of 10 and 30 years. In about one-third of A-T cases, the cause is a nonsense mutation in the ATM (Ataxia-Telangiectasia mutated) gene that encodes a premature termination codon (PTC). No effective treatments are available. However, our group has been developing and testing a series of compounds that effectively readthrough PTCs in the transcribed mRNA. Published and unpublished studies demonstrate the capability of these “SMRT” compounds (for Small Molecule ReadThrough) to readthrough PTCs and restore translation of functional ATM protein in in vivo and ex vivo experiments. The rationale to further develop SMRT compounds is strengthened by promising therapeutic results in mouse models for Duchenne muscular dystrophy and hereditary pulmonary arterial hypertension by our collaborators. However, success in these models does not ensure success in a multisystem, neurological disorder like A-T, in part because A-T uniquely requires the compound to cross the blood-brain barrier in adequate amounts. We have made considerable progress in our preclinical studies. We present data indicating that SMRT compounds elicit synthesis of full-length functional protein that penetrates the brain. We also recently solved a major hurdle in the field of A-T research: lack of an animal model that faithfully reflects clinical disease. In NINDS-supported studies, we used a double hit strategy to generate a mouse harboring both a clinically relevant PTC in the ATM gene and a knockout of a related DNA repair gene called aprataxin (Aptx). Characterization of this mouse model, including the profound, progressive ataxia that is a hallmark of A-T is complete. Now, we move to next logical phase: to use a rationalized and comprehensive approach to optimize our top candidate SMRT compound via medicinal chemistry. In AIM 1 we will develop and validate a novel potency assay specifically designed to evaluate potency across the 10 most common A-T causing nonsense mutations. In AIM 2 we will develop and validate an assay designed to confirm ATM function in human cells taking advantage of our unique repository of A-T patient derived cell lines. Finally, in AIM 3, these assays (along with those already standard in our labs to assess solubility, protein binding, blood brain barrier permeability, and toxicity) will be utilized to conduct a medicinal chemistry optimization campaign to generate a small set of candidate compounds with properties that maximize their chances of success in follow-on efficacy studies in our new A-T mouse model. Our work represents the first real hope for kids suffering from A-T's devastating effects.

项目摘要共济失调 - telangiectia（A-T）是罕见的（每10万中〜1），但灾难性和致命疾病引起 10至30岁之间的运动功能和死亡的逐渐丧失。在大约三分之一的A-T中病例，原因是ATM中的一个胡说八道突变（thaxia-telangiectia突变）基因，该基因编码A 过早终止密码子（PTC）。没有有效的治疗方法。但是，我们的小组一直在开发和测试一系列化合物，这些化合物在转录的mRNA中有效地读取PTC。已发表和未发表的研究证明了这些“ SMRT”化合物的能力（对于小分子读取）以读取PTC并恢复体内和Ex Vivo的功能性ATM蛋白的翻译实验。通过有希望的治疗结果，可以加强进一步发展SMRT化合物的基本原理在小鼠模型中，用于我们的肌肉营养不良症和遗传性肺动脉高压合作者。但是，这些模型的成功并不能确保在多系统的神经系统中取得成功诸如A-T之类的疾病，部分原因是A-T独特需要化合物越过血脑屏障足够的数量。我们在临床前研究中取得了长足的进步。我们提出指示的数据 SMRT复合引起穿透大脑的全长功能蛋白的合成。我们最近也解决了A-T研究领域的一个主要障碍：缺乏忠实地反映临床疾病的动物模型。在Ninds支持的研究中，我们使用了双重命中策略来产生携带临床上的小鼠 ATM基因中的相关PTC和称为Aprataxin（APTX）的相关DNA修复基因的敲除。该小鼠模型的表征，包括A-T的标志的深刻的，进行性的共济失调完全的。现在，我们转到下一个逻辑阶段：使用合理和全面的方法来优化我们的顶级候选SMRT化合物通过医学化学。在AIM 1中，我们将开发和验证小说效力测定专门设计用于评估10个最常见的A-T的效力，从而引起废话突变。在AIM 2中，我们将开发并验证旨在确认人类细胞中ATM功能的测定法利用我们独特的A-T患者衍生细胞系的存储库。最后，在AIM 3中，这些测定（沿着在我们实验室中已经标准的那些可以评估溶解度，蛋白质结合，血脑屏障渗透性和毒性）将用于进行医学化学优化运动，以产生一小部分具有特性的候选化合物在我们的后续效率研究中获得成功的机会新的A-T鼠标模型。我们的工作代表了患有A-T毁灭性影响的孩子的第一个真正希望。