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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.

项目概要共济失调-毛细血管扩张症 (A-T) 是一种罕见的疾病（大约每 100,000 人中就有 1 人），但却是灾难性的致命疾病，可导致运动功能逐渐丧失并在 10 至 30 岁之间死亡。大约三分之一的 A-T 在某些情况下，原因是 ATM（共济失调毛细血管扩张突变）基因中的无义突变，该基因编码提前终止密码子（PTC）。没有有效的治疗方法。然而我们组已经开发和测试一系列能够有效读取转录 mRNA 中 PTC 的化合物。已发表和未发表的研究证明了这些“SMRT”化合物（对于小分子 ReadThrough）可通读 PTC 并在体内和离体恢复功能性 ATM 蛋白的翻译实验。有希望的治疗结果强化了进一步开发 SMRT 化合物的理由我们的研究人员在杜氏肌营养不良症和遗传性肺动脉高压的小鼠模型中进行了研究合作者。然而，这些模型的成功并不能确保多系统、神经系统的成功像 A-T 这样的疾病，部分原因是 A-T 独特地需要该化合物穿过血脑屏障足够的量。我们的临床前研究取得了相当大的进展。我们提供的数据表明 SMRT 化合物会引发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：缺乏忠实反映临床疾病的动物模型。在 NINDS 支持的研究中，我们使用双重打击策略来产生具有临床 ATM 基因中的相关 PTC 以及称为 aprataxin (Aptx) 的相关 DNA 修复基因的敲除。该小鼠模型的特征，包括作为 A-T 标志的深刻的渐进性共济失调完全的。现在，我们进入下一个逻辑阶段：使用合理化和全面的方法来优化我们通过药物化学获得的最佳候选 SMRT 化合物。在 AIM 1 中，我们将开发并验证一部小说效力测定专门设计用于评估 10 种最常见的导致无意义的 A-T 的效力突变。在 AIM 2 中，我们将开发并验证一种旨在确认人类细胞中 ATM 功能的检测方法利用我们独特的 A-T 患者衍生细胞系存储库。最后，在 AIM 3 中，这些测定（以及与我们实验室中已经标准的那些一起评估溶解度、蛋白质结合、血脑屏障渗透性和毒性）将用于进行药物化学优化活动，以生成一小组候选化合物的特性可最大程度地提高我们在后续功效研究中的成功机会新的 A-T 鼠标模型。我们的工作为遭受 A-T 毁灭性影响的孩子们带来了第一个真正的希望。