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

• 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
• 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

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.

项目总结 共济失调-毛细血管扩张症(A-T)是一种罕见的(每100,000人中有1例)但灾难性和致命的疾病，可导致 在10到30岁之间逐渐丧失运动功能和死亡。在大约三分之一的A-T 病例中，病因是ATM(共济失调-毛细血管扩张突变)基因的无义突变，该基因编码 提前终止密码子(PTC)。目前还没有有效的治疗方法。然而，我们的团队一直在 开发和测试一系列化合物，有效地阅读转录的mRNA中的PTCs。 已发表和未发表的研究证明了这些“SMRT”化合物(对于小分子)的能力 通读)通读PTCs并在体内和体外恢复功能性ATM蛋白的翻译 实验。前景看好的治疗结果加强了进一步开发SMRT化合物的理由 在Duchenne肌营养不良和遗传性肺动脉高压小鼠模型上 合作者。然而，在这些模型中的成功并不确保在多系统、神经学上的成功 像A-T这样的障碍，部分原因是A-T独特地要求化合物在体内穿过血脑屏障 足够的数量。我们在临床前研究方面取得了相当大的进展。我们提供的数据表明 这种SMRT化合物可以诱导合成穿透大脑的全长功能蛋白。我们最近也是 解决了A-T研究领域的一个主要障碍：缺乏真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一只既有临床上 ATM基因中的相关PTC和被称为aprataxin(AptX)的相关DNA修复基因的敲除。 这种小鼠模型的特征，包括作为A-T的标志的深刻的、进行性共济失调是 完成。现在，我们进入下一个逻辑阶段：使用合理而全面的方法来优化 我们的首选SMRT化合物通过药物化学。在目标1中，我们将开发和验证一部小说 专门设计的效力测试，用于评估10种最常见的A-T引起的无稽之谈的效力 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功能的方法 利用我们独一无二的A-T患者衍生细胞系。最后，在AIM 3中，这些分析(沿着 使用我们实验室中已有的评估溶解性、蛋白质结合、血脑屏障通透性和 毒性)将被用于进行药物化学优化活动，以产生一小套 候选化合物具有最大限度地提高其在后续疗效研究中的成功机会 新的A-T小鼠模型。我们的工作为遭受A-T破坏性影响的孩子们带来了第一个真正的希望。