Implications of Genetic Diversity in Muscular Dystrophy

遗传多样性对肌营养不良症的影响

• 批准号: 10244204
• 负责人: Dwi Utami Kemaladewi
• 金额: $ 126.91万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10244204
• 关键词: Animals; Award; Biological; Biology; Clinical Treatment; Clinical Trials; Diagnosis; Disease; Failure; Future; Genetic; Genetic Variation; Genome; Goals; Human; Inbred Strains Mice; Inbreeding; Individual; Inherited; Lead; Methods; Modeling; Mus; Muscular Dystrophies; Mutation; Outcome; Patients; Population; Safety; Severity of illness; Technology; Therapeutic Intervention; Treatment Efficacy; United States National Institutes of Health; adverse outcome; base; career; design; disease phenotype; experimental study; gene therapy; genome editing; genomic variation; innovation; neuromuscular; patient population; precision medicine; preclinical study; response; therapeutic development; therapeutic genome editing

ABSTRACT Differences in our individual genomes give rise to most of human diversity. This uniqueness of every human being underpins the purpose of precision medicine, which posits that disease prediction, diagnosis, and treatment for each individual is based on personal genomic variations. The rapid advancement of genome editing technology has led to numerous promising preclinical studies in muscular dystrophies (MDs). These studies were performed in inbred animals, with mice being the most extensively used models, in which the component of genetic diversity has been largely ignored. Genetically speaking, developing a therapeutic intervention in a single inbred mouse strain is the equivalent of treating a single patient and limits the generalizability and translatability of the results into human applications. Failure to anticipate the genetic diversity in patient populations will confound future clinical trials and may lead to adverse outcomes. In this NIH Innovator Award, my goal is to revolutionize the conventional method by which we develop genetic therapy to reflect diverse and more realistic human populations. First, I will integrate the naturally occurring genetic reference panel into a model harboring MD-causing mutation to better simulate diverse patient population and elevate its translational value. I will use this innovative model to investigate whether the introduced genetic variation profoundly modifies the neuromuscular presentations. Furthermore, I will study the implications of genetic variation on the safety and efficacy of therapeutic genome editing approaches that I have developed throughout my career. As we move closer towards designing clinical treatment that is based on an individual's biological makeup, it is imperative that we understand how inherited variability influences disease phenotypes, how it can confound experiments, and how it can be exploited to reveal new truths about disease biology. Using MD as a starting point, successful outcome of this project can be integrated into a framework for future therapeutic developments in different diseases and across patient populations.

摘要 我们个体基因组的差异产生了人类的大部分多样性。每个人的独特性 存在是精准医学的基础，精准医学认为疾病预测、诊断和 每个人的治疗基于个人基因组变异。基因组的快速发展 编辑技术已经在肌营养不良症（MD）中导致了许多有希望的临床前研究。这些 研究是在近交系动物中进行的，小鼠是最广泛使用的模型， 遗传多样性在很大程度上被忽视了。从遗传学上讲，开发一种治疗药物 对单个近交系小鼠品系的干预相当于治疗单个患者， 将结果推广到人类应用中的可推广性和可翻译性。未能预测遗传 患者群体的多样性将混淆未来的临床试验，并可能导致不良结果。 在本届NIH创新者奖中，我的目标是彻底改变我们开发遗传学的传统方法 治疗，以反映多样化和更现实的人口。首先，我将整合自然发生的 遗传参考面板到一个模型窝藏MD引起的突变，以更好地模拟不同的患者 提升其翻译价值。我将使用这个创新的模型来调查是否 引入的遗传变异深刻地改变了神经肌肉的表现。此外，我将研究 遗传变异对治疗性基因组编辑方法的安全性和有效性的影响， 我在我的职业生涯中发展。 随着我们越来越接近设计基于个人生物组成的临床治疗， 我们必须了解遗传变异性如何影响疾病表型，它如何混淆 实验，以及如何利用它来揭示疾病生物学的新真相。以MD为起点 点，该项目的成功结果可以整合到未来治疗的框架中， 不同疾病和患者人群的发展。