Molecular Therapies for Cystic Fibrosis Lung Disease

囊性纤维化肺病的分子疗法

• 批准号: 10470331
• 负责人: PAUL B MCCRAY
• 金额: $ 231.16万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470331
• 关键词: Address; Adenine; Airway Disease; Amphotericin B; Animal Model; Anions; Apical; Bacteria; Bicarbonates; Biology; Cells; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; Complement; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA; Data; Deaminase; Defect; Development; Disease; Epithelial Cells; Family suidae; Ferrets; Formulation; Genetic Diseases; Genetic Engineering; Goals; Guide RNA; Host Defense; Human; In Vitro; Infrastructure; Ion Channel; Knowledge; Life; Lung; Lung diseases; Mediating; Missense Mutation; Modeling; Molecular; Morbidity - disease rate; Mucociliary Clearance; Mutation; Natural Immunity; Nebulizer; Nucleotides; Pathogenesis; Peptides; Persons; Prevention; Property; Proteins; Pulmonary Cystic Fibrosis; RNA Splicing; Records; Research; Research Personnel; Respiratory Failure; Ribonucleoproteins; Role; Services; Site; Surface; Techniques; Testing; Variant; Work; adeno-associated viral vector; airway epithelium; airway obstruction; airway surface liquid; antimicrobial; base editing; base editor; cell type; cellular targeting; cystic fibrosis airway; cystic fibrosis airway epithelia; gain of function; gene discovery; gene repair; gene replacement; gene therapy; in vivo; innovation; loss of function; mortality; novel therapeutic intervention; novel therapeutics; null mutation; overexpression; prevent; progenitor; programs; protein function; recurrent infection; repaired; small molecule; tool

OVERALL COMPONENT PROJECT SUMMARY Cystic fibrosis (CF) is a common life-shortening genetic disease that causes progressive lung failure due to recurrent infections and airway obstruction. While our knowledge of CFTR function has advanced greatly in the 30 years since the discovery of the gene, treatments for the disease remain suboptimal and CF remains progressive and fatal. Advances with small molecule CFTR modulator therapies have helped restore protein function for many mutations, but approximately 10% of people with CF have not benefited from these strategies, including people with nonsense and splicing mutations. The central theme of this proposal is developing new molecular therapies to prevent or treat CF lung disease. The goal of our three projects and four cores is to exploit the power of our in vitro and animal models to address questions fundamental to lung disease pathogenesis and to use this knowledge to inform new therapeutic strategies to complement CF defects, including gene repair and the addition of a small molecule that forms anion channels. The three closely interrelated Projects will work together to accomplish the following goals: 1) To restore CFTR function using targeted single nucleotide editing. We hypothesize that cells in the surface airway epithelium, including those with progenitor capacity, can be targeted to repair CFTR mutations using base editing. 2) To understand the mechanisms of amphotericin B (AmB)-induced anion secretion in airway epithelia and to test the hypothesis that AmB can restore CF host defenses in vivo. AmB is a small molecule that forms anion channels. 3) To determine how CFTR expression in pulmonary ionocytes and ciliated cells regulates properties of the airway surface liquid that are crucial for clearance and innate immunity. The development of effective gene therapies for cystic fibrosis lung disease must be guided by a clear understanding of pathophysiologic mechanisms of disease and the relevant cellular targets for CFTR gene replacement or editing. The Project Leaders and their teams have outstanding track records of collaborative CF research, and here they sharpen their focus to a common goal. Their highly creative research is supported by four cores that provide innovative infrastructure and services. Through these studies we hope to accelerate the development of new therapeutics for CF lung disease. !

整体组成 项目概要 囊性纤维化 (CF) 是一种常见的缩短寿命的遗传性疾病，可导致进行性肺衰竭，原因是 反复感染和气道阻塞。虽然我们对 CFTR 函数的了解有所进步 自发现该基因以来的 30 年里，该疾病的治疗方法仍然不够理想，而且 CF 仍然是进展性和致命性的。小分子 CFTR 调节剂疗法的进展 有助于恢复许多突变的蛋白质功能，但大约 10% 的 CF 患者尚未恢复 受益于这些策略的人，包括患有无义突变和剪接突变的人。中央 该提案的主题是开发新的分子疗法来预防或治疗 CF 肺病。 我们三个项目和四个核心的目标是利用我们的体外和动物模型的力量 解决肺部疾病发病机制的基本问题，并利用这些知识为新的疾病提供信息 补充 CF 缺陷的治疗策略，包括基因修复和添加小分子 形成阴离子通道的分子。这三个密切相关的项目将共同努力 完成以下目标：1）使用靶向单核苷酸恢复CFTR功能 编辑。我们假设气道表面上皮细胞，包括那些具有祖细胞的细胞 能力，可以使用碱基编辑来靶向修复 CFTR 突变。 2）了解 两性霉素 B (AmB) 诱导气道上皮阴离子分泌的机制并测试 假设 AmB 可以恢复 CF 宿主体内的防御能力。 AmB 是一种小分子，形成 阴离子通道。 3) 确定CFTR在肺离子细胞和纤毛细胞中的表达情况 调节气道表面液体的特性，这对于清除和固有的至关重要 免疫。必须指导开发针对囊性纤维化肺病的有效基因疗法 通过清楚地了解疾病的病理生理机制和相关的细胞靶标 CFTR 基因替换或编辑。 项目负责人及其团队在 CF 协作研究方面拥有出色的记录，并且 在这里，他们将注意力集中到一个共同的目标上。他们极具创造性的研究得到了四个方面的支持 提供创新基础设施和服务的核心。通过这些研究，我们希望加速 CF肺病新疗法的开发。 ！