Editing Alveolar Progenitor Cells for Correction of Monogenic Disease

编辑肺泡祖细胞以纠正单基因疾病

• 批准号: 10198995
• 负责人: Darrell N. Kotton
• 金额: $ 125.83万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-23 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198995
• 关键词: ABCA3 gene; Acute; Adult; Affect; Air Pollution; Alleles; Alveolar; Amniotic Fluid; Biological; Birth; Boston; CRISPR/Cas technology; Cell Survival; Cell physiology; Cells; Cellular biology; Child; Childhood; Chronic; Chronic lung disease; Clinic; Clinical; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Communities; Complex; DNA sequencing; Data; Defect; Development; Disease; Disease model; Doctor of Medicine; Doctor of Philosophy; Environmental Risk Factor; Epithelial; Epithelial Cells; Face; Functional disorder; Future; Generations; Genes; Genetic; Genetic Diseases; Goals; Guide RNA; Hereditary Disease; Homeostasis; Human; In Vitro; Individual; Infant; Inflammation; Interstitial Lung Diseases; Laboratories; Lead; Lipids; Liposomes; Lung; Lung diseases; Mediating; Mendelian disorder; Modeling; Morbidity - disease rate; Mus; Mutation; Natural regeneration; Neonatal; Other Genetics; Pathogenesis; Pathologic; Patients; Pediatric Hospitals; Peripheral; Pharmacology; Phenotype; Prevention; Production; Proteins; Pulmonary Fibrosis; Pulmonary Surfactants; RNA; RNA delivery; Reagent; Research; Respiration Disorders; Respiratory Failure; Respiratory distress; Role; Route; Smoking; Structure; Surface; System; TACSTD1 gene; Technology; Telomerase; Testing; Transgenic Mice; Universities; Variant; Vascular remodeling; Viral; Washington; Work; airway epithelium; alveolar epithelium; base; cell injury; design; disease-causing mutation; effective therapy; epithelial stem cell; gene correction; genetic disorder diagnosis; human model; human tissue; in vivo; induced pluripotent stem cell; infancy; lung injury; mRNA delivery; member; mortality; mouse model; nanoparticle; neonate; novel strategies; progenitor; programs; prototype; reagent testing; repaired; self-renewal; skills; stem cells; success; surfactant; surfactant deficiency; trafficking; vector

PROJECT SUMMARY Interstitial Lung Diseases (ILDs), represent a large group of chronic pulmonary disorders that are common causes of morbidity and mortality of both children and adults worldwide. Alveolar dysfunction, pulmonary fibrosis, and vascular remodeling associated with chronic ILDs lead to progressive respiratory failure for which they are few effective therapies. Both genetic and environmental factors underlie the pathogenesis of ILDs; including smoking, air pollution, and chronic inflammation and genetic disorders. Mutations in genes regulating surfactant homeostasis or alveolar type 2 (AT2) cell function or survival includes ABCA3, SFTPB, SFTPC, SFTPA, Telomerase (and related genes) that cause respiratory failure in neonates, children, and older individuals. Our PCTC Consortium seeks to develop novel strategies designed to use CRISPR/CAS9 gene editing for lung progenitor cells for correction of a prototypic Childhood Interstitial Lung Diseases (CHILD) disorder that disrupts pulmonary surfactant homeostasis (ABCA3 deficiency) that leads to fatal infantile lung disease. Mutations in in the ABCA3 gene disrupts surfactant lipid and protein production gene causing severe respiratory dysfunction after birth or chronic lung disease in infancy. We will apply CRISPR/CAS9 mediated gene editing to correct ABCA3 in alveolar progenitor cells as disease targets applicable to other genetic and acquired disorders affecting AT2 cells and their progenitors. The identification, targeting and gene editing of alveolar AT2 cells and their progenitors will be widely applicable for the treatment of both genetic and acquired diseases of the peripheral lung in the future.

项目摘要 间质性肺疾病（ILD）代表一大组慢性肺部疾病， 是全世界儿童和成人发病和死亡的共同原因。肺泡功能障碍， 肺纤维化和与慢性ILD相关的血管重塑导致进行性呼吸道疾病， 失败，他们是很少有效的治疗方法。遗传和环境因素都是导致 ILD的发病机制;包括吸烟、空气污染、慢性炎症和遗传性疾病。 调节表面活性物质稳态或肺泡2型（AT 2）细胞功能或存活的基因突变包括 引起新生儿呼吸衰竭的ABCA 3、SFTPB、SFTPC、SFTPA、端粒酶（及相关基因）， 儿童和老年人。我们的PCTC联盟寻求开发新的策略， CRISPR/CAS9基因编辑肺祖细胞以纠正原型儿童间质性肺 疾病（儿童）：破坏肺表面活性物质稳态（ABCA 3缺乏症），导致 致命的婴儿肺病ABCA 3基因突变破坏表面活性剂脂质和蛋白质的产生 基因导致出生后严重呼吸功能障碍或婴儿期慢性肺病。我们将应用 CRISPR/CAS9介导的基因编辑以纠正肺泡祖细胞中的ABCA 3作为疾病靶点 适用于影响AT 2细胞及其祖细胞的其他遗传性和获得性疾病。身份证明， 肺泡AT 2细胞及其祖细胞的靶向和基因编辑将广泛适用于治疗 遗传性和获得性周围性肺疾病的研究。