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）代表了一大批慢性肺部疾病 全世界儿童和成人的发病率和死亡率的常见原因。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 它们很少有效疗法的失败。遗传和环境因素是 ILD的发病机理；包括吸烟，空气污染以及慢性炎症和遗传疾病。 调节表面活性剂稳态或2型肺泡（AT2）细胞功能或生存的基因突变包括 ABCA3，SFTPB，SFTPC，SFTPA，端粒酶（及相关基因），导致新生儿呼吸衰竭， 儿童和年长的人。我们的PCTC财团旨在制定旨在使用的新型策略 CRISPR/CAS9基因编辑肺祖细胞校正原型儿童期肺 疾病（儿童）疾病会破坏导致肺表面活性剂稳态（ABCA3缺乏症） 致命的婴儿肺病。 ABCA3基因中的突变破坏了表面活性剂脂质和蛋白质的产生 出生后导致严重的呼吸障碍或婴儿期慢性肺部疾病。我们将申请 CRISPR/CAS9介导的基因编辑以校正肺泡祖细胞中的ABCA3作为疾病靶标 适用于影响AT2细胞及其祖细胞的其他遗传和获得性疾病。身份证明， 牙槽AT2细胞及其祖细胞的靶向和基因编辑将广泛适用于治疗 未来的遗传和获得性疾病的遗传疾病。