Editing Alveolar Progenitor Cells for Correction of Monogenic Disease

项目总结 间质性肺疾病(ILDS)代表一大组慢性肺部疾病，这些疾病 世界各地儿童和成人发病和死亡的常见原因。肺泡功能障碍， 与慢性ILDS相关的肺纤维化和血管重构导致进行性呼吸 对于失败，他们几乎没有有效的治疗方法。遗传和环境因素都是导致 ILDS的发病机制；包括吸烟、空气污染、慢性炎症和遗传疾病。 调节表面活性物质稳态或肺泡2型(AT2)细胞功能或存活的基因突变包括 导致新生儿呼吸衰竭的ABCA3、SFTPB、SFTPC、SFTPA、端粒酶(及相关基因)， 儿童和老年人。我们的PCTC联盟寻求开发新的战略，旨在使用 针对肺祖细胞的CRISPR/Cas9基因编辑用于矫正典型的儿童间质肺 疾病(儿童)扰乱肺表面活性物质稳态(ABCA3缺乏症)，导致 致命的婴儿肺部疾病。ABCA3基因突变扰乱表面活性物质脂肪和蛋白质的产生 导致出生后严重呼吸功能障碍或婴儿期慢性肺部疾病的基因。我们会申请 CRISPR/Cas9介导的基因编辑纠正作为疾病靶点的肺泡祖细胞中的ABCA3 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， 肺泡AT2细胞及其前体细胞的靶向和基因编辑将广泛应用于治疗 未来周围肺的遗传性和获得性疾病。

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.