Development of novel therapeutic approaches for treatment of Alveolar Capillary Dysplasia

开发治疗肺泡毛细血管发育不良的新疗法

• 批准号: 10218489
• 负责人: Tanya Kalin
• 金额: $ 53.95万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10218489
• 关键词: ACVRL1 gene; Alleles; Alveolar; Alveolar capillary dysplasia with misalignment of pulmonary veins; Applications Grants; Birth; Blood Circulation; Blood capillaries; Bronchopulmonary Dysplasia; Cell Lineage; Cell Proliferation; Cell Therapy; Cell Transplantation; Cells; Complementary DNA; Congenital Disorders; Congenital alveolar dysplasia; Cyanosis; Data; Development; Diaphragmatic Hernia; Diffuse; Disease; Donor person; Embryo; Endothelial Cells; Endothelium; Engraftment; Exhibits; FOXF1 gene; Gene Delivery; Genes; Genetic Transcription; Hemorrhage; Heterogeneity; Human; In Vitro; Infant; Inherited; Laboratories; Life; Link; LoxP-flanked allele; Lung; Lung Transplantation; Modeling; Mus; Mutation; Neonatal; Newborn Infant; PECAM1 gene; PTPRC gene; Pathologic; Pathway interactions; Patients; Prognosis; Protocols documentation; Publishing; Pulmonary Circulation; Pulmonary veins; Resistance; Respiratory Failure; Respiratory Insufficiency; Respiratory physiology; STAT3 gene; Signal Pathway; Signal Transduction; Stem cell transplant; TEK gene; Testing; Therapeutic; Transgenic Mice; Transplantation; Vascular Endothelial Growth Factors; angiogenesis; base; bone morphogenetic protein 9; c-myc Genes; clinically relevant; density; effective therapy; embryonic stem cell; endothelial stem cell; expression vector; gene delivery system; genomic locus; human embryonic stem cell; improved; in vivo; innovation; lung development; mortality; mouse model; nanoparticle; nanoparticle delivery; neonate; novel; novel therapeutic intervention; postnatal; preservation; prevent; pulmonary arterial hypertension; respiratory; self-renewal; single-cell RNA sequencing; transcription factor

PROJECT SUMMARY. Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV) is a fatal congenital disorder of neonates and infants which leads to respiratory insufficiency due to reduced numbers of alveolar capillaries and is associated with lung hypoplasia, hemorrhage, malposition of pulmonary veins and pulmonary arterial hypertension (PAH). ACDMPV is linked to mutations in the Forkhead Box F1 (FOXF1) gene and is resistant to all available therapies and respiratory support, causing cyanosis and respiratory failure in the first month after birth. In rare cases, ACDMPV patients survive several months or even years, but they require lung transplantation early in life. Given the lack of effective treatments for ACDMPV, there is an urgent need for innovative therapeutic approaches to stimulate pulmonary angiogenesis and preserve respiratory function in ACDMPV infants. In our preliminary data, we have generated a clinically relevant model of ACDMPV by introducing the S52F FOXF1 mutation (found in ACDMPV patients) into the endogenous mouse Foxf1 gene locus. Foxf1WT/S52F newborn mice exhibited alveolar capillary dysplasia, misalignment of pulmonary veins, PAH, and increased mortality, all key features of human ACDMPV. Endothelial proliferation and STAT3 signaling were decreased in Foxf1WT/S52F mice and human ACDMPV lungs. In the present grant application, we will test the hypothesis that increasing neonatal lung angiogenesis will decrease PAH, improve survival and prevent lung remodeling in mouse ACDMPV models. In Aim 1, we have developed a novel nanoparticle gene delivery system targeting >85% of pulmonary endothelial cells in vivo when delivered into the neonatal blood circulation. Nanoparticle delivery of STAT3 cDNA after birth induced endothelial proliferation and increased alveolar microvascular density in Foxf1WT/S52F neonatal lungs. We will use two mouse models of ACDMPV (Foxf1WT/S52F and Foxf1+/-) to test whether nanoparticle delivery of STAT3 or FOXF1 will decrease PAH, improve survival and prevent lung remodeling. We will also determine whether the FOXF1/STAT3/cMYC transcriptional cascade is required for neonatal lung angiogenesis. In Aim 2, we provided preliminary data demonstrating that a cell transplantation with pulmonary endothelial progenitor cells (EPCs) (FOXF1+cKit+CD31+CD45-) increases the capillary density in Foxf1WT/S52F lungs. We will investigate heterogeneity of pulmonary EPCs and test their therapeutic potential in mouse ACDMPV models. We will test if EPCs stimulate neonatal lung angiogenesis via the BMP-9/ACVRL1 signaling pathway. Finally, we will use a novel protocol for in vitro differentiation of EPCs from mouse and human embryonic stem cells (ES) and determine if a cell therapy with ES-derived EPCs will be beneficial in mouse ACDMPV models. Altogether, the proposed studies will directly test whether endothelial delivery of STAT3 or cell therapy with EPCs have therapeutic potential in ACDMPV.

项目总结。肺泡毛细血管发育不良伴肺静脉错位（ACDMPV）