子宫内胎儿遗传疾病,CRISPR技术 z-bo 2020-10-26 351

　　A research team at the Children's Hospital of Philadelphia (CHOP) and the Pennsylvania School of Medicine used CRISPR gene editing technology to successfully prevent a deadly lung disease in an animal model. In this animal model, a harmful mutation can cause the larvae to die within a few hours after birth. Related research results were published in Science Translational Medicine recently. This proof-of-concept study suggests that in-utero editing may be a kind of A promising new treatment method for treating lung diseases before birth.

　　The developing fetus has many innate attributes, which makes it an attractive recipient of therapeutic gene editing," said Dr. William H. Peranteau, co-leader of the study, a researcher at the CHOP Fetal Research Center and also a CHOP researcher. Pediatrics and fetal surgeons at the Fetal Diagnosis and Treatment Center. "In addition, the ability of gene editing to cure or alleviate disease in the middle and late stages of pregnancy (ie before birth) and during irreversible pathology is very exciting. This is especially true for diseases that affect the lungs, because lung function is very important at birth. "

　　The lung congenital diseases that the research team hopes to solve include surfactant protein deficiency, cystic fibrosis, and α-1 antitrypsin. These diseases are characterized by respiratory failure or chronic lung disease at birth. There are few treatment options. Approximately 22% of pediatric hospitalizations are caused by respiratory diseases. Although scientists have made some progress in treatment and have a better understanding of their molecular causes, congenital respiratory diseases are often fatal. Since the lung is a barrier organ in direct contact with the external environment, targeted delivery of drugs to correct defective genes is an attractive treatment method.

　　Dr. Edward E. Morrisey, Professor of Cardiovascular Medicine at the Perelman School of Medicine at the University of Pennsylvania and co-leader of the study, said: "We want to know whether this method is feasible. The key is how to guide the gene editor to target the air in the lungs. Cells in the tract.” The researchers found that accurate injection of the CRISPR gene editor into the amniotic fluid during fetal development can cause targeted changes in the lungs of mice. They introduced the gene editor into the mouse 4 days before the mouse was born, which is similar to the human third trimester. The results of the study found that the cells with the highest editing rate were alveolar epithelial cells and airway secretory cells arranged in the lung airways.

　　In 2018, a research team led by Morrisey discovered the alveolar epithelial progenitor cell (AEP) lineage, which is embedded in a larger alveolar type 2 cell population. These cells produce lung surfactants, which can reduce the surface tension of the lungs and prevent them from collapsing with each breath. AEPs are a stable cell type in the lungs, which replicate rapidly after injury, regenerate the inner wall of the alveoli, and restore the lung's gas exchange capacity.

　　In the second experiment, the researchers used prenatal gene editing technology to reduce the severity of pulmonary interstitial disease-surfactant protein C (SFTPC) deficiency in a mouse model. Untreated mice with this mutation all died of respiratory failure within a few hours after birth. In contrast, prenatal gene editing inactivates the mutant Sftpc gene, which can improve lung morphology and survival in more than 22% of animals. Future research will focus on improving the efficiency of gene editing in lung epithelial tissue and evaluating different mechanisms for delivering gene editing technology to the lung.

　　Morrisey said: "People are still exploring different gene editing technologies, and maybe we can one day correct the exact mutations observed in infants with inherited lung diseases." Morrisey is currently collaborating with a research team led by Peranteau Kiran Musunuru, MD. The study demonstrated the possibility of saving a fatal metabolic liver disease by in-utero gene editing in a mouse model. This is the first time that CRISPR-mediated gene editing in utero has prevented a fatal animal metabolic disorder.

　　Similar to the study, Peranteau said: "The current study is a proof-of-concept study that highlights the exciting future prospects of prenatal treatment, including the use of gene editing and alternative gene therapy to treat congenital diseases."