Certain inherited diseases, including those that affect the lungs, can lead to death at or shortly after birth. And if we could use CRISPR to remove dysfunctional genes before the birth of a baby? A team of scientists from the Philadelphia Children's Hospital (CHOP) and the University of Pennsylvania School of Medicine have completed this task, providing proof of the concept of the use of editing. genetics to treat congenital lung disorders.
In their experiments, the researchers targeted hereditary surfactant protein syndromes, a family of lung diseases in which a single unwanted gene is responsible for each case. These monogenic disorders are marked by the failure of surfactant, a lung protein that lowers surface tension in the lungs and prevents them from collapsing.
By delivering the CRISPR gene editing system to developing mouse fetuses, the team inactivated the mutation responsible for surfactant protein C deficiency (SFTPC), and over 22% of the animals survived. , according to a new study published in the journal Science Translational Medicine.
"By targeting the lung, this study has a thorough analysis to determine what types of cells in the lung are changed, if any," said William Peranteau, MD, pediatric and fetal surgeon at CHOP, of an email interview with FierceBiotechResearch. "In this analysis, we found that the predominant modified cell type was the pulmonary epithelial cell. This was encouraging because it is the type of cell involved in surfactant protein deficiency and in other congenital genetic lung diseases. "
Peranteau previously co-directed a Nature Medicine study using CRISPR-Cas9 and basic editing tools to treat fetuses from mice with lethal genetic liver disease. For this study, the team showed that in utero administration of CRISPR reagents in the amniotic fluid – rather than intravenous injection, as had been done in the hepatic experience – could effectively and efficiently alter accurately the pulmonary epithelial cells that cover the airways. Mutations in SFTPC may cause respiratory failure in neonates or idiopathic pulmonary fibrosis later in life.
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Using CRISPR to edit genes before birth is an idea that has generated much controversy recently, since a Chinese scientist, He Jiankui, applied this technology to human embryos to produce the first genetically modified babies in the world. But Peranteau told FierceBiotechResearch that the editing of early embryos is different from that of the fetus in mid-pregnancy or late gestation. When his colleagues and he analyzed the animals' ovaries and sperm, they did not find evidence of the possibility of a germ line editing, he said. "[T]he argues that publishing will not be passed on to subsequent generations, unlike early editing of embryos where this is more likely to happen, "he said.
Another major difference lies in the fact that the fetal edition takes place in the uterus, while the embryo approach is to perform ex vivo modifications followed by implantation. However, Peranteau recognizes the potential risk of affecting the mother during a fetal intervention. "Thus, injection techniques and delivery vectors for gene editing will need to be optimized to avoid any exposure to the mother," the authors wrote.
The ability to cure or alleviate disease before birth, particularly in the case of lung diseases that severely affect survival, is indeed promising. But Peranteau pointed out that the results on the liver and lungs in mice provided nothing more than a proof of concept. Further studies will need to be conducted on large and small animal models, he said, and the team will need to test different approaches to CRISPR implementation before the technique can be translated into trials. on the man.