One step forward in the possibility of applying CRISPR in utero to correct diseases

The CRISPR gene editing tool has been applied in utero in mice to correct a mutation that causes a lethal lung disease in mice. These experiments, published recently in Science Translational Medicine, are a new proof of concept of the possibility of applying CRISPR in utero to correct diseases in the fetal state that may be very serious, and even lethal, after birth.

The lethal human desease object of the experiment

In this study, the authors used a mouse model of a human mutation in the SFTPC gene, which causes a surfactant deficiency. The surfactant is a lipoprotein mixture that is essential for normal lung function. Thus, babies born with surfactant deficiency due to this or another mutation suffer rapid death due to respiratory failure. For this reason, in this and other diseases that cause perinatal death, any effective intervention should be applied before delivery. Gene editing in utero also provides the opportunity to take advantage of the developmental properties of the fetus, such as its small size and immunologic immaturity, to achieve efficient gene editing; this prevents an immune response to the Cas9 protein of the CRISPR system or to the viral transfer vector of the gene editing system. Furthermore, the target cell population may be more accessible in the fetus. In the postnatal lung, immunological and physical barriers limit access to the pulmonary epithelial cells, but these barriers are not yet established during fetal development.

The researchers in this study showed that correcting the genetic defect before birth improved lung development and survival in the treated animals, which are highly promising outcomes. Nevertheless, as the study authors acknowledge, this research still has certain limitations that must be overcome before the procedure can be considered safe for use in humans. Thus, intra-amniotic injection of the gene editing system caused death of the fetuses in numerous cases. Although the authors attribute this mortality to the small size of the mice, they conclude that “the safety and efficacy of in utero gene editing in humans remain unknown, highlighting the importance of continued studies in small and large animal models”. Additionally, adenovirus vectors were used, which can induce dangerous immune responses, so the researchers consider the advisability of using another type of vector in the future. They also consider it necessary to collect data on the development of large groups of mice in the long term, to achieve statistically significant results. Finally, they highlight the possibility that the gene editing system also acts on the mother, modifying genes that are fine and possibly inducing a dangerous immune response.