Paper of the month May 2019

In utero gene editing for monogenic lung disease

CRISPR represents a powerful tool to deliver gene editing at precise location. This technology holds promising medical applications for medical conditions such as correction of monogenic disorders. In this paper, the researchers wanted to prove the ability to correct a monogenic lung disease characterised by a mutation in the SFTPC gene which is sources of morbidity and mortality in children due to respiratory failure or chronic diffuse lung disease. A mouse model carrying the human SFTPC I73T mutation is used in this paper and CRISPR/Cas9 gene editing reagents are delivered in a pregnant mouse via in utero intra-amniotic injection to target the lungs of the foetus, the closest setting to human.  In the first experiment-as proof of concept -  they take advantage of a mouse model whose ACTB gene promoter – a prenatal lung gene – controls the expression of two different reporter genes that can be discriminated as Red or Green Fluorescence. Based on this double colours system they are able to establish the best conditions for the next experiments on the therapeutic relevant target. Once that the best conditions were established they decide to test which of the different cell types that constitute the lung epithelium like epithelial, endothelial, and mesenchymal cells were edited with the highest efficiency. It was observed  that the epithelial cells – rather than the endothelial or mesenchymal  - were the cell type with the highest degree of gene editing, up to 18%.  Then it was important to assess the persistence of the gene editing and they could verify that the genetic modification was stable up to 6 months postnatal. Once that they could set the best conditions for the editing and verify the persistence of the treatment, the scientists turned to the SFTPC I73T mutation, known to be one of the most common mutation in human prenatal lung disease. By using a mouse model carrying this specific mutation they delivered in utero via intra amniotic injection the CRISPR machinery and by targeting the SFTPC I73T they could observe an improved histology of the lung tissues and most importantly they could prove an increased survival of the young newborn mice after the treatment.

Overall in this paper they scientist could show that CRISPR can be used to perform gene editing in tissue undergoing development by in utero intra-amniotic delivery to rescue a perinatal lethal monogenic lung disease. This study also poses a new alternative to the highly debated germ line editing. In fact, with this approach is possible to address a spectrum of disease lethal at birth but contrary to a germ line editing, it is possible to specifically target only the cell type of interest rather than the whole zygote or early-stage embryo thereby lowering or override the risk that the applied gene editing may be passed on to the off-spring of the patient underwent gene editing. Such approach may be more amenable for such treatments and rise less ethical concerns compared to germ line editing.