Research ArticleGENE EDITING

In utero gene editing for monogenic lung disease

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Science Translational Medicine  17 Apr 2019:
Vol. 11, Issue 488, eaav8375
DOI: 10.1126/scitranslmed.aav8375

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Editing out a lethal lung disease

Surfactant, a lipoprotein mixture that reduces lung surface tension, is essential for normal lung function. In rare cases, infants are born with genetic surfactant deficiency, resulting in rapid death from respiratory failure. Because of the immediate perinatal fatality associated with this disease, any effective intervention would need to be applied before delivery. Alapati et al. used a mouse model of genetic surfactant deficiency to demonstrate the feasibility of in utero gene editing to delete the mutant allele. The authors showed that correction of the genetic defect before birth improved lung development and survival in the treated animals, demonstrating the feasibility of this therapeutic intervention.

Abstract

Monogenic lung diseases that are caused by mutations in surfactant genes of the pulmonary epithelium are marked by perinatal lethal respiratory failure or chronic diffuse parenchymal lung disease with few therapeutic options. Using a CRISPR fluorescent reporter system, we demonstrate that precisely timed in utero intra-amniotic delivery of CRISPR-Cas9 gene editing reagents during fetal development results in targeted and specific gene editing in fetal lungs. Pulmonary epithelial cells are predominantly targeted in this approach, with alveolar type 1, alveolar type 2, and airway secretory cells exhibiting high and persistent gene editing. We then used this in utero technique to evaluate a therapeutic approach to reduce the severity of the lethal interstitial lung disease observed in a mouse model of the human SFTPCI73T mutation. Embryonic expression of SftpcI73T alleles is characterized by severe diffuse parenchymal lung damage and rapid demise of mutant mice at birth. After in utero CRISPR-Cas9–mediated inactivation of the mutant SftpcI73T gene, fetuses and postnatal mice showed improved lung morphology and increased survival. These proof-of-concept studies demonstrate that in utero gene editing is a promising approach for treatment and rescue of monogenic lung diseases that are lethal at birth.

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