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Sci Transl Med. 2019 Apr 17;11(488). pii: eaav8375. doi: 10.1126/scitranslmed.aav8375.

In utero gene editing for monogenic lung disease.

Author information

1
Department of Pediatrics Nemours, Alfred I duPont Hospital for Children, Wilmington, DE 19803, USA.
2
Department of Pediatrics Sidney Kimmel Medical College, Thomas Jefferson University Philadelphia, Philadelphia, PA 19107, USA.
3
Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
4
Penn Center for Pulmonary Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Penn Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania Philadelphia, Philadelphia, PA 19104, USA.
6
Division of Pulmonary Biology Cincinnati Children's Hospital, Department of Pediatrics University of Cincinnati College of Medicine, Cincinnati, OH 45529, USA.
7
Center for Fetal Research, Division of General, Thoracic, and Fetal Surgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
8
Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. emorrise@pennmedicine.upenn.edu peranteauw@email.chop.edu.
9
Center for Fetal Research, Division of General, Thoracic, and Fetal Surgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. emorrise@pennmedicine.upenn.edu peranteauw@email.chop.edu.

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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