In utero gene editing for monogenic lung disease

Deepthi Alapati, William J Zacharias, Heather A Hartman, Avery C Rossidis, John D Stratigis, Nicholas J Ahn, Barbara Coons, Su Zhou, Hiaying Li, Kshitiz Singh, Jeremy Katzen, Yaniv Tomer, Alexandra C Chadwick, Kiran Musunuru, Michael F Beers, Edward E Morrisey, William H Peranteau

Research output: Contribution to journalArticle

47 Citations (Scopus)

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.

Original languageEnglish
Article numbereaav8375
Number of pages14
JournalScience Translational Medicine
Volume11
Issue number488
DOIs
Publication statusPublished - 17 Apr 2019

Bibliographical note

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Keywords

  • Animals
  • CRISPR-Cas Systems/genetics
  • Disease Models, Animal
  • Epithelial Cells/metabolism
  • Gene Editing/methods
  • Humans
  • Lung Diseases/genetics
  • Mice
  • Mutation/genetics
  • Pulmonary Surfactant-Associated Protein C/genetics

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