In utero CRISPR-mediated therapeutic editing of metabolic genes

Avery C Rossidis, John D Stratigis, Alexandra C Chadwick, Heather A Hartman, Nicholas J Ahn, Haiying Li, Kshitiz Singh, Barbara E Coons, Li Li, Wenjian Lv, Philip W Zoltick, Deepthi Alapati, William Zacharias, Rajan Jain, Edward E Morrisey, Kiran Musunuru, William H Peranteau

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

In utero gene editing has the potential to prenatally treat genetic diseases that result in significant morbidity and mortality before or shortly after birth. We assessed the viral vector-mediated delivery of CRISPR-Cas9 or base editor 3 in utero, seeking therapeutic modification of Pcsk9 or Hpd in wild-type mice or the murine model of hereditary tyrosinemia type 1, respectively. We observed long-term postnatal persistence of edited cells in both models, with reduction of plasma PCSK9 and cholesterol levels following in utero Pcsk9 targeting and rescue of the lethal phenotype of hereditary tyrosinemia type 1 following in utero Hpd targeting. The results of this proof-of-concept work demonstrate the possibility of efficiently performing gene editing before birth, pointing to a potential new therapeutic approach for selected congenital genetic disorders.

Original languageEnglish
Pages (from-to)1513-1518
Number of pages6
JournalNature Medicine
Volume24
Issue number10
DOIs
Publication statusPublished - Oct 2018

Keywords

  • Animals
  • CRISPR-Cas Systems/genetics
  • Disease Models, Animal
  • Gene Editing
  • Genetic Therapy
  • Genetic Vectors/genetics
  • Humans
  • Oxidoreductases/genetics
  • Proprotein Convertase 9/genetics
  • Tyrosinemias/genetics

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