In utero CRISPR-mediated therapeutic editing of metabolic genes

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 clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated 9 (CRISPR-Cas9) or base editor 3 (BE3) in utero, seeking therapeutic modification of Pcsk9 or Hpd in wild-type mice or the murine model of hereditary tyrosinemia type 1 (HT1), 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 HT1 following in utero Hpd targeting. The results of this proof-of-concept work demonstrate the possibility to efficiently perform gene editing before birth, pointing to a potential new therapeutic approach for select congenital genetic disorders.