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Nat Med. 2018 Oct;24(10):1513-1518. doi: 10.1038/s41591-018-0184-6. Epub 2018 Oct 8.

In utero CRISPR-mediated therapeutic editing of metabolic genes.

Author information

1
Division of Pediatric General, Thoracic, and Fetal Surgery, The Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
2
Department of Medicine, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
3
Department of Genetics, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
4
Department of Cell and Developmental Biology, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
5
Department of Medicine, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. kiranmusunuru@gmail.com.
6
Department of Genetics, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. kiranmusunuru@gmail.com.
7
Division of Pediatric General, Thoracic, and Fetal Surgery, The Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA. peranteauw@email.chop.edu.

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.

PMID:
30297903
PMCID:
PMC6249685
DOI:
10.1038/s41591-018-0184-6
[Indexed for MEDLINE]
Free PMC Article

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