In utero CRISPR-mediated therapeutic editing of metabolic genes.

Autor: Rossidis AC; Division of Pediatric General, Thoracic, and Fetal Surgery, The Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Stratigis JD; Division of Pediatric General, Thoracic, and Fetal Surgery, The Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Chadwick AC; Department of Medicine, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; Department of Genetics, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Hartman HA; Division of Pediatric General, Thoracic, and Fetal Surgery, The Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Ahn NJ; Division of Pediatric General, Thoracic, and Fetal Surgery, The Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Li H; Division of Pediatric General, Thoracic, and Fetal Surgery, The Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Singh K; Division of Pediatric General, Thoracic, and Fetal Surgery, The Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Coons BE; Division of Pediatric General, Thoracic, and Fetal Surgery, The Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Li L; Department of Medicine, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; Department of Genetics, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Lv W; Department of Medicine, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; Department of Genetics, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Zoltick PW; Division of Pediatric General, Thoracic, and Fetal Surgery, The Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Alapati D; Department of Medicine, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; Department of Cell and Developmental Biology, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Zacharias W; Department of Medicine, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; Department of Cell and Developmental Biology, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Jain R; Department of Medicine, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; Department of Cell and Developmental Biology, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Morrisey EE; Department of Medicine, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; Department of Cell and Developmental Biology, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Musunuru K; Department of Medicine, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. kiranmusunuru@gmail.com.; Department of Genetics, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. kiranmusunuru@gmail.com., Peranteau WH; 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.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2018 Oct; Vol. 24 (10), pp. 1513-1518. Date of Electronic Publication: 2018 Oct 08.
DOI: 10.1038/s41591-018-0184-6
Abstrakt: 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.
Databáze: MEDLINE
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