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.
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The data that support the findings of this study are available within the paper and its supplementary information files. DNA sequencing data have been deposited on the NCBI Sequence Read Archive under accession SRP155635.
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This work was supported by grants T32-HL007843 (A.C.W.), R01-HL118744 and R01-HL126875 (K.M.) from the National Institutes of Health; grant UL1-TR001878 from the National Center for Advancing Translational Sciences of the National Institutes of Health and the Institute for Translational Medicine and Therapeutics at the University of Pennsylvania (W.H.P. and K.M.); grant GE-16-001-IU from the University of Pennsylvania Orphan Disease Center (W.H.P.); the Winkelman Family Fund in Cardiovascular Innovation (K.M.); the Burroughs Wellcome Fund Career Award for Medical Scientists (R.J.); and generous family gifts to the Children’s Hospital of Philadelphia (CHOP) (W.H.P.). We thank A. Weilerstein and L. Ma for their help with animal care, the Translational Core Laboratory at CHOP for assistance with liver function tests, and A. Radu, the Pathology Core at CHOP and the Histology Core at the Cardiovascular Institute at the University of Pennsylvania for their assistance with histology.
The authors declare no competing interests.
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Rossidis, A.C., Stratigis, J.D., Chadwick, A.C. et al. In utero CRISPR-mediated therapeutic editing of metabolic genes. Nat Med 24, 1513–1518 (2018). https://doi.org/10.1038/s41591-018-0184-6
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