In utero CRISPR-mediated therapeutic editing of metabolic genes
Open accessAbstract
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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In utero gene editing has rescued the lethal phenotype of hereditary tyrosinemia type 1, improved the pulmonary phenotype of surfactant protein C deficiency, and ameliorated metabolic, musculoskeletal, and cardiac disease in mucopolysaccharidosis type I (MPS-IH, Hurler syndrome) in mouse models.
“Previously, we demonstrated the therapeutic potential of in utero gene editing in mouse models of human diseases, rescuing the lethal phenotype of hereditary tyrosinemia type 1, improving the pulmonary phenotype of surfactant protein C deficiency, and ameliorating metabolic, musculoskeletal, and cardiac disease in mucopolysaccharidosis type I (MPS-IH, Hurler syndrome) (7–9).”
From Ionizable Lipid Nanoparticles for Therapeutic Base Editing of Congenital Brain Disease (2023) · cites this paper as [7]
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Experimental — accuracy not yet measuredCNS targeting via prior viral vector approaches was not efficient.
“Although encouraging, CNS targeting via these approaches was not efficient, highlighting the need to evaluate alternative delivery approaches to treat genetic CNS diseases.”
From Ionizable Lipid Nanoparticles for Therapeutic Base Editing of Congenital Brain Disease (2023) · cites this paper as [7]
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In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates
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Self-citation
- Authors
- Rossidis, A. C., Stratigis, J. D., Chadwick, A. C., Hartman, H. A., Ahn, N. J., Li, H., Singh, K., Coons, B. E., Li, L., Lv, W., Zoltick, P. W., Alapati, D., Zacharias, W., Jain, R., Morrisey, E. E., Musunuru, K., & Peranteau, W. H.
- Affiliations
- Children's Hospital of Philadelphia (US)
- University of Pennsylvania (US)
- Corresponding author
- Musunuru, Kiran
- Peranteau, William H.
- ORCID
- Venue
- Nature Medicine
- Published
- 2018-10
- Volume
- 24
- Issue
- 10
- Pages
- 1513-1518
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6249685
- OpenAlex
- W2895334061
- Cited by
- 216
- References
- 7
- Citations by year
- 2026: 16 · 2025: 18 · 2024: 14 · 2023: 30 · 2022: 24 · 2021: 37 · 2020: 31 · 2019: 36 · 2018: 10
- FWCI
- 9.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR001878)
- National Heart, Lung, and Blood Institute (R01HL126875, R01HL118744, T32HL007843)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- CRISPR/Cas9, base editing, PCSK9, HPD, tyrosinemia type I, viral gene delivery, fetal therapy, cholesterol levels
- MeSH terms
- Proprotein Convertase 9, Gene Editing, Animals, Disease Models, Animal, Genetic Vectors, Humans, Oxidoreductases, Genetic Therapy, Tyrosinemias, CRISPR-Cas Systems
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