Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease
Base editors can correct disease-causing genetic variants. After a neonate had received a diagnosis of severe carbamoyl-phosphate synthetase 1 deficiency, a disease with an estimated 50% mortality in early infancy, we immediately began to develop a customized lipid nanoparticle-delivered base-editing therapy. After regulatory approval had been obtained for the therapy, the patient received two infusions at approximately 7 and 8 months of age. In the 7 weeks after the initial infusion, the patient was able to receive an increased amount of dietary protein and a reduced dose of a nitrogen-scavenger medication to half the starting dose, without unacceptable adverse events and despite viral illnesses. No serious adverse events occurred. Longer follow-up is warranted to assess safety and efficacy. (Funded by the National Institutes of Health and others.).
Authors
- Michael A. Collingwood (ORCID: https://orcid.org/0000-0002-8849-4038)
- Morgan Sturgeon (ORCID: https://orcid.org/0000-0003-4814-1446)
- Shweta Sharma (ORCID: https://orcid.org/0000-0001-9784-8902)
- Logan T. Hille (ORCID: https://orcid.org/0000-0001-7515-124X)
- Taylor R. Hudson
- Venkata S.K. Indurthi
- Kate Keogh (ORCID: https://orcid.org/0000-0001-8338-5177)
- Christina M. Wright (ORCID: https://orcid.org/0000-0002-7004-3829)
- Samantha Burke (ORCID: https://orcid.org/0000-0001-6902-974X)
- Garrett R. Rettig (ORCID: https://orcid.org/0000-0003-4634-5787)
- Christian M. Brommel
- Thomas F. Osborne (ORCID: https://orcid.org/0000-0002-8896-2487)
- Julia Hacker (ORCID: https://orcid.org/0000-0001-5216-5016)
- Petros Giannikopoulos (ORCID: https://orcid.org/0000-0003-4342-1756)
- Fyodor D. Urnov (ORCID: https://orcid.org/0000-0001-7542-4084)
- Ashley M. Jacobi (ORCID: https://orcid.org/0000-0002-9364-6518)
- Ali Oğul (ORCID: https://orcid.org/0000-0003-4886-7060)
- Christopher A. Vakulskas (ORCID: https://orcid.org/0000-0001-8510-4332)
- Sean C. Semple
- Kiran Musunuru (ORCID: https://orcid.org/0000-0003-3298-0368)
- Sarah McCague
- Gavin Kurgan (ORCID: https://orcid.org/0000-0002-4047-1427)
- Cathleen Lutz
- Juliana C. Small (ORCID: https://orcid.org/0000-0003-2076-4190)
- Lindsey A. George (ORCID: https://orcid.org/0000-0002-9763-1559)
- Rachel A. Silverstein (ORCID: https://orcid.org/0000-0001-5724-2252)
- Benjamin P. Kleinstiver (ORCID: https://orcid.org/0000-0002-5469-0655)
- Sadik H. Kassim
- Anne Marie Berry
- Kyle J. Kinney (ORCID: https://orcid.org/0000-0002-1029-3279)
- Ying K. Tam (ORCID: https://orcid.org/0000-0002-4083-5251)
- David R. Liu (ORCID: https://orcid.org/0000-0002-9943-7557)
- Alvin Hsu (ORCID: https://orcid.org/0000-0003-4034-2788)
- Mohamad‐Gabriel Alameh (ORCID: https://orcid.org/0000-0002-5672-6930)
- Kevin Briseno
- Sarah K. Bick (ORCID: https://orcid.org/0000-0003-0753-1720)
- Rebecca C. Ahrens‐Nicklas (ORCID: https://orcid.org/0000-0001-8243-7123)
- Christopher Barbosa
- Ellen Schmaljohn
- Xiao Wang (ORCID: https://orcid.org/0000-0002-5893-5162)
- He Zhang (ORCID: https://orcid.org/0009-0002-1575-1782)
- Kim T. Ng
- Sarah Grandinette
- Nancy A. Robinson-Garvin
- Michael Jepperson
Institutions
- Broad Institute (US)
- Children's Hospital of Philadelphia (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- University of California, San Francisco (US)
- Danaher (United States) (US)
- Massachusetts General Hospital (US)
- Innovative Genomics Institute (US)
- Jackson Laboratory (US)
- Aldevron (United States) (US)
- Acuitas Therapeutics (Canada) (CA)
- Integrated DNA Technologies (United States) (US)
- University of Pennsylvania (US)
- University of California, Berkeley (US)
Publication Details
- Journal
- New England Journal of Medicine
- Published
- 2025-05-15
- DOI
- https://doi.org/10.1056/nejmoa2504747
- Citations
- 211
- Primary Topic
- CRISPR and Genetic Engineering
- Type
- article
- Field-Weighted Citation Impact
- 170.07
Funders
- Children's Hospital of Philadelphia
- National Heart, Lung, and Blood Institute
- NIH Office of the Director
- National Institute of Neurological Disorders and Stroke
- National Center for Advancing Translational Sciences