Authors: Kiran Musunuru, M.D., Ph.D. https://orcid.org/0000-0003-3298-0368, Sarah A. Grandinette, B.S., Xiao Wang, Ph.D., Taylor R. Hudson, M.S., Kevin Briseno, B.S., Anne Marie Berry, M.S., Julia L. Hacker, M.S., +37 , Alvin Hsu, B.S., Rachel A. Silverstein, B.S., Logan T. Hille, Ph.D., Aysel N. Ogul, Nancy A. Robinson-Garvin, Ph.D., Juliana C. Small, Ph.D., Sarah McCague, M.S., Samantha M. Burke, B.S.N., Christina M. Wright, M.D., Ph.D., Sarah Bick, M.D., Venkata Indurthi, Ph.D., Shweta Sharma, M.S., Michael Jepperson, M.S., Christopher A. Vakulskas, Ph.D. https://orcid.org/0000-0001-8510-4332, Michael Collingwood, B.S., Katie Keogh, Ph.D., Ashley Jacobi, B.S., Morgan Sturgeon, Ph.D., Christian Brommel, M.S., Ellen Schmaljohn, Ph.D., Gavin Kurgan, Ph.D., Thomas Osborne, B.S., He Zhang, Ph.D., Kyle Kinney, Ph.D. https://orcid.org/0000-0002-1029-3279, Garrett Rettig, Ph.D., Christopher J. Barbosa, Ph.D., Sean C. Semple, Ph.D., Ying K. Tam, Ph.D., Cathleen Lutz, Ph.D., Lindsey A. George, M.D., Benjamin P. Kleinstiver, Ph.D., David R. Liu, Ph.D., Kim Ng, M.D., Sadik H. Kassim, Ph.D., Petros Giannikopoulos, M.D., Mohamad-Gabriel Alameh, Ph.D., Fyodor D. Urnov, Ph.D. https://orcid.org/0000-0001-7542-4084, and Rebecca C. Ahrens-Nicklas, M.D., Ph.D.
Published May 15, 2025
N Engl J Med 2025;392:2235-2243
DOI: 10.1056/NEJMoa2504747
Summary
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.)
Notes
This article was published on May 15, 2025, at NEJM.org.
Supported by grants from the National Institutes of Health (U01TR005355 and U19NS132301, to Drs. Musunuru and Ahrens-Nicklas; R35HL145203, to Dr. Musunuru; U19NS132303, to Dr. Urnov; and DP2CA281401 and P01HL142494, to Dr. Kleinstiver). In-kind contributions were made by Acuitas Therapeutics, Integrated DNA Technologies, Aldevron, and Danaher. Additional funding was provided by the Children’s Hospital of Philadelphia Research Institute’s Gene Therapy for Inherited Metabolic Disorders Frontier Program.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank the patient and his family for their participation in this study; all the persons involved in the rapid manufacturing and evaluation of k-abe, including Kamila Wlodarczyk, Nicholas Tougas, Robert Leone, and Jon Le Huray (at Acuitas Therapeutics), Mark Wetzel, Lane Womack, Tao Lu, Matt Sliva, A.J. Muehlberg, Megan Wohl, Jenna Sjoerdsma, Bezhin Mesho, Jacob Scherb, Helen Velishek, and Jon Cooper (at Aldevron), and the teams at Integrated DNA Technologies, AmplifyBio, BioAgilytix, and the Penn Vet Transgenic Mouse Core; the members of the Division of Human Genetics, the Section of Biochemical Genetics, the Department of Clinical Nutrition, and the Department of Nursing at the Children’s Hospital of Philadelphia (CHOP) for providing clinical care for the patient; the members of the Multidisciplinary Clinical Oversight Committee and the CHOP Gene Team for providing oversight of the study; the staff at the CHOP Research Institute, including Daniel Colbert, Anne Titterton, Amy Murry, Zev Sunleaf, Emily Blecker, and Weilong Li, for facilitating the timely implementation of the study; Jennifer Doudna and Brad Ringeisen at the Innovative Genomics Institute for their support during the course of this work, as well as the staff of the Innovative Genomics Institute Next Generation Sequencing Core; Anne Cappola for feedback during the writing of the manuscript; the reviewers at the Center for Biologics Evaluation and Research of the Food and Drug Administration for their expeditious review of the Investigational New Drug application; and the Somatic Cell Genome Editing Consortium of the National Institutes of Health, especially P.J. Brooks and Tim LaVaute for their vision and support of this endeavor.