Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease
Kiran Musunuru, Sarah Grandinette, Xiao Wang, Taylor R. Hudson, Kevin Briseno, Anne Marie Berry, Julia Hacker, Alvin Hsu, Rachel A. Silverstein, Logan T. Hille, Aysel N. Ogul, Nancy A. Robinson-Garvin, Juliana C. Small, Sarah McCague, Samantha Burke, Christina M. Wright, Sarah K. Bick, Venkata S.K. Indurthi, Shweta Sharma, Michael Jepperson, Christopher A. Vakulskas, Michael A. Collingwood, Kate Keogh, Ashley M. Jacobi, Morgan Sturgeon, Christian M. Brommel, Ellen Schmaljohn, Gavin Kurgan, Thomas F. Osborne, He Zhang, Kyle J. Kinney, Garrett R. Rettig, Christopher Barbosa, Sean C. Semple, Ying K. Tam, Cathleen Lutz, Lindsey A. George, Benjamin P. Kleinstiver, David R. Liu, Kim T. Ng, Sadik H. Kassim, Petros Giannikopoulos, Mohamad‐Gabriel Alameh, Fyodor D. Urnov, Rebecca C. Ahrens‐Nicklas
Abstract
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.).