Document Type
Article
Publication Date
8-7-2025
Original Citation
Sousa A,
Terrey M,
Sakai H,
Simmons C,
Arystarkhova E,
Morsci N,
Anderson LC,
Xie J,
Suri-Payer F,
Laux L,
Roze E,
Forlani S,
Gao G,
Frost S,
Frost N,
Sweadner K,
George A,
Lutz C,
Liu D.
In vivo prime editing rescues alternating hemiplegia of childhood in mice. Cell. 2025;188(16):4275-94 e23.
Keywords
JMG, SS1, Animals, Sodium-Potassium-Exchanging ATPase, Hemiplegia, Humans, Mice, Gene Editing, Disease Models, Animal, Mutation, Male, CRISPR-Cas Systems, Female, Genetic Therapy, Mice, Inbred C57BL, HEK293 Cells, Brain
JAX Source
Cell. 2025;188(16):4275-94 e23.
ISSN
1097-4172
PMID
40695277
DOI
https://doi.org/10.1016/j.cell.2025.06.038
Grant
C.M.L. discloses support for this study from NIH U54 OD030187 (The Center for Precision Genetics at the Jackson Laboratory), NIH U42 OD010921 (The Mouse Mutant Resource and Research Center), and the Chan-Zuckerberg Initiative 2022-316747 and 2024-347822. M.T. and C.M.L. disclose support for this study from the Davis Family Foundation.
Abstract
Alternating hemiplegia of childhood (AHC) is a neurodevelopmental disorder with no disease-modifying treatment. Mutations in ATP1A3, encoding an Na+/K+ ATPase subunit, cause 70% of AHC cases. Here, we present prime editing (PE) and base editing (BE) strategies to correct ATP1A3 and Atp1a3 mutations in human cells and in two AHC mouse models. We used PE and BE to correct five prevalent ATP1A3 mutations with 43%–90% efficiency. AAV9-mediated in vivo PE corrects Atp1a3 D801N and E815K in the CNS of two AHC mouse models, yielding up to 48% DNA correction and 73% mRNA correction in bulk brain cortex. In vivo PE rescued clinically relevant phenotypes, including restoration of ATPase activity; amelioration of paroxysmal spells, motor defects, and cognition deficits; and dramatic extension of animal lifespan. This work suggests a potential one-time PE treatment for AHC and establishes the ability of PE to rescue a neurological disease in animals.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.