哈佛大学David R. Liu团队近日取得一项新成果。经过不懈努力，他们的研究开发出了体内启动编辑可挽救小鼠儿童期交替性偏瘫。2025年7月21日出版的《细胞》杂志发表了这项成果。

研究小组提出了引体编辑（PE）和碱基编辑（BE）策略来纠正人类细胞和两种AHC motif模型中的ATP1A3和ATP1A3突变。该研究组以PE和BE为主题，以43%-90%的效率纠正5种流行的ATP1A3突变。AAV9介导的体内PE在两种AHC小鼠模型的中枢神经系统中纠正Atp1a3 D801N和E815K，在大块脑皮层中产生高达48%的DNA纠正和73%的mRNA纠正。体内PE挽救了临床相关表型，包括ATP酶活性的恢复；改善阵发性发作、运动缺陷和认知缺陷；以及动物寿命的大幅延长。这项工作提示了一种潜在的一次性PE治疗AHC，并建立了PE在动物中拯救神经系统疾病的能力。

据悉，儿童交替性偏瘫（AHC）是一种没有改善疾病治疗的神经发育障碍。编码Na⁺/K⁺ ATP酶亚基的ATP1A3突变占AHC病例的70%。

附：英文原文

Title: In vivo prime editing rescues alternating hemiplegia of childhood in mice

Author: Alexander A. Sousa, Markus Terrey, Holt A. Sakai, Christine Q. Simmons, Elena Arystarkhova, Natalia S. Morsci, Laura C. Anderson, Jun Xie, Fabian Suri-Payer, Linda C. Laux, Emmanuel Roze, Sylvie Forlani, Guangping Gao, Simon Frost, Nina Frost, Kathleen J. Sweadner, Alfred L. George, Cathleen M. Lutz, David R. Liu

Issue&Volume: 2025-07-21

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.

DOI: 10.1016/j.cell.2025.06.038

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00740-8