Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Boston, MA 02115, USA.
Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Science. 2023 Apr 21;380(6642):eadg6518. doi: 10.1126/science.adg6518. Epub 2023 Apr 14.
Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, arises from survival motor neuron (SMN) protein insufficiency resulting from loss. Approved therapies circumvent endogenous SMN regulation and require repeated dosing or may wane. We describe genome editing of , an insufficient copy of harboring a C6>T mutation, to permanently restore SMN protein levels and rescue SMA phenotypes. We used nucleases or base editors to modify five regulatory regions. Base editing converted T6>C, restoring SMN protein levels to wild type. Adeno-associated virus serotype 9-mediated base editor delivery in Δ7SMA mice yielded 87% average T6>C conversion, improved motor function, and extended average life span, which was enhanced by one-time base editor and nusinersen coadministration (111 versus 17 days untreated). These findings demonstrate the potential of a one-time base editing treatment for SMA.
脊髓性肌萎缩症（SMA）是导致婴儿死亡的主要遗传原因，由运动神经元存活（SMN）蛋白不足引起，这是由于缺失所致。已批准的治疗方法规避了内源性 SMN 调节，需要重复给药或可能减弱。我们描述了对 进行基因组编辑，该基因是一个携带 C6>T 突变的 拷贝不足，以永久恢复 SMN 蛋白水平并挽救 SMA 表型。我们使用核酸酶或碱基编辑器来修饰五个 调节区。碱基编辑将 T6>C 转化，将 SMN 蛋白水平恢复为野生型。腺相关病毒血清型 9 介导的碱基编辑器在 Δ7SMA 小鼠中的递送使平均 T6>C 转化率达到 87%，改善了运动功能并延长了平均寿命，通过一次碱基编辑和 nusinersen 联合给药（未治疗的 111 天与 17 天）得到了增强。这些发现表明，一次性碱基编辑治疗 SMA 具有潜力。
