美国哈佛大学刘如谦研究组发现，碱基编辑可拯救细胞和小鼠的脊髓性肌肉萎缩症。这一研究成果于2023年3月30日发表在国际学术期刊《科学》上。

研究人员表示，脊髓性肌肉萎缩症（SMA）是婴儿死亡的主要遗传原因，是由于SMN1丢失后SMN蛋白不足而引起的。已获批准的治疗方法规避了内源性SMN调节，需要反复给药或可能减弱。

研究人员报道了对SMN2的基因组编辑，即对携带C6>T突变的SMN1的一个不充分拷贝的编辑，以永久恢复SMN蛋白水平和拯救SMA表型。研究人员使用核酸酶或碱基编辑器来修改了五个SMN2调控区域。碱基编辑将SMN2 T6>C转换，使SMN蛋白水平恢复到野生型。AAV9介导的碱基编辑在Δ7SMA小鼠中产生了87%的平均T6>C转换，改善了运动功能，并延长了平均寿命，一次性碱基编辑+nusinersen联合给药（111天对17天未治疗）使其寿命延长。这些发现证明了一次性碱基编辑治疗SMA的潜力。

附：英文原文

Title: Base editing rescue of spinal muscular atrophy in cells and in mice

Author: Mandana Arbab, Zaneta Matuszek, Kaitlyn M. Kray, Ailing Du, Gregory A. Newby, Anton J. Blatnik, Aditya Raguram, Michelle F. Richter, Kevin T. Zhao, Jonathan M. Levy, Max W. Shen, W. David Arnold, Dan Wang, Jun Xie, Guangping Gao, Arthur H. M. Burghes, David R. Liu

Issue&Volume: 2023-03-30

Abstract: Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, arises from SMN protein insufficiency following SMN1 loss. Approved therapies circumvent endogenous SMN regulation and require repeated dosing or may wane. We describe genome editing of SMN2, an insufficient copy of SMN1 harboring a C6>T mutation, to permanently restore SMN protein levels and rescue SMA phenotypes. We used nucleases or base editors to modify five SMN2 regulatory regions. Base editing converted SMN2 T6>C, restoring SMN protein levels to wild-type. AAV9-mediated base editor delivery in Δ7SMA mice yielded 87% average T6>C conversion, improved motor function, and extended average lifespan, which was enhanced by one-time base editor+nusinersen co-administration (111 versus 17 days untreated). These findings demonstrate the potential of a one-time base editing treatment for SMA.

DOI: adg6518

Source: https://www.science.org/doi/10.1126/science.adg6518