Death after High-Dose rAAV9 Gene Therapy in a Patient with Duchenne's Muscular Dystrophy
Death after High-Dose rAAV9 Gene Therapy in a Patient with Duchenne's Muscular Dystrophy
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DOI：
10.1056/nejmoa2307798
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发表时间：
2023-09-28
影响因子：
158.5
通讯作者：
Flotte, Terence
中科院分区：
文献类型：
--
作者：
Lek, Angela;Wong, Brenda;Flotte, Terence
我们用含有dSaCas9的重组腺相关病毒（rAAV）血清型9（即“死亡”的金黄色葡萄球菌Cas9，其中Cas9核酸酶活性已失活）与VP64融合治疗了一名27岁的杜氏肌营养不良症（DMD）患者；该转基因被设计用于上调皮质肌营养不良蛋白，作为定制的crispr -反激活剂治疗。使用的rAAV剂量为每公斤体重1 × 1014个载体基因组。转基因治疗6天后出现轻度心功能障碍和心包积液，随后出现急性呼吸窘迫综合征（ARDS）和心脏骤停；患者2天后死亡。尸检显示严重的弥漫性肺泡损伤。转基因在肝脏中的表达很少，器官中没有AAV血清9型抗体或效应t细胞反应性的证据。这些发现表明，在接受高剂量rAAV基因治疗的晚期DMD患者中，先天性免疫反应导致ARDS。（由Cure Rare Disease资助。）一名27岁的杜氏肌萎缩症患者接受了CRISPR-Cas9转基因治疗，死于对用于传递转基因的高剂量重组AAV的先天免疫反应。
We treated a 27-year-old patient with Duchenne's muscular dystrophy (DMD) with recombinant adeno-associated virus (rAAV) serotype 9 containing dSaCas9 (i.e., "dead" Staphylococcus aureus Cas9, in which the Cas9 nuclease activity has been inactivated) fused to VP64; this transgene was designed to up-regulate cortical dystrophin as a custom CRISPR-transactivator therapy. The dose of rAAV used was 1x1014 vector genomes per kilogram of body weight. Mild cardiac dysfunction and pericardial effusion developed, followed by acute respiratory distress syndrome (ARDS) and cardiac arrest 6 days after transgene treatment; the patient died 2 days later. A postmortem examination showed severe diffuse alveolar damage. Expression of transgene in the liver was minimal, and there was no evidence of AAV serotype 9 antibodies or effector T-cell reactivity in the organs. These findings indicate that an innate immune reaction caused ARDS in a patient with advanced DMD treated with high-dose rAAV gene therapy. (Funded by Cure Rare Disease.)A 27-year-old man with Duchenne's muscular dystrophy who was treated with a CRISPR-Cas9 transgene died from an innate immune response to the high dose of recombinant AAV used for delivery of the transgene.