Biodistribution of onasemnogene abeparvovec DNA, mRNA and SMN protein in human tissue
Biodistribution of onasemnogene abeparvovec DNA, mRNA and SMN protein in human tissue
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DOI：
10.1038/s41591-021-01483-7
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发表时间：
2021-10-04
期刊：
影响因子：
82.9
通讯作者：
Foust, Kevin D.
中科院分区：
文献类型：
--
作者：
Thomsen, Gretchen;Burghes, Arthur H. M.;Foust, Kevin D.
1型脊髓性肌萎缩症（SMA 1）是一种由运动神经元生存基因（SMN 1）缺失/突变引起的衰弱性神经退行性疾病。Onasemnogene abeparvovec（以前称为AVXS-101）是一种通过一次性全身给药恢复SMN生产的基因疗法。本研究证明了在静脉内施用AAV 9介导的基因疗法后，载体基因组和转基因在整个中枢神经系统（CNS）和外周器官中的广泛生物分布。两名有症状的SMA 1婴儿入组III期研究，接受了onasemnogene abeparvovec。两名患者均死于与onasemnogene abeparvovec无关的呼吸系统并发症。一名患者的运动功能得到改善，另一名患者在观察到明显的临床获益前不久死亡。在这两名患者中，onasemnogene abeparvovec DNA和信使RNA分布广泛的外周器官和中枢神经系统。在肝脏中检测到载体基因组的最大浓度，比在CNS组织中检测到的浓度增加300- 1，000倍。SMN蛋白在未治疗的SMA 1对照中较低，但在治疗患者的运动神经元、脑、骨骼肌和多个外周器官中可清楚地检测到。这些数据支持这样一个事实，onasemnogene abeparvovec具有有效的分布，转导和表达后，静脉注射给药，并恢复SMN的表达在human.Biodistribution分析的两名脊髓性肌萎缩症患者显示广泛onasemnogene abeparvovec的DNA，mRNA和SMN蛋白在整个中枢神经系统和外周器官静脉基因治疗管理。
Spinal muscular atrophy type 1 (SMA1) is a debilitating neurodegenerative disease resulting from survival motor neuron 1 gene (SMN1) deletion/mutation. Onasemnogene abeparvovec (formerly AVXS-101) is a gene therapy that restores SMN production via one-time systemic administration. The present study demonstrates widespread biodistribution of vector genomes and transgenes throughout the central nervous system (CNS) and peripheral organs, after intravenous administration of an AAV9-mediated gene therapy. Two symptomatic infants with SMA1 enrolled in phase III studies received onasemnogene abeparvovec. Both patients died of respiratory complications unrelated to onasemnogene abeparvovec. One patient had improved motor function and the other died shortly after administration before appreciable clinical benefit could be observed. In both patients, onasemnogene abeparvovec DNA and messenger RNA distribution were widespread among peripheral organs and in the CNS. The greatest concentration of vector genomes was detected in the liver, with an increase over that detected in CNS tissues of 300-1,000-fold. SMN protein, which was low in an untreated SMA1 control, was clearly detectable in motor neurons, brain, skeletal muscle and multiple peripheral organs in treated patients. These data support the fact that onasemnogene abeparvovec has effective distribution, transduction and expression throughout the CNS after intravenous administration and restores SMN expression in humans.Biodistribution analysis of two patients with spinal muscular atrophy shows widespread onasemnogene abeparvovec DNA, mRNA and SMN protein throughout the central nervous system and peripheral organs following intravenous gene therapy administration.