Severe Toxicity in Nonhuman Primates and Piglets with Systemic High-Dose Administration of Adeno-Associated Virus Serotype 9-Like Vectors: Putting Patients First
Severe Toxicity in Nonhuman Primates and Piglets with Systemic High-Dose Administration of Adeno-Associated Virus Serotype 9-Like Vectors: Putting Patients First
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DOI：
10.1089/hum.2018.021
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发表时间：
2018-02-07
影响因子：
4.2
通讯作者：
Buening, Hildegard
中科院分区：
文献类型：
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作者：
Flotte, Terence R.;Buening, Hildegard
CONCURRENT WITH THE RELEASE of this editorial, Human Gene Therapy will publish online a potentially important original research article from the laboratory of Dr. James Wilson, demonstrating severe, life-threatening toxicity from highdose (2× 1014 vg/kg) intravenous administration of adeno-associated vector serotype 9 (AAV9)-like vectors (AAVhu68) expressing the human SMN1 in juvenile rhesus macaques and newborn piglets. 1 There were two major classes of toxicity observed:(1) acute, severe hepatotoxicity, which was fatal in one of three nonhuman primates (NHPs); and (2) toxicity associated with effects on the dorsal root ganglia (DRG) in the piglets. It is important to note that the time course of the hepatotoxicity was very rapid and was not associated with the development of an effector T-cell response to the AAV capsid. Thus, this appears to represent a different form of toxicity from that observed in the human hemophilia trials. 2 More specifically, the peak of transaminase elevations in the current study was at 5 days after infusion, a time course suggestive of oxidant injury. As the authors point out, this is reminiscent of that observed with acute acetominophen poisoning, which results from diffuse hepatocellular injury caused by release of excessive reactive oxygen species and depletion of reduced glutathione and other intracellular, particularly mitochondrial, antioxidant molecules. 3There are important limitations to the study published here. First, the number of animals included in the work was small (n= 3 per species), and since all of the animals were treated with the same dose of vector, it was not possible to explore dose–response relationships with either form of toxicity. Second, the entire set of data was gener-
