Severe Toxicity in Nonhuman Primates and Piglets Following High-Dose Intravenous Administration of an Adeno-Associated Virus Vector Expressing Human SMN
Severe Toxicity in Nonhuman Primates and Piglets Following High-Dose Intravenous Administration of an Adeno-Associated Virus Vector Expressing Human SMN
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DOI：
10.1089/hum.2018.015
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发表时间：
2018-02-12
影响因子：
4.2
通讯作者：
Wilson, James M.
中科院分区：
文献类型：
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作者：
Hinderer, Christian;Katz, Nathan;Wilson, James M.
嗜神经性腺相关病毒（AAV）血清型如AAV 9已被证明当静脉内（i. v.）高剂量的这一观察结果导致最近成功应用静脉内AAV 9递送来治疗患有脊髓性肌萎缩症的婴儿，脊髓性肌萎缩症是一种运动神经元存活（SMN）蛋白的遗传性缺陷，其特征在于下运动神经元的选择性死亡。为了评估使用该方法用AAV 9变体（AAVhu 68）转导运动神经元的效率，用静脉内注射携带人SMN转基因的AAVhu 68载体以类似于脊髓性肌萎缩症临床试验中使用的剂量处理三只幼年非人灵长类动物（NHP; 14月龄）和三只小猪（7-30日龄）。每公斤体重给予2x 10（14）个基因组拷贝，导致两个物种的脊髓运动神经元广泛转导。然而，严重的毒性发生在NHP和仔猪。所有三种NHP均表现出明显的转氨酶升高。在2名NHP中，转氨酶升高消退，无临床后遗症，而1名NHP发生急性肝衰竭和休克，并在载体注射后4天实施安乐死。尽管NHP没有表现出临床上明显的感觉缺陷，但还观察到背根神经节感觉神经元变性。在NHP中，临床发现与T细胞对载体衣壳或转基因产物的反应之间没有相关性。仔猪没有表现出肝毒性的证据，但在载体注射的14天内，所有三只动物都表现出本体感受缺陷和共济失调，这严重损害了免疫力，需要安乐死。这些临床结果与更严重的背根神经节感觉神经元病变比NHP中观察到的。肝脏和感觉神经元的发现似乎是独立于对衣壳或转基因产物的免疫应答的AAV转导的直接结果。目前的结果和利用不同AAV 9变体和转基因的另一项最近研究的结果表明，全身和感觉神经元毒性可能是高剂量静脉内递送AAV载体的一般性质，而与衣壳血清型或转基因无关。涉及高全身剂量AAV载体的临床前和临床研究应包括对类似毒性的仔细监测。
Neurotropic adeno-associated virus (AAV) serotypes such as AAV9 have been demonstrated to transduce spinal alpha motor neurons when administered intravenously (i.v.) at high doses. This observation led to the recent successful application of i.v. AAV9 delivery to treat infants with spinal muscular atrophy, an inherited deficiency of the survival of motor neuron (SMN) protein characterized by selective death of lower motor neurons. To evaluate the efficiency of motor neuron transduction with an AAV9 variant (AAVhu68) using this approach, three juvenile nonhuman primates (NHPs; aged 14 months) and three piglets (aged 7-30 days) were treated with an i.v. injection of an AAVhu68 vector carrying a human SMN transgene at a dose similar to that employed in the spinal muscular atrophy clinical trial. Administration of 2x10(14) genome copies per kilogram of body weight resulted in widespread transduction of spinal motor neurons in both species. However, severe toxicity occurred in both NHPs and piglets. All three NHPs exhibited marked transaminase elevations. In two NHPs, the transaminase elevations resolved without clinical sequelae, while one NHP developed acute liver failure and shock and was euthanized 4 days after vector injection. Degeneration of dorsal root ganglia sensory neurons was also observed, although NHPs exhibited no clinically apparent sensory deficits. There was no correlation between clinical findings and T-cell responses to the vector capsid or transgene product in NHPs. Piglets demonstrated no evidence of hepatic toxicity, but within 14 days of vector injection, all three animals exhibited proprioceptive deficits and ataxia, which profoundly impaired ambulation and necessitated euthanasia. These clinical findings correlated with more severe dorsal root ganglia sensory neuron lesions than those observed in NHPs. The liver and sensory neuron findings appear to be a direct consequence of AAV transduction independent of an immune response to the capsid or transgene product. The present results and those of another recent study utilizing a different AAV9 variant and transgene indicate that systemic and sensory neuron toxicity may be general properties of i.v. delivery of AAV vectors at high doses, irrespective of the capsid serotype or transgene. Preclinical and clinical studies involving high systemic doses of AAV vectors should include careful monitoring for similar toxicities.