Therapeutic AAV9-mediated Suppression of Mutant SOD1 Slows Disease Progression and Extends Survival in Models of Inherited ALS
Therapeutic AAV9-mediated Suppression of Mutant SOD1 Slows Disease Progression and Extends Survival in Models of Inherited ALS
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DOI：
10.1038/mt.2013.211
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发表时间：
2013-12-01
影响因子：
12.4
通讯作者：
Kaspar, Brian K.
中科院分区：
文献类型：
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作者：
Foust, Kevin D.;Salazar, Desiree L.;Kaspar, Brian K.
超氧化物歧化酶1（SOD1）的突变与家族性肌萎缩侧索硬化症（ALS）有关，通过一种或多种获得性毒性导致进行性运动神经元死亡。野生型SOD1的参与与散发性ALS有关，因为在散发性患者的受影响组织中已经报道了错误折叠的SOD1，并且已经报道了来源于散发性ALS患者的星形胶质细胞对运动神经元的毒性通过降低SOD1的合成而降低。我们现在报告减缓疾病的发病和发展后，在两个小鼠模型的治疗交付使用一个单一的外周注射腺相关病毒血清型9（AAV9）编码的shRNA，以减少合成ALS引起的人类SOD1突变体。对发展为攻击性、致命性瘫痪的年轻小鼠进行药物治疗，通过延迟疾病发作和减缓疾病进展来延长生存期。在晚发型模型中，发病后的AAV9递送显著减缓了疾病进展并显著延长了存活期。此外，经鞘内递送至非人灵长类动物的AAV9被证明在整个脊髓的运动神经元和神经胶质中产生稳健的SOD1抑制，因此，为人类临床试验中的AAV9介导的治疗奠定了基础。
Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (ALS) resulting in progressive motor neuron death through one or more acquired toxicities. Involvement of wild-type SOD1 has been linked to sporadic ALS, as misfolded SOD1 has been reported in affected tissues of sporadic patients and toxicity of astrocytes derived from sporadic ALS patients to motor neurons has been reported to be reduced by lowering the synthesis of SOD1. We now report slowed disease onset and progression in two mouse models following therapeutic delivery using a single peripheral injection of an adeno-associated virus serotype 9 (AAV9) encoding an shRNA to reduce the synthesis of ALS-causing human SOD1 mutants. Delivery to young mice that develop aggressive, fatal paralysis extended survival by delaying both disease onset and slowing progression. In a later-onset model, AAV9 delivery after onset markedly slowed disease progression and significantly extended survival. Moreover, AAV9 delivered intrathecally to nonhuman primates is demonstrated to yield robust SOD1 suppression in motor neurons and glia throughout the spinal cord and therefore, setting the stage for AAV9-mediated therapy in human clinical trials.