Optogenetic Peripheral Nerve Immunogenicity.
Optogenetic Peripheral Nerve Immunogenicity.
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DOI：
10.1038/s41598-018-32075-0
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发表时间：
2018-09-19
影响因子：
4.6
通讯作者：
Herr HM
中科院分区：
文献类型：
--
作者：
Maimon BE;Diaz M;Revol ECM;Schneider AM;Leaker B;Varela CE;Srinivasan S;Weber MB;Herr HM
光遗传学技术因其能够揭开中枢神经系统 (CNS) 和周围神经系统 (PNS) 复杂神经生理通路的神秘面纱而成为科学界极大兴奋的主题。围绕光遗传学的兴奋也延伸到了临床，目前正在进行 ChR2 治疗色素性视网膜炎的试验，预计在不久的将来还会进行更多试验。在这项工作中，我们确定了在前室（AC）注射带有或不带有荧光报告基因的AAV6-hSyn-ChR2（H134R）后，光遗传学活性腓神经经皮照射导致表达缺失的原因。使用 Sprague Dawley Rag2−/− 大鼠和适当的对照，我们发现光遗传学表达缺失主要是由 ChR2 介导的脊髓免疫原性引起的，在低和高腺相关病毒 (AAV) 剂量下都会导致中枢神经系统运动神经元死亡和同侧肌肉萎缩。我们进一步使用缓释他克莫司颗粒进行药理学免疫抑制，以证明持续的透皮光遗传学表达长达 12 周。这些结果表明，PNS 内 AAV 介导的光遗传学表达的所有剂量可能都是不安全的。 PNS 和 CNS 应用的临床光遗传学在使用视蛋白治疗疾病时应格外小心，并且可能需要同时进行免疫抑制。光遗传学的未来工作应集中于设计免疫原性较低的视蛋白。
Optogenetic technologies have been the subject of great excitement within the scientific community for their ability to demystify complex neurophysiological pathways in the central (CNS) and peripheral nervous systems (PNS). The excitement surrounding optogenetics has also extended to the clinic with a trial for ChR2 in the treatment of retinitis pigmentosa currently underway and additional trials anticipated for the near future. In this work, we identify the cause of loss-of-expression in response to transdermal illumination of an optogenetically active peroneal nerve following an anterior compartment (AC) injection of AAV6-hSyn-ChR2(H134R) with and without a fluorescent reporter. Using Sprague Dawley Rag2−/− rats and appropriate controls, we discover optogenetic loss-of-expression is chiefly elicited by ChR2-mediated immunogenicity in the spinal cord, resulting in both CNS motor neuron death and ipsilateral muscle atrophy in both low and high Adeno-Associated Virus (AAV) dosages. We further employ pharmacological immunosuppression using a slow-release tacrolimus pellet to demonstrate sustained transdermal optogenetic expression up to 12 weeks. These results suggest that all dosages of AAV-mediated optogenetic expression within the PNS may be unsafe. Clinical optogenetics for both PNS and CNS applications should take extreme caution when employing opsins to treat disease and may require concurrent immunosuppression. Future work in optogenetics should focus on designing opsins with lesser immunogenicity.
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影响因子：
4.6
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10.1093/gerona/54.2.m59
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影响因子：
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