As the technological hurdles are overcome and optogenetic techniques advance to have more control over neurons, therapies based on these approaches will begin to emerge in the clinic. Here, we consider the technical challenges surrounding the transition of this breakthrough technology from an investigative tool to a true therapeutic avenue. The emerging strategies and remaining tasks surrounding genetically encoded molecules which respond to light as well as the vehicles required to deliver them are discussed.The use of optogenetics in humans would represent a completely new paradigm in medicine and would be associated with unprecedented technical considerations. To be applied for stimulation of neurons in humans, an ideal optogenetic tool would need to be non-immunogenic, highly sensitive, and activatable with red light or near-infrared light (to maximize light penetration while minimizing photodamage). To enable sophisticated levels of neuronal control, the combined use of optogenetic actuators and indicators could enable closed-loop all-optical neuromodulation. Such systems would introduce additional challenges related to spectral orthogonality between actuator and indicator, the need for decision making computational algorithms and requirements for large gene cassettes. As in any gene therapy, the therapeutic efficiency of optogenetics will rely on vector delivery and expression in the appropriate cell type. Although viral vectors such as those based on AAVs are showing great potential in human trials, barriers to their general use remain, including immune responses, delivery/transport, and liver clearance. Limitations associated with the gene cassette size which can be packaged in currently approved vectors also need to be addressed.

中文翻译：

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基于视蛋白的光遗传学工具在人类治疗应用中的挑战。

随着技术障碍的克服和光遗传学技术的进步，可以更好地控制神经元，基于这些方法的疗法将开始出现在临床中。在这里，我们考虑围绕这项突破性技术从调查工具转变为真正的治疗途径所面临的技术挑战。围绕对光作出反应的基因编码分子以及传递它们所需的载体的新兴策略和剩余任务进行了讨论。光遗传学在人类中的应用将代表一种全新的医学范式，并将与前所未有的技术考虑相关联。要应用于刺激人类神经元，理想的光遗传学工具需要是非免疫原性的、高度敏感的、并且可用红光或近红外光激活（以最大限度地提高光穿透性，同时最大限度地减少光损伤）。为了实现复杂的神经元控制水平，光遗传执行器和指示器的结合使用可以实现闭环全光神经调节。这样的系统将引入与致动器和指示器之间的光谱正交性、决策计算算法的需要以及对大型基因盒的要求相关的额外挑战。与任何基因治疗一样，光遗传学的治疗效率将依赖于载体递送和在适当细胞类型中的表达。尽管基于 AAV 的病毒载体在人体试验中显示出巨大的潜力，但其普遍使用的障碍仍然存在，包括免疫反应、递送/运输和肝脏清除。