权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Development of a Translational Strategy to Overcome Muscle Paralysis Using Stem Cell Derived Neural Grafts and Optogenetics

利用干细胞源性神经移植物和光遗传学开发克服肌肉麻痹的转化策略

基本信息

批准号：
MR/R011648/1
负责人：
Linda Greensmith
金额：
$ 108.49万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FR011648%2F1
关键词：
Development Translational Strategy Overcome Muscle

项目摘要

The ability to control muscle contraction is critical to all motor behaviour in humans, including respiration. However, as a result of disease or traumatic injury, this ability is often lost, causing muscle paralysis that can be permanent, and even life-threatening. The extent of paralysis can vary greatly between affected individuals, ranging at one end of the spectrum from tetraplegia following high-level spinal cord injury and locked-in syndrome in late-stage amyotrophic lateral sclerosis (ALS), to more localized paralysis of individual limbs or muscle groups, following peripheral nerve injury. In addition to the devastating personal effects of paralysis, the socio-economic implications are also profound, for example following severe spinal cord injury. Importantly, no effective therapy currently exists that can restore lost motor function. There is therefore an urgent need to develop effective therapies to overcome paralysis. In this project, we will build upon a novel strategy we have recently developed to overcome muscle paralysis in which specialised nerve cells produced from stem cells are transplanted into injured nerves in order to replace lost or damaged motor nerves. Since these nerve cells are grafted outside the central nervous system, away from their normal source of stimulation, we have genetically modified them so they can be stimulated with high specificity, using pulses of light. Thus, in our recent high-impact study, we showed that grafts of these photosensitive nerve cells, produced from mouse stem cells, survive when implanted in injured nerves in the hindlimb of mice, grow fibres to connect with paralysed muscles, and following stimulation with pulses of light, can induce contraction of the previously paralysed muscles. This strategy has several key advantages over existing, conventional approaches to artificially restore muscle function, which only work when the motor nerve is intact and depend on delivering electrical stimuli directly to the nerve. Electrical stimulation is not only non-specific, activating both motor nerves that control muscle contraction as well as sensory fibres that convey pain, but can also directly damage muscle fibres. In contrast, optical stimulation is highly specific and painless, only activating the grafted photosensitive nerve cells, and critically, unlike electrical stimulation, activates muscles in "normal" fashion, thereby avoiding the rapid muscle fatigue associated with electrical stimulation. In this project, we have assembled a team of leading experts including specialists in stem cells, electronics and muscle physiology, that will enable the development of this strategy from the current proof of concept stage, using mouse nerve cells in mouse models of muscle paralysis, towards a more clinically relevant stage applicable for use in humans. Specifically, we will develop human motor nerve cells, produced from adult human stem cells that have been safely modified to enable them to be controlled using pulses of light. Moreover, we will develop implantable light stimulators that can be used to control the function of specific muscles in awake, freely moving animals. Finally, we will demonstrate the ability to finely control a pair of paralysed opposable muscles in the rat forepaw to emulate hand-grasping, as an example of a functionally useful human movement that could be restored using this strategy.In principle, the complexity of the motor function that can be artificially controlled using this approach is limited only by the sophistication of the optical stimulation device. In addition, by coupling this strategy with emerging technology that can decipher the brain's intention to carry out a specific movement (brain-computer interface technology), it will pave the way for restoring autonomous control over the body's own muscle in a diverse range of patients affected by paralysis.

控制肌肉收缩的能力对人类的所有运动行为都至关重要，包括呼吸。然而，由于疾病或创伤性损伤，这种能力往往会丧失，导致肌肉瘫痪，可能是永久性的，甚至危及生命。瘫痪的程度在受影响的个体之间可以有很大的不同，范围从高位脊髓损伤后的四肢瘫痪和晚期肌萎缩侧索硬化症（ALS）中的闭锁综合征到外周神经损伤后个体肢体或肌肉群的更局部的瘫痪。瘫痪除了对个人造成毁灭性影响外，还造成深刻的社会经济影响，例如严重的脊髓损伤。重要的是，目前还没有有效的治疗方法可以恢复失去的运动功能。因此，迫切需要开发有效的治疗方法来克服瘫痪。在这个项目中，我们将建立在我们最近开发的一种新策略的基础上，以克服肌肉麻痹，其中将干细胞产生的专门神经细胞移植到受伤的神经中，以取代丢失或受损的运动神经。由于这些神经细胞被移植到中枢神经系统之外，远离它们正常的刺激源，我们对它们进行了基因改造，使它们可以使用光脉冲进行高度特异性的刺激。因此，在我们最近的高影响力研究中，我们表明，这些光敏神经细胞的移植物，从小鼠干细胞中产生，当植入小鼠后肢受伤的神经中时存活，生长纤维与瘫痪的肌肉连接，并在光脉冲刺激后，可以诱导先前瘫痪的肌肉收缩。与现有的人工恢复肌肉功能的传统方法相比，这种策略具有几个关键优势，这些方法仅在运动神经完好无损时起作用，并且依赖于直接向神经传递电刺激。电刺激不仅是非特异性的，激活控制肌肉收缩的运动神经以及传递疼痛的感觉纤维，而且还可以直接损伤肌肉纤维。相比之下，光学刺激是高度特异性和无痛的，仅激活移植的光敏神经细胞，并且关键的是，与电刺激不同，以“正常”方式激活肌肉，从而避免与电刺激相关的快速肌肉疲劳。在这个项目中，我们组建了一个由干细胞、电子学和肌肉生理学专家组成的领先专家团队，这将使该策略从目前的概念验证阶段（在肌肉麻痹的小鼠模型中使用小鼠神经细胞）发展到适用于人类的更具临床相关性的阶段。具体来说，我们将开发人类运动神经细胞，这些细胞是从成年人干细胞中产生的，这些干细胞已经过安全的修饰，使它们能够使用光脉冲进行控制。此外，我们将开发可植入的光刺激器，可用于控制清醒、自由活动的动物的特定肌肉功能。最后，我们将展示的能力，精细地控制一对瘫痪的对生肌在大鼠前爪模仿手抓，作为一个功能上有用的人类运动，可以恢复使用这种strategy.In原则上，运动功能的复杂性，可以人为地控制使用这种方法是有限的，只有复杂的光学刺激设备。此外，通过将这一策略与能够破译大脑进行特定运动的意图的新兴技术（脑机接口技术）相结合，它将为恢复瘫痪患者对身体自身肌肉的自主控制铺平道路。