Light activation of motor neurons to treat paralysis

Recent work by neuroscientists, geneticists, and bioengineers has developed a means by which to control the activity of individual neurons using light. Though this technology seems futuristic, it relies on bacterial genes for light-responsive ion channels (thus its name, optogenetics). Because it requires genetic manipulations, which despite many years of research towards gene therapy remains challenging in patients, the concept has long been considered simply a research tool, but recent work published in Science suggests that it may eventually be useful in the clinic.

The cell type-specific control of optogenetics promises relevance to a variety of neurological conditions, including neuropathic pain, paralysis, epilepsy, and Parkinson’s. However, the clinical relevance of previous studies has been limited by the difficulty of inducing stable expression of these ion channels, called opsins. In this new development, researchers at King’s College London and University College London solved this problem by expressing the channels in transplanted cells, in this case derived from embryonic stem cells (ESCs). This approach is especially appropriate to treating paralysis because it both replaces damaged neurons and allows selective activation of transplanted and not surviving endogenous neurons. No currently available method of transplanting ESC-derived neurons allows integration with inputs from the brain, so they must be externally activated; electrical stimulation not only triggers excessive, spasmodic muscle contractions but may also activate sensory neurons and thus cause pain.

The most likely clinical application would be to support breathing in patients with high-level spinal cord injury by transplanting optogenetically altered neurons into the phrenic nerve, as these contractions would not require coordination with other muscles. Given the challenges of modeling such a severe condition in animals, the team led by Linda Greensmith and Ivo Lieberam instead proved the principle in the sciatic nerve.  Transplantation of ESC-derived, channelrhodopsin 2-transfected motor neurons was shown to allow light-triggered contraction of the lower hindlimb muscles, illustrating that this approach leads to sufficient expression of the channel. As has been shown in a previous optogenetic study, light activation induces a contraction pattern that more closely matches that caused by endogenous motor signals than electrical stimulation (which minimizes muscle fatigue), suggesting that this combination of optogenetics with regenerative medicine has advantages over either approach alone.

Light control of motor neurons
Expression of a light-activated ion channel in ESC-derived transplanted neurons enables light-triggered muscle contraction in an anesthetized mouse with peripheral nerve injury in an anesthetized animal. Image by H. MacDonald, Science Magazine.

While these results are an exciting step forward, translation to patients is still a far-off goal. Most importantly, an implantable light-emitting device must be developed; in this work, the nerve had to be surgically exposed to be accessible to the LED. Further, the long-term effects of exogenous ion channel expression and stem cell-derived neuron transplantation must be characterized, and the work must be replicated (or built upon in the phrenic nerve setting) using induced pluripotent stem cells, so that a future therapy could use a patient’s own cells rather than foreign ESCs.