Towards the clinical translation of optogenetic skeletal muscle stimulation

Abstract

Paralysis is a frequent phenomenon in many diseases, and to date, only functional electrical stimulation (FES) mediated via the innervating nerve can be employed to restore skeletal muscle function in patients. Despite recent progress, FES has several technical limitations and significant side effects. Optogenetic stimulation has been proposed as an alternative, as it may circumvent some of the disadvantages of FES enabling cell type–specific, spatially and temporally precise stimulation of cells expressing light-gated ion channels, commonly Channelrhodopsin2. Two distinct approaches for the restoration of skeletal muscle function with optogenetics have been demonstrated: indirect optogenetic stimulation through the innervating nerve similar to FES and direct optogenetic stimulation of the skeletal muscle. Although both approaches show great promise, both have their limitations and there are several general hurdles that need to be overcome for their translation into clinics. These include successful gene transfer, sustained optogenetic protein expression, and the creation of optically active implantable devices. Herein, a comprehensive summary of the underlying mechanisms of electrical and optogenetic approaches is provided. With this knowledge in mind, we substantiate a detailed discussion of the advantages and limitations of each method. Furthermore, the obstacles in the way of clinical translation of optogenetic stimulation are discussed, and suggestions on how they could be overcome are provided. Finally, four specific examples of pathologies demanding novel therapeutic measures are discussed with a focus on the likelihood of direct versus indirect optogenetic stimulation.

Direct optogenetic stimulation of smooth muscle cells to control gastric contractility

“…Therefore the recently described expandable integrated optoelectronic mash with µLEDs allows quasi panoramic illumination 69 which could be applied simultaneously but also sequentially to simulate physiological contractility waves. On the other hand, the thinness of the SMC layers allows the use of blue light activated ChR variants although red light can be applied with much higher energies without toxic effects 26 . The best suited ChR variant can thus be freely chosen and will be determined by the optimal kinetics but also less pronounced inward rectification 46 and thus more effective depolarization to activate Ca 2+ channels.…”

“…Furthermore, the immune response against the combination of the various parts required for this treatment have to be carefully characterized and prevented 26 , 84 . Importantly, we herein deliver only a proof-of-concept for the mere feasibility to control gastric contractions as well as motility ex vivo .…”

“…Channelrhodopsin2 (ChR2) is a light-gated channel conducting non-selectively cations upon illumination with blue light and allows to control the membrane potential with high spatial and temporal resolution 25 . In clear contrast to EFS, optogenetic stimulation can be performed cell-specific: If ChR2 is only expressed selectively in SMC, these alone will be affected by the illumination whereas other cell types such as nociceptive neurons in close proximity are not excited 26 .…”

A flexible and versatile system for multicolor fiber photometry and optogenetic manipulation

“…Similar approaches for light delivery and collection have previously been used for optical coherence tomography (Lee et al, 2013; Lorenser et al, 2013), endoscopy (Lemire-Renaud et al, 2010; Lorenser et al, 2013), temperature sensing (Musolino et al, 2016), and monitoring of opsin-eGFP expression (Diester et al, 2011), but they have not been applied to infer and manipulate neuronal activity. Notably, application of the FFP system is not limited to neuroscientific research, but it can also be employed for other excitable cells: For example, tools for simultaneous delivery and collection of light are requested for all-optical readout and control of cardiac activity (Entcheva, 2013; Entcheva & Bub, 2016; Entcheva & Kay, 2021; O’Shea et al, 2019) and skeletal muscles (Gundelach et al, 2020). In addition, the conceptual simplicity and potential for miniaturization may be of particular advantage when considering mobile devices, such as in research involving freely moving animals or even clinical applications.…”

Gene delivery to the hypoglossal motor system: preclinical studies and translational potential

“…Optogenetic stimulation can also effectively depolarize skeletal myofibers or motor axons, typically using ChR2. This potentially offers greater spatial and temporal precision as compared to direct electrical stimulation [ 89 ]. To our knowledge these techniques have not yet been applied to the tongue and/or XII nerve, and this represents a promising research opportunity.…”