Brightening the Future of ALS using Optogenetics

Amyotrophic Lateral Sclerosis (ALS) is a lethal neurodegenerative disease that degenerates predominantly motor neurons in the brain, brainstem, and spinal cord, leading to complete paralysis of muscles essential for daily motor activities. Difficulty in swallowing (dysphagia) is one of the most severe symptoms, contributing to poor quality of life and an eightfold increase in mortality rates due to malnutrition, dehydration, and aspiration pneumonia. Dysphagia onset in ALS coincides with tongue weakness, due to the degeneration of hypoglossal motor units (XII MUs) providing the sole motor innervation of the tongue. Current treatments do not specifically target XII MU degeneration. To address this unmet clinical need, we propose optogenetics, a neuromodulation method that uses light to precisely control neural activity with high temporal and spatial resolution. We hypothesize that optogenetics will act as a targeted gene therapy approach to slow or halt the degeneration of XII MUs by therapeutically exciting them to drive neuronal repair and nerve terminal proliferation. In our previous study, we used a translational mouse model of ALS ( SOD1-G93A ) with dysphagia and injected adeno associated virus (AAV) mediated excitatory opsin Channelrhodopsin2 (ChR2) into the hypoglossal nucleus (HGN) to directly stimulate and record neural activity via an implanted optrode. Currently, we are developing a minimally invasive method using intralingual injections to retrogradely transfect XII MUs as a more translationally feasible approach. In our pilot study, AAV mediated ChR2 was injected into the tongue to transfect neurons and muscle cells in transgenic (n=4, at disease onset) and wild-type (n=7) mice. Results 3-4 weeks post-injection showed that midline injections into the tongue base and blade were sufficient to evoke visible tongue contractions via optogenetic stimulation (opto-stim) of the tongue surface under anesthesia, and to drive opsin expression in the HGN (tongue tissue not yet analyzed). However, both results were suboptimal compared to our direct HGN injection method. That this peripheral-based optogenetics approach worked at all is exciting because it was applied after clinical disease onset (to mirror intervention timing for human ALS), when mice presumably had axonal transport deficits (a hallmark early feature of ALS). We are now exploring methods to improve opsin expression in XII MUs to likewise improve opto-stim evoked tongue contractions. Following optimization, we will investigate the therapeutic effects of XII MU-targeted opto-stim in awake mice (while drinking from a light-emitting spout) vs. at rest (via a light-emitting patch implanted subcutaneously under the tongue). This essential pre-clinical work will demonstrate if this innovative optogenetics approach can safely and effectively slow or halt XII MU degeneration to preserve swallowing function and extend lifespan, setting the stage for translation to ALS clinical trials. This project is funded by NIH R21 NS123761 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.