A cell therapy approach to prevent muscle atrophy and paralysis in an aggressive mouse model of ALS

Abstract: Breakdown of neuromuscular junctions (NMJs) is an early pathological hallmark of amyotrophic lateral sclerosis (ALS) that blocks neuromuscular transmission, leading to muscle weakness, paralysis and, ultimately, premature death. Currently, there are no available therapies to prevent progressive motor neuron degeneration, muscle denervation or paralysis in ALS. Here, we report important advances in the development of an optogenetic cell therapy for ALS that can restore innervation of targeted skeletal muscles and provide an interface to selectively control their function. Complete survival of intraneural grafts of channelrhodopsin-2 (ChR2) expressing motor neurons, derived from allogeneic embryonic stem cells (ESCs), is enabled by transient immunosuppression using a T-cell-β receptor targeting antibody. Importantly, the engrafted light-sensitive motor neurons robustly reinnervate target muscles in the highly-aggressive SOD1^G93A mouse model of ALS, even following engraftment after overt symptom-onset. Moreover, daily optical stimulation training of the engrafted ChR2-motor neurons reinforces de novo NMJs, resulting in a significant enhancement of the force generating capacity of the targeted muscle in response to optical stimulation and prevention of muscle fibre atrophy. These beneficial effects are maintained long term, even until late-stage disease in SOD1^G93A mice. Together, these advances pave the way for the development of a combinatorial therapeutic approach to restore function of paralyzed muscles and prevent muscle atrophy that could benefit all ALS patients, irrespective of the pathogenic or genetic trigger.