An optogenetic cell therapy to restore control of target muscles in an aggressive mouse model of amyotrophic lateral sclerosis.
J Barney BrysonAlexandra KourgiantakiDai JiangAndreas DemosthenousLinda GreensmithPublished in: eLife (2024)
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, no therapies exist that can prevent progressive motor neuron degeneration, muscle denervation, or paralysis in ALS. Here, we report important advances in the development of an optogenetic, neural replacement strategy that can effectively restore innervation of severely affected skeletal muscles in the aggressive SOD1 G93A mouse model of ALS, thus providing an interface to selectively control the function of targeted muscles using optical stimulation. We also identify a specific approach to confer complete survival of allogeneic replacement motor neurons. Furthermore, we demonstrate that an optical stimulation training paradigm can prevent atrophy of reinnervated muscle fibers and results in a tenfold increase in optically evoked contractile force. Together, these advances pave the way for an assistive therapy that could benefit all ALS patients.
Keyphrases
- amyotrophic lateral sclerosis
- cell therapy
- mouse model
- skeletal muscle
- end stage renal disease
- high resolution
- single molecule
- newly diagnosed
- chronic kidney disease
- stem cells
- bone marrow
- high speed
- spinal cord
- prognostic factors
- mesenchymal stem cells
- patient reported outcomes
- cancer therapy
- spinal cord injury
- smooth muscle
- free survival
- drug delivery
- replacement therapy