Summary: Researchers have discovered a promising method to restore muscle function in a severe mouse model of ALS using a blend of grafted motor neurons and optical nerve stimulation.
This study showcases compelling evidence that suggests potential therapy avenues for all ALS patients. Current treatments cannot halt the progression of symptoms in ALS patients due to the intricate changes underlying neuron degeneration.
However, this novel method has demonstrated that muscles in ALS models remain responsive to reinnervation by healthy grafted motor neurons, even in the disease’s advanced stages.
The team used optical nerve stimulation (ONS) on grafted replacement motor neurons that are light-sensitive, resulting in restored muscle function in a severe ALS model.
To ensure proper neuromuscular junction formation, researchers employed a wireless optical stimulation system, leading to a 13-fold improvement in muscle contraction force after 21 days.
While the results are promising, numerous challenges remain, including validating the grafting procedure with human motor neurons and assessing its long-term effectiveness.
Scientists have detailed how a combination of grafted replacement motor neurons and optical nerve stimulation—using light to activate neurons—can improve muscle function in a highly aggressive mouse model of amyotrophic lateral sclerosis (ALS).
Their research in mice, published today as an eLife Reviewed Preprint, is described by the editors as a fundamental study that presents convincing evidence for the restoration of muscle innervation and contractions in an advanced form of ALS.
The findings could eventually pave the way for an assistive therapy that can be uniformly applied to all ALS patients.
ALS is the most common form of Motor Neuron Disease (MND) in adults. An early hallmark of ALS is the breakdown of neuromuscular junctions—the connection between the end of a motor nerve and a muscle—which causes the muscle to become denervated.
This breakdown leads to muscle weakness, paralysis and ultimately a premature death. The median survival time in ALS, following initial onset of symptoms, is around 20–48 months.
“The cellular and molecular changes that underlie neuron degeneration in ALS are extremely complex, and can vary greatly between individual patients,” explains study lead and co-senior author, Dr. Barney Bryson, MND Association Senior Non-Clinical Research Fellow and NIHR BRC UCL Excellence Fellow, in the Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
“Due to this, there are currently no therapies that can prevent the progression of symptoms in ALS patients.”
Bryson and colleagues have previously demonstrated a proof-of-concept strategy to overcome muscle denervation in a nerve injury model of muscle paralysis in mice.
The strategy uses a technique called optical nerve stimulation (ONS) to stimulate grafted replacement motor neurons which have been modified to be light sensitive, using a small light-emitting diode.
In the current study, the team aimed to determine whether this strategy could be adapted to reinnervate and restore muscle function in a highly aggressive model of ALS.
First, the team sought to ensure the donor healthy motor neurons could survive the grafting process and would not be attacked by the recipient’s immune system. After tests with the immunosuppressive drug tacrolimus—which is regularly used in human organ transplants—showed it was unsafe for use in the ALS mouse model, they looked for a more specific form of immunosuppression, leading them to try a type of antibody called H57-597.
This treatment helped prevent graft rejection and successfully restored some of the nerve connections to the target muscles. However, the force of the muscle contractions afforded by the treatment was still relatively weak.
The formation and maintenance of neuromuscular junctions are activity-dependent processes. This means that, without regular stimulation, grafted motor neurons may survive but are unlikely to form mature neuromuscular junctions—which could explain the weak muscle contractions observed by the team.
To ensure regular stimulation, they therefore used a wireless optical stimulation system in the mice to impose regular muscle contractions for 1 hour each day. After 21 days of this optical stimulation training, the mice showed a more-than 13-fold improvement in muscle contraction force.
These findings are important as they show that affected muscles in an ALS mouse model remain receptive to reinnervation by healthy engrafted motor neurons, even until the late stages of the disease.
The authors say there are still many challenges to overcome before this approach could be used to restore muscle function in ALS patients. Further studies are required to validate whether the grafting procedure would work with human motor neurons, and whether it would be sufficient to improve the patient’s quality of life.
Furthermore, the approach needs to be tested in other forms of MND, especially those with a longer life expectancy, to validate the long-term effectiveness of the procedure.
“Our study demonstrates that replacement motor neurons can robustly and reliably reinnervate target muscles in an advanced model of ALS,” concludes senior author Linda Greensmith, a Professor in the Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology.
“If this approach can be successfully translated to ALS patients, the redundancy of the motor neuron subtype used would mean that a single type of motor neuron could be produced to target a large number of different muscles in individual ALS patients. This in turn would lead to a more efficient and wide-scale treatment option.”
About this ALS research news
Author: Linda Greensmith Source: eLife Contact: Linda Greensmith – eLife Image: The image is credited to Neuroscience News
An optogenetic cell therapy to restore control of target muscles in an aggressive mouse model of Amyotrophic Lateral Sclerosis
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 SOD1G93A 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 10-fold increase in optically-evoked contractile force.
Together, these advances pave the way for an assistive therapy that could benefit all ALS patients.