Gene Therapy to Strengthen Nerve-Muscle Connection Prevents ALS Progression in Mice

A gene therapy aimed at strengthening the connection between motor neurons and muscle prevented nerve degeneration and increased the life span of mice with amyotrophic lateral sclerosis (ALS), a study showed.

Since researchers believe that neurodegeneration in ALS starts at the junction between nerves and muscle, the findings suggest that preventing the connection from breaking down could be a good way to stop the disease from progressing.

The study, “DOK7 gene therapy enhances motor activity and life span in ALS model mice,” was published in the journal EMBO Molecular Medicine.

Interestingly, the University of Tokyo researchers did not develop the gene therapy with ALS in mind. They were trying to prevent a disease called DOK7 myasthenia that is caused by mutations of the DOK7 gene.

The gene encodes a protein that is a key component of the neuromuscular junction. Without it, the connection does not form properly, and patients with DOK7 myasthenia develop severe muscle weakness.

When the team used gene therapy to try to restore DOK7 expression, they discovered that it not only prevented deterioration of the nerve-muscle connection, but it also improved movement and increased survival in mouse models with the muscle condition. The researchers saw the same thing in a type of muscular dystrophy.

Since scientists believe that the neuromuscular junction is the starting point for the nerve deterioration in ALS, the Tokyo researchers decided to try DOK7 gene therapy to treat ALS.

Using it in an ALS mouse model prevented degeneration of the nerve-muscle connection, as in the earlier experiments. This, in turn, prevented muscles from breaking down, while having no effect on the number of spinal motor neurons.

The therapy not only strengthened the mice’s neuromuscular junctions but also increased their life span, the team said.

DOK7 is a protein found on the muscle side of the neuromuscular junction. It activates a protein called MuSK, or muscle-specific kinase, which the body needs to maintain nerve-muscle connections.

Earlier studies in animal models of ALS suggested that loss of the nerve-muscle connection occurs independently from the death of motor neurons. That prompted the Tokyo research team to argue that gene therapies targeting the neuromuscular junction in ALS might be even more effective when used in combination with treatments capable of boosting motor-neuron survival.