Model of the neuromuscular junction using motor neurons derived from ALS patients. Source: Tatsuya Osaki/MITThe ALS Ice Bucket Challenge raised $115 million in the summer of 2014, bringing greater awareness to a progressive neurodegenerative disease for which there is currently no cure. Also known as Lou Gehrig’s disease, amyotrophic lateral sclerosis gradually kills off the motor neurons that control muscles and is diagnosed in nearly 6,000 people per year in the United States.

Now, in an advance that could help scientists develop and test new drugs, MIT engineers have designed a microfluidic chip containing the first 3D human tissue model of the interface between motor neurons and muscle fibers. The researchers used cells from either healthy subjects or ALS patients to generate the model’s neurons, allowing them to test potential drug effectiveness.

"We found striking differences between the healthy cells and the ALS cells,” said Roger Kamm, an MIT professor of mechanical and biological engineering and the senior author of a just-published study on the research.

Although tissue models of the connections between neuromuscular junctions have existed for decades, they were limited to two-dimensional structures that do not fully replicate the complex physiology. The newly developed 3D model, by contrast, consists of neurons and muscle fibers occupying adjacent compartments of a microfluidic chip. The neurons, which are engineered to be controllable by light, control the movement of the muscles through extending long fibers called neurites.

Kamm and his colleagues originally developed their model in 2016, using mouse cells to grow the neurons and muscles. Because the species difference can affect drug screening, they shifted to using induced pluripotent human stem cells for the new version.

One of the team’s key findings was that the model incorporating ALS cells showed a slower growth of neurites, which were also unable to form strong connections with the muscle fibers. After two weeks, muscles innervated by ALS motor neurons were generating only about one-quarter of the force produced by muscles controlled by healthy neurons.

The researchers used their model to test two new drugs, rapamycin and bosutinib, that are now in clinical trials. They found that giving both drugs together restored most of the muscle strength lost in the ALS motor units, along with reducing the rate of cell death.

Next, the team hopes to collect stem cells from 1,000 ALS patients in order to perform larger-scale drug studies. They also plan to add more types of cells that play supportive roles in the nervous system.

The research appears in the October 10, 2018, issue of Science Advances.