Testing ALS Therapies on a 3D Chip

There is no cure for amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease), a disease which attacks the body’s motor neurons and affects nearly 6000 people annually in the United States. However, a 3D model of the disease can be used to test the safety and efficacy of different potential drugs, according to the results of a recent study.

Investigators from the Massachusetts Institute of Technology developed a microfluidic chip that is a model of the motor neurons and muscle fibers known as the neuromuscular junction. The investigators said that “organ-on-a-chip technology” has been used recently to mimic in vivo conditions, and specifically measure phenotypes, cell death, synapse formation, neurodegeneration, muscle contraction, and atrophy. They tested their model’s success as a physiological model by measuring muscle contraction force and the synchronicity of contractions.

The team found major differences between the healthy and ALS cells, as well as the effects of 2 drugs that are currently being tested in clinical trials. For example, they found that neurites grew more slowly in the ALS model compared with the healthy model and seemed unable to develop strong connections to the muscle fibers. In essence, this meant that the ALS model showed weaker muscle control, according to the study authors. After observing the model for 2 weeks, the ALS motor neurons were only producing about a quarter of the force demonstrated by the healthy neurons muscle model leading the authors to believe that ALS motor neurons attack healthy skeletal muscle tissues.

“We were surprised that healthy muscle tissues were also damaged as evidenced by the increased number of apoptotic cells and decreased myogenic expression as measured by polymerase chain reaction when we co-cultured the muscle cells with ALS patient-derived motor neurons,” MIT postdoc and study author Tatsuya Osaki told Rare Disease Report®. “Furthermore, when we treated the motor unit with drugs, the muscle tissues also recovered. This may suggest the importance of focusing on the drug efficacy to not only motor neurons but also skeletal muscle cells when conducting drug screening.”

The investigators tested rapamycin and bosutinib on their ALS model through endothelial cells and found that administering both drugs as a combination therapy produced the most muscle strength that had been lost in the ALS motor units. Furthermore, the treatment reduced the rate of cell death that is normally observed in ALS.

“From the perspective of tailor-made therapeutics, physicians may eventually be able to harvest patient cells, use them to generate patient-specific induced pluripotent stem cells, and then test drugs by using our model to estimate drug efficacy. This, along with the patient’s genetic information, would help the physician determine the most efficacious treatment (especially, whether they recommend inspiratory muscle training),” Mr. Osaki concluded.

Eventually, the investigators want to collect stem cell samples from 1000 ALS patients. They are working with a biotech company in order to do so, which also allows them to perform larger-scale drug studies, according to a statement. Their hope is to test more cell types in the future, such as Schwann cells and microglial cells, which are part of the nervous system.

The paper, titled “Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from human iPS-derived muscle cells and optogenetic motor neurons,” was published in Science Advances.