How is 3D tissue modeling opening new doors for ALS drug testing?
Researchers are developing "ALS-on-a-chip": a novel method of identifying and testing drugs that could be beneficial in the treatment of amyotrophic lateral sclerosis (ALS) using 3D tissue models.
Amyotrophic lateral sclerosis (ALS) is a debilitating disease that is diagnosed in approximately 6000 people every year in the US. ALS is a progressive disease that causes the death of neurons responsible for controling voluntary muscles.
Research engineers from Massachusetts Institute of Technology (MIT; MA, USA) have been designing a new 3D tissue model to show the interface between motor neurons and muscle fibers on a microfluidic chip. The motor neurons used were taken from both healthy control subjects and patients with ALS, allowing the researchers to test the effectiveness of potential drugs.
"We found striking differences between the healthy cells and the ALS cells, and we've been able to show the effects of two drugs that are in clinical trials right now," commented Roger Kamm, the Cecil and Ida Green Distinguished Professor of Mechanical and Biological Engineering at MIT and the senior author of the study.
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The idea of creating a model of neuromuscular junctions is not a new one; the first model was created decades previously, however this was only two dimensional and could not provide an accurate enough representation of the tissue for it to be an effective tool.
Two years ago, Kamm and fellow engineers developed the first 3D neuromuscular junction model. The model is built around a microfluidic chip, with neurons and muscle fibers occupying adjacent compartments. Once assembled, the neurons are able to extend long fibers – neurites – which attach to the muscle cells and control the mechanisms of their movement.
The researchers have developed the neurons so that their activity can be controlled using light, a technique termed optogenetics. When the muscles fibers, which encase two flexible pillars, are activated by light, they contract, which in turn moves the pillars. The researchers can quantitively measure the displacement of the pillars to find out how much the muscle fibers have contracted.
Another improvement made recently to the model was the use of human induced pluripotent stem cells (iPSCs) to differentiate into both neurons and muscle cells. In the past, mouse cells were utilized to grow the muscle cells and neurons, however, the difference in species meant the results were not always accurate when it came to drug screening.
Once the stem cells had proven effective in the model, Kamm and his team started to use neurons that were developed from stem cells extracted from a patient with sporadic ALS, which accounts for 90% of all cases.
The model using the ALS neurons demonstrated that the neurites grew more slowly and appeared unable to form strong connections with muscles fibers when compared with the neurites derived from the healthy stem cells.
"You can see that the healthy neurites are going directly to the individual myotubes and then activating them. However, the ALS neurons don't seem to be able to connect very well," Kamm explained.
This leads to a 75%reduction of force generated by the ALS neurons compared to the healthy neurons, and therefore weaker muscle overall after just two weeks. The model also showed that the ALS motor neurons attacked the healthy skeletal muscle tissues.
The model, having been proven accurate, was the then used to test two drugs that are currently in clinical development for treatment of ALS – rapamycin and bosutinib. The drugs, given in combination, are hoped to restore much of the muscle strength lost in the ALS motor units, as well as reduce the rate of cell death caused by the ALS neurons in the motor unit.
In the future, Kamm and his team are hoping to work with a biotech company to conduct larger scale drug studies using stem cells from 1000 ALS patients. There are also plans to include different types of cells, such as Schwann cells and microglial cells, and to test more samples at one time so that effects throughout the nervous system can be observed.
This could open up a new field of testing for nervous system diseases, including spinal muscular atrophy.
Osaki T, Uzel SGM, Kamm RD. Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from human iPS-derived muscle cells and optogenetic motor neurons. Science Advances 4(10), (2018); http://news.mit.edu/2018/testing-new-drugs-als-chip-1010