‘Human-on-a-Chip’ Disease Model Can Potentially Test Therapies Better
“This system has the potential to help researchers understand which mechanisms are driving a specific patient’s disease, including presence of particular autoantibodies [self-targeting antibodies], and could be used to further evaluate targeted therapeutic interventions,” Michael Shuler, PhD, president and CEO of Hesperos, said in a press release.
The study, “A Functional Human-on-a-Chip Autoimmune Disease Model of Myasthenia Gravis for Development of Therapeutics,” was published in the journal Frontiers in Cell and Developmental Biology.
MG is a disease of the neuromuscular junction (NMJ), the place where nerve cells come into contact with muscle cells. When activated, nerves send chemical signaling molecules across the NMJ, which bind to receptors on muscle cells and prompt them to contract.
In MG, autoantibodies bind to proteins in the NMJ, disrupting the communication between nerves and muscles, ultimately resulting in muscle weakness. The most common type of MG-causing autoantibody targets the nicotinic acetylcholine receptor (nAChR).
To study MG, researchers need laboratory models that accurately reflect disease processes. Even though animal models are often used, they have notable drawbacks — as they tend to induce a more severe disease course than human MG — that “can lead to severe animal suffering and death resulting in skewed statistical analysis,” according to the researchers.
Scientists at Hesperos and the University of Central Florida had previously created a cellular model of the NMJ. Simply put, this model contains two chambers, one with nerve cells and one with muscle cells, with a specialized configuration that allows for the two types of cells to meet in a manner that mimics the NMJ.
Researchers had previously shown that muscle fibers in this model are able to contract similarly to how they might in humans. This model is part of Hesperos’ Human-on-a-Chip (HoaC) program.
Now, scientists have conducted a series of experiments to examine whether this model could be used to recapitulate, or mimic, MG. To model the disease, researchers treated muscle cells in the model with a commercially available antibody against the nAChR.
“In this study, we used our HoaC technology to provide insights into the mechanisms behind a rare disease,” said James J. Hickman, PhD, chief scientist at Hesperos and professor at the University of Central Florida. “In our NMJ model, we were able to reproduce the disease phenotypes [features] similar to what has been described clinically in MG patients.”
MG-driving autoantibodies are thought to work through three broad mechanisms: by blocking nAChR on muscle cells; by activating mechanisms leading to their degradation; and by activating the complement system — a group of immune proteins that can damage cells when activated.
Through their experiments, the researchers showed that their model could recapitulate all three of these mechanisms. Treatment with anti-nAChR antibodies disrupted the NMJ and reduced the number of receptors available on muscle cells, while also leading to complement activation.
“Our system is the first human MG model system to mimic the three pathogenic [disease-causing] mechanisms in a concentration-dependent manner,” the researchers wrote, though they noted that the model “needs further complexity to begin to deduce mechanistic insights.”
The team is now conducting experiments with the model using serum — the non-cellular part of blood, which contains antibodies and other substances — from people with MG.
“We are confident that our human MG system has the potential to be a sensitive mimic of MG pathology and provide a quick and cost-effective platform to evaluate [treatments],” the researchers concluded.
This study was funded by grants from the National Institutes of Health.