New ALS Chip Model Closely Mimics Disease, May Aid Research

Researchers report having created a new human-on-a-chip model, one able to more accurately simulate the clinical features of amyotrophic lateral sclerosis (ALS) in people.

The chip uses motor neurons — the nerve cells responsible for controlling voluntary muscles — derived from stem cells isolated from ALS patients. This approach shows promise as a potential platform for identifying new therapies.

The model is described in the study, “A Human‐Based Functional NMJ System for Personalized ALS Modeling and Drug Testing,” published in the journal Advanced Therapeutics. 

At present, two therapies — riluzole (marketed as Rilutek and Tiglutik) and Radicava (edaravone) — have been approved by the U.S. Food and Drug Administration specifically to treat ALS. Both are only able to slow disease progression by a few months, the researchers wrote.

Currently available ALS models fail to capture all the human features of this heterogeneous disease, which may explain why findings in animal models have failed to translate into meaningful therapies. New ALS models are needed to develop more effective treatment.

Although ALS symptoms can vary widely from patient to patient, loss of the neuromuscular junction (NMJ) — the site where nerve cells and muscles communicate — is an early hallmark seen across all patients.

“Accordingly, a human functional NMJ model would be of great value for overall ALS pathological studies and drug development,” the team wrote.

Developed by researchers at the University of Central Florida and Cornell University, the new chip harbors motor neurons derived from ALS patients’ induced pluripotent stem cells (iPSCs) and muscle fibers in a compartmentalized chamber.

Since researchers cannot take motor neurons directly from patients, the use of iPSCs is a helpful alternative. iPSCs can be generated from a patient’s blood or skin cells and, as their name suggests, these cells are pluripotent — meaning that, like other stem cells, they are able to differentiate into other types of cells.

They selected three distinct ALS iPSC cell lines, two carrying mutations in the SOD1 gene and one carrying a mutation in the FUS gene. The SOD1 gene is commonly mutated in ALS patients. They also generated motor neurons derived from iPSCs of healthy individuals who served as controls.

Compared with controls, motor neurons derived from all three iPSC cell lines showed ALS-like features. The severity of these impairments was greater in motor neurons with SOD1 mutations.

The researchers added either healthy or ALS motor neurons in one of the chip’s chambers and the muscle fibers in other. The two chambers are connected via microtunnels, through which the motor neurons send axons to reach the muscle. Electrical stimulation of the chamber, given in increasing measures, led to muscle fiber contraction, meaning that functional NMJs were formed. (Of note, axons are the long projections of a nerve cell whose job is to transmit information — electrical impulses — to different neurons, muscles, and glands.)

Compared with healthy motor neurons, however, those from ALS patients formed fewer NMJs, with significantly poorer signal transmission and an increased fatigue index, a clinical parameter used for measuring muscle fatigue, a hallmark of ALS.

“These findings correspond to clinical symptoms observed in ALS patients such as muscle weakness, fatigue, and wasting,” the researchers wrote.

“To our knowledge, this is the first study to demonstrate that while different ALS mutations display various [clinical features], all have the common point-of-origin deficit at the NMJ for each mutation,” James J. Hickman, professor at the University of Central Florida and the study’s lead author, said in a press release.

Finally, they tested the Deanna protocol, a regimen of five nutritional supplements that has been proposed as a potential therapy for ALS, with patients reporting symptom relief, but whose efficacy has never been shown outside of animal models of ALS. This over-the-counter treatment is aimed at facilitating cell metabolism and lowering oxidative stress, a condition known to occur in ALS that can damage cells.

They started treating the motor neuron side of the chip with the protocol, replenishing every other day. Results showed this treatment corrected the NMJ deficits in all the ALS mutant lines tested. Specifically, it promoted the formation of NMJs, and improved electrical transmission and muscle contraction at higher stimulation frequencies. Protocol effects were more pronounced in the SOD1-mutated motor neurons.

This is “the first data to demonstrate the efficacy of the Deanna protocol for the treatment of ALS, utilizing a clinically relevant assay system,” said Hickman, who also serves as chief scientist at Hesperos.

The human-on-a-chip ALS model has been licensed to Hesperos, a company founded by Hickman and Michael L. Shuler that specializes in chip technology.

“Hesperos is looking forward to exploring how this interconnected multi-organ platform could be used to reveal additional patient-specific phenotypes in ALS and for high-content screening of drug candidates,” said Shuler, company CEO.