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Flea technology (a bit like an organ on a chip that can simulate the functioning of tissues or organs) has been used to recreate amyotrophic lateral sclerosis (ALS), allowing researchers to identify two treatments for blood cancers – rapamycin and bosutinib – as a possible combination of ALS.
The study, "Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from muscle cells derived from human iPS and optogenetic motor neurons, "Was published in the newspaper Progress of science.
Only two treatments – riluzole (marketed as Rilutek by Sanofi) and edaravone (marketed as Radicava, by MT Pharma America) – are FDA-approved to help alleviate symptoms in patients with from the.
The search for new drugs requires extensive research as well as disease models that can go beyond the limits of animal testing.
Organ-on-a-chip devices can help overcome these limitations. They consist of miniaturized devices with personalized patterns containing small channels and chambers in which cells are cultured to recreate organ function.
Once established, these chips can house different types of cells and be used to study diseases, their mechanisms and their potential treatments.
Researchers at the Massachusetts Institute of Technology (MIT) and Harvard University have developed a 3D ALS-on-a-chip device containing motor neurons and muscle cells, the two main types of cells affected by the disease. .
Motor neurons are derived from human-induced pluripotent stem cells (hiPS), a type of stem cell that can potentially differentiate into specialized cells. in vitroor in the laboratory. These cells came from a person with sporadic ALS, the most common form of the disease. As a result, the motor neurons derived from hiPS carried the disease.
"Significant species differences in mice and humans probably contribute to the failure of clinical trials of drug candidates identified through screening using an ALS mouse model," the researchers wrote. "This highlights the importance of using cells derived from a human source."
The team loaded the chip with healthy skeletal muscle cells and light-sensitive motor neurons derived from HiPS (nerve cells). Light has been used to induce muscle contraction and control the neuronal activity of the device.
A similar device was loaded with healthy motoneurons, serving as a control to the experiment.
Compared with healthy nerve cell chips, ALS-on-a-chip showed weaker and fewer muscle contractions, impaired motor neurons, and increased muscle cell death.
The researchers then tested two approved treatments – molecules known for their neuroprotective potential – in the ALS-on-a-chip system: rapamycin (a treatment for lymphoma, labeled Sirolimus) and bosutinib (a treatment for leukemia, called Bosulif). Used in combination, these drugs were considered to help recover the muscle contraction generated by motor neuron activity and improve neuronal survival.
Each of these molecules has a limited ability to penetrate the blood-brain barrier, essential in the treatment of ALS. But, interestingly, the researchers found that this limitation could be overcome if the two molecules were combined – using a BBB-on-a-chip device. The greatest ability of the combination to effectively reach the brain is the result of a reduction in the expression of P-glycoprotein, a cell membrane protein that prevents foreign substances from entering the brain. cells.
According to a press release, these results highlight the potential of organ-on-a-chip technologies as promising platforms for testing treatment candidates in ALS.
"Our model represents an important advance in the simulation of human physiological and pathological conditions associated with motor units and neuromuscular junctions, which is useful for studying the underlying mechanisms of ALS and for drug testing," the authors wrote. researchers.
Rapamycin is currently being tested in a Phase 2 clinical trial (NCT03359538) in patients with ALS in Italy; an open-label phase 1 study (NCT02921477) on bosutinib in dementia patients may be taking place in California, but its status is unknown.
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