Multiple sclerosis: Test-tube "brains" accelerate drug development

Imagine having a sort of "model" of the human brain, through which you could closely study some of the mechanisms involved in the onset of diseases like multiple sclerosis. A group of scientists led by Simona Lange, a researcher at the Roche Innovation Center in Basel, Switzerland, has succeeded in developing something similar, creating human brain organoids that can mimic and analyze in detail the mechanisms of production and removal of the myelin sheath that protects neurons. The research results were published in Science Translational Medicine .

Rebuilding a human brain model in a test tube

The so-called myelin sheath ensures the proper functioning of nerve cells, and its degradation is implicated in several pathologies, including neurodegenerative and autoimmune diseases like Alzheimer's and multiple sclerosis. Over the course of life, this protective layer undergoes physiological changes in both thickness and chemical composition. However, when the sheath degrades and is not adequately regenerated, the transmission of nerve impulses along axons (the "tails" that connect one nerve cell to another) becomes less effective, and cognitive or movement disorders can arise.

The physiological mechanisms that enable its repair are typically studied in animal models such as mice, whose nervous systems, however, present obvious differences from the human one. In an attempt to overcome this and other obstacles, the authors of the new research used oligodendrocytes, neurons, and microglia (obtained from pluripotent stem cells) to develop human brain organoids. Oligodendrocytes are cells of the central nervous system involved in the remyelination process (i.e., regeneration of the myelin sheath) of axons. Microglia are immune cells that in turn support the ability of oligodendrocytes to regenerate myelin.

Organoids effectively mimic some key mechanisms

Using the resulting organoids, the research team then induced demyelination of neurons by exposing them to specific toxins. They first observed that sheath regeneration occurred only in the presence of microglia, confirming their role. Furthermore, the team tested the ability of three molecules to promote the remyelination process. Two of these are in the preclinical phase of study, while one, clemastine, has already been tested in human clinical trials. All three proved effective in promoting repair of the protective layer, although again, only in the presence of microglia. The organoids developed during the research, the authors conclude, could therefore constitute useful and adaptable models for studying in detail the processes of myelin sheath destruction and regeneration, and have "the potential to accelerate the development of new treatments for demyelination-related diseases."