Modelling myelination

Some of the most important processes in our body are among the hardest to study. Scientists have known about the protective insulation on the long arms of our neurons, known as myelin, in our brain since Vesalius first described it in 1717. But it has been challenging to test how this protective layer is lost due to disease or drug treatments — and how it might be restored. While researchers have historically used animal models to study this question, mice remyelinate their neurons at a different rate than people, leaving a huge gap between the lab and the clinic.

Now, Roche scientists have developed a powerful new tool to probe these questions: a human-based brain organoid model that recapitulates myelination and allows researchers a new window into the process of losing and reestablishing the myelin coating, or sheath, on our neurons. Described in a publication in Science Translational Medicine,this new tool in the drug discovery toolkit will be important for developing new treatments for disorders such as multiple sclerosis (MS), where the immune system attacks and destroys myelin. It will also enable researchers to test potential medicines to ensure they do not damage myelin or myelin generating cells.

Six years ago, Simona Lange, Senior Scientist in Roche’s Pharmaceutical Sciences unit, began developing a novel myelin brain organoid model. At the time, there were several different protocols for building brain organoids. However, most of the models were focused on representing the earliest stages of brain development, and took a long time to mature. Myelination is one of the last steps to occur during human brain development — only beginning after birth and completing around two years of age — so Simona took a different approach: starting from neural stem cells already headed on the path to mature cell types. This allowed her to rapidly grow an elegantly simple model, ready for use within two months. Crucially, this system can be used to model diseases where myelin is lost (demyelination) and to test compounds that promote its natural repair (remyelination).“The model is complex as necessary for our scientific purposes, but otherwise fairly simple,” she explained. 

Simona and her colleagues found that the model translated well to what had been observed in mice. However, they also found some surprises — in particular, an important role for microglia, the brain’s immune cells, in cleaning up broken down myelin and enabling remyelination to occur. It took the development of this new model system to establish this important role of microglia in human remyelination.

Then, as the model matured, Simona collaborated with colleagues in Roche’s pRED Neuroscience and Rare Diseases to further develop and apply it to drug discovery. “This was a nice, discovery-based collaboration between our groups,” said Lynette Foo, Principal Scientist in pRED Neuroscience and Rare Diseases. “Human model systems are useful to complement animals for translatability to patients, because they increase the confidence of the project.”

Simona and Lynette envision the model being useful for developing effective drugs that can restore lost myelin in disorders such as MS, but also for testing the safety of other potential treatments for their impact on myelin and neurotoxicity.

“Ultimately, this first human system to evaluate pro-remyelinating drugs allows us to gain deeper insights into human biology, helping us to design more precise and efficient in vivo studies and select the safest and most efficacious compounds to move forward with,” Simona said.