Researchers at the University of Cambridge have developed ‘mini brains’ in the lab that model amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two often overlapping conditions, and have also successfully tested a drug candidate on them.

Although such mini brains have already been developed, they have often been short lived in the past, making it difficult to use them to study neurodegenerative diseases like ALS. For the first time, this study has shown that it is possible to cultivate them for almost a year.

New, more effective treatments for neurodegenerative diseases such as ALS / FTD are desperately needed. The team hopes the information they can glean from their model could help develop better therapies for these devastating conditions.

Laboratory-grown “organoids” are being developed to model various organs such as the liver, heart and brain, and more accurately test the responses of human tissues to exposure to a variety of different drugs than using animals or cell lines alone. While the first versions of these mini-organs were quite basic, they become more sophisticated and realistic as technology and knowledge of the area improves.

These organoids are typically created by extracting cells from a patient’s skin, reprogramming those cells to the stem cell stage, and then differentiating them according to the type of cell and organ required. This allows researchers to create specific models for certain diseases, especially if they are due to some kind of genetic mutation carried by the patient.

In this study published in Neuroscience of nature, scientists based at the John van Geest Center for Brain Repair, University of Cambridge, extracted cells from patients with ALS / FTD overlap (C9ORF72 mutation) to grow brain organoids for 240 days – in unpublished work the same group managed to grow mini brains for 340 days.

A key difference from other similar organoids that other groups have grown is that they were grown as “slices” of brain rather than a standard-shaped mini-brain, which helped ensure that all cells receive a good level of nutrition.

As the organoids grew, the team were able to observe subtle signs indicating abnormalities seen in ALS / FTD. Using unique cell sequencing and a range of different tests, they observed disruption of proteomic and DNA repair in astroglial cells and neurons.

Specifically, the astroglia had increased levels of the autophagy signaling protein P62 and some of the neurons had high levels of the poly dipeptide repeat protein (GA) and exhibited DNA damage and early signs. cell death.

In particular, the team was successful in reversing many of these changes using a drug candidate known as GSK2606414, including toxic protein buildup, cellular stress, and loss of nerve cells. Drugs similar to this candidate are currently being tested in clinical trials to find treatments for neurodegenerative diseases.

“Neurodegenerative diseases are very complex disorders that can affect many different cell types and the way these cells interact at different times as the disease progresses. To get closer to this complexity, we need models that last longer and mimic the makeup of those populations of human brain cells in which disturbances typically occur, and this is what our approach offers, ”said András Lakatos. , the lead author who led the research based at Cambridge’s Department of Clinical Neuroscience, in a press release.

“Not only can we see what can happen early in the disease – long before a patient can experience symptoms – but we can also begin to see how the disturbances change over time in each cell.”