Using brain organoids to model and target reactive gliosis
This project aims to establish advanced human models for reactive gliosis that will contribute to the understanding of the molecular and cellular processes that lead to brain diseases. Gliosis occurs in ageing and in many brain diseases (i.e., Alzheimer, Parkinson, epilepsy, and MS). During gliosis, the neuron-supporting glial cells lose their support functions, which affects neuronal communication. This then leads to cognitive decline (dementia), overstimulation (epilepsy), or loss of function (MS). The Hol Lab at Brain Center UMCU has partnered with Swiss biotech company GliaPharm to develop novel models and readouts of gliosis, and to test new medications on them that specifically target glial cells.
The models developed in this project can potentially be used to screen for the effects of genetic variants and drugs on neural function across a wide array of diseases. This will accelerate both 1) the drug testing process and 2) the development of drugs targeting glial cells. In the long-term this has the potential to prevent the progression of specific brain diseases. The has particularly strong implications for dementia patients: in the Netherlands for example, 1 in 5 people will develop dementia (alzheimer.nl). The WHO characterizes dementia as a global epidemic. Currently, no cure exists, which poses an increasing worldwide physical, psychological and socioeconomic burden. Our models and validation of GliaPharm’s proprietary compounds together promise to open a new glia-oriented frontier in treating dementia and other diseases characterized by reactive gliosis.
The innovation inherent to this project lies in using reactive astrocytes as a target for treating brain disease. Functional changes caused by gliosis have been mainly studied in rodents, and in this project, we will employ iPSC-technology to build new human cell models to study gliosis and work towards a screening platform to test astrocyte-targeted drugs. Furthermore, we will develop new tools to functionally assess changes in astrocyte and neuron physiology induced by gliosis. The description and characterization of the electrical and calcium activity of these organoid cultures is the first fundamental step to developing a treatment allowing organoids to recover normal physiology. This will then allow the development of a personalized medicine approach based on the culture of organoids from patient cells. These individual organoid cultures may be considered time-consuming and costly but compared to the benefits of finding an early adapted and specific treatment, there is a real commercial and societal opportunity. The ambitious goals of the project will be attainable through the public-private partnership between UMCU and GliaPharm. Both partners bring complementary background knowledge such as neurodegenerative diseases and stem cell research (UMCU) and preclinical cell models and market knowhow (GliaPharm) that, combined, enable maximum scientific, societal and economic impact of the project.
