Our brains consist of many different types of cells. Each cell has its own function, which is executed by proteins. Alexander disease (AxD) is a rare brain disease, caused by an error in the gene encoding the protein GFAP. This protein is mostly present in a specific cell type called astrocytes. Faulty GFAP protein accumulates and aggregates, resulting in malfunction and finally loss of brain tissue. It is still unclear how the faulty protein results in brain damage. To develop new therapies for AxD, which is currently incurable, we need to discover the order of events that lead to faulty protein functioning.

In this project, we will use single cell proteomics – the global analysis of proteins in individual cells – to study how proteins in different cell types are affected during the development of AxD. We will use lab-grown mini-brains, called organoids, from AxD patients and compare how these develop over time compared to mini-brains in which the mutation in GFAP is corrected. This will enhance our understanding of how AxD originates and how we can potentially intervene.

Project financed by ELA up to: 100 000 €

Alexander disease (AxD) is a rare autosomal dominant disorder caused by point mutations in the gene encoding for the glial fibrillary acidic protein (GFAP), the major intermediate filament protein in astrocytes. Accumulation of GFAP protein in Rosenthal fibers leads to astrocytic dysfunctions and altered development and homeostasis of affected brain tissues.

No cures are currently available for AxD patients. In the proposed pilot project, the team aim to develop a gene editing approach to specifically downregulate the expression of the mutated GFAP protein in affected AxD astrocytes. This project will collect solid proof-of-concept data for the future progress of a novel and definitive gene therapy strategy for the treatment of AxD patients. In addition, they expect to outline novel editing platforms that could be applied prospectively for disease modelling studies and therapeutic treatments of other leukodystrophies characterized by astrocyte degeneration or dysfunctional/maladaptive astrogliosis.

Project financed by ELA up to: 60 000 €

Alexander disease (AxD) is a rare autosomal dominant disorder caused by point mutations in the gene encoding for the glial fibrillary acidic protein (GFAP), the major intermediate filament protein in astrocytes. Accumulation of GFAP protein in Rosenthal fibers leads to astrocytic dysfunctions and altered development and homeostasis of affected brain tissues. No cures are currently available for AxD patients.

In the proposed pilot project, we aim to develop gene-editing approaches to downregulate the expression of the mutated GFAP protein or correct mutations in the Gfap gene in an animal AxD model. This project will collect solid proof-of-concept data for the future progress of a novel and definitive gene therapy strategy for the treatment of AxD patients. In addition, we expect to outline novel editing platforms that could be applied prospectively for disease modeling studies and treatments of other leukodystrophies characterized by astrocyte degeneration or dysfunctional/maladaptive astrogliosis

Project financed by ELA up to: 100 000 €