With a combined incidence of 1:14,700, X-linked adrenoleukodystrophy (X-ALD) is the most common monogenetically inherited leukodystrophy. It is caused by a genetic defect in the ABCD1 gene that leads to the build-up of saturated very long-chain fatty acids (VLCFAs) in tissues and body fluids of patients. X-ALD shows a striking clinical heterogeneity with inflammatory cerebral ALD (CALD) being the most severe form. What triggers the onset of CALD is currently unknown, and the mechanisms resulting in the damage of brain cells and leading to the progressive loss of physical and mental functions remain unclear.

In this project, we focus on a type of brain cells called astrocytes. Astrocytes normally support and protect nerve cells, but in X-ALD, the build-up of VLCFAs may cause a loss of helpful functions and instead contribute to brain damage. To address this, we will generate astrocytes and nerve cells from reprogrammed stem cells of patients with X-ALD and study their behaviour in cell culture. We will also test two different drugs, RGFP966 and RGFP109, that block an enzyme called HDAC3 in astrocytes. These drugs have shown promising results in studies with mice, and RGFP109 has already been safely tested in patients with the disorder Friedreich´s ataxia.

Our goal is to selectively block HDAC3 using these compounds to prevent astrocytes from becoming harmful and to protect neurons from damage in patients with X-ALD. Together, our research could uncover new insights into how the lack of ABCD1 damages the brain and open up new possibilities for treatment.

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.

Krabbe Disease (KD), also known as Globoid Cell Leukodystrophy, is a rare genetic disorder that affects the brain and nervous system. It is caused by mutations in a gene called GALC, which leads to the loss of an important lysosomal enzyme called β-galactosylceramidase. Without this enzyme, different sphingolipids accumulate in the brain, damaging the cells that produce myelin—the protective layer around nerves—and causing severe neurodegeneration, especially in infants.

Until now, most research has focused on a toxic molecule called psychosine, believed to be the main cause of this damage. However, new findings suggest that another substance called lactosylceramide (LacCer), which also accumulates when the GALC enzyme is missing, might play a significant role in the disease. LacCer is known to trigger inflammation in the brain and is found in high amounts in the brains of patients and animal models of KD—even in cases where psychosine is not elevated. This project will explore whether LacCer contributes to the damage seen in KD, especially how it affects the cells responsible for forming myelin (called oligodendrocytes).

The ultimate goal is to determine if LacCer can be targeted by new treatments to slow or stop the disease. Because current treatments for Krabbe Disease—like stem cell transplants—are only effective before symptoms appear, this research could lead to new therapies that work even after the disease has begun. By uncovering a previously overlooked disease mechanism, this project offers a new direction for treating KD and gives hope to patients and families affected by this devastating disorder.

Leukodystrophies are a group of disorders that affect the white matter of the brain, which is crucial for normal brain function. These disorders mainly disrupt the glial cells, which support neurons. Neurons need a substance called myelin, produced by oligodendrocytes, to work properly. Myelin formation happens after birth and is essential for the brain’s full development.

Leukodystrophies are often caused by genetic mutations, many of which are not yet fully understood. Current research is exploring various treatments, including drugs, genetic repairs, and cell replacement therapies.

Our research focuses on a new stem cell therapy. This therapy aims to introduce healthy cells into the brain to produce functional myelin and support normal brain development. We identified a way to overcome limitations of previous cell therapy attempts. We identified how to control the cell type specificity of the transplanted cells to increase the generation of healthy oligodendrocytes. Our new method allows the production of millions of gene corrected cells of a patient ready for transplantation in a couple of weeks.

We plan to test if this new approach can more effectively replace faulty cells, improve brain development, and offer long-term benefits without needing prolonged immune suppression. Our technology will allow the safe use of the patient’s own cells and speeding up the time from diagnosis to treatment.

Our goal of this project is to test a new drug, 2BAct, to see if it can help treat a rare and devastating childhood brain disease called Pelizaeus-Merzbacher Disease (PMD). PMD has no approved treatment and is caused by genetic problems that damage a type of brain cell called oligodendrocytes. These cells generate myelin, which is a protective coating around nerves and essential for proper brain function. When oligodendrocytes do not work properly, the brain’s communication system slows down or even stops, leading to developmental delay, movement problem, and often early death.

Our research focuses on a process inside these cells called the integrated stress response (ISR). This process can become overactive in PMD and cause harm to oligodendrocytes. We believe that calming down this stress response could help these cells survive and function better, allowing the brain to repair the myelin and improve nerve communication.

To test this idea, we will use 2BAct, which helps reduce cell stress response effectively, in three different mouse models of PMD. Each of them represents different forms of the disease. We will measure how well the drug extends lifespan of mice and improves brain health by looking at myelin repair under the microscope, testing motor function, and studying changes in gene activity. If successful, this study will lead to a new treatment strategy for PMD that probably work across different genetic subtypes of this disease as well as help other never-damaging diseases where brain cells are also under stress, such as other rare leukodystrophies.

Vanishing White Matter Disease (VWM) is a rare brain disorder that mostly affects children. It gradually destroys the brain’s white matter, leading to severe disability and early death. The disease is usually caused by mutations in EIF2B5 gene, which is important for making proteins and handling cell stress.

There are currently no treatments available for VWM. Based on past research, we know that brain cells such as astrocytes are unable to function properly and ultimately lead to the loss of white matter. Therefore, astrocytes are a promising target for therapy. In our work, we are using a gene therapy approach that delivers healthy copies of the EIF2B5 gene specifically to astrocytes using a non-disease-causing virus called AAV9.

We’ve tested this therapy in two mouse models of VWM and seen some improvements in survival, weight, and movement. While the therapy increased levels of the EIF2B5 gene in the brain, one important stress response pathway still isn’t working correctly. To address this, we have two new goals:

• Improve gene delivery to more astrocytes across the brain using a specially designed genetic switch (called a promoter).

• Combine gene therapy with a drug called ISRIB, which helps control the stress response, to see if this dual approach works better.

We will test these strategies in our mouse model of VWM using clinical brain scans (MRIs), and movement tests. We will also look at the brain tissue to see if white matter returns and if the stress response is corrected after treatment. Overall, we hope to develop a safe and effective long-term treatment for children with this devastating disease.

Megalencephalic Leukoencephalopathy with Subcortical Cysts (MLC) is a rare brain disease that mainly affects children. It is caused by changes in a gene called MLC1, which is active in a type of brain cell known as an astrocyte. When this gene doesn’t work properly, water builds up in the brain, leading to swelling, cysts, and damage to the brain’s white matter. This causes symptoms like an enlarged head, balance problems, muscle stiffness, seizures, and mild learning difficulties.

There is currently no cure for MLC. Our team is working on a gene therapy approach that uses a harmless virus (called AAV) to deliver a healthy copy of the MLC1 gene directly to the brain. In mouse models of MLC, we have already shown that this treatment restores normal brain function—even when given months after the disease has started. The treated mice showed long-lasting correction of brain abnormalities and improvement in movement.

To move closer to treating patients, we are now optimizing how the therapy is delivered, which viral vector to use, and how to ensure safety. Importantly, we have created a new regulatory sequence that helps the therapy target only the right brain cells. We will test this new approach in non-human primates to confirm that the treatment works across species and reaches all necessary brain regions. These studies are a key step toward launching clinical trials and bringing the first effective therapy for MLC to patients.

This research project aims to develop a new treatment for X-linked adrenoleukodystrophy (X-ALD), a severe brain disorder caused by genetic mutations. Current treatments, while promising, have limitations. The proposed approach uses advanced gene editing techniques to insert a healthy copy of the ABCD1 gene into specific cells of the patient’s own blood stem cells.

The researchers plan to use a method called CRISPR-Cas9 to precisely place the healthy gene in a way that could make the treatment more effective and safer than current gene therapy approaches. This technique is designed to produce long-lasting effects, while reducing the risks and limitations of currently available therapies.

The team will test this new approach in laboratory models, including 3D structures that mimic human brain tissue and in mice with X-ALD. They will also compare it to a more traditional gene therapy method as a backup strategy.

If successful, this innovative approach could overcome current limitations in X-ALD treatment and potentially serve as a model for treating other brain disorders. The project combines proven principles with cutting-edge technologies, aiming to translate scientific advancements into real-world medical treatments.

Free sialic storage diseases are rare genetic lysosomal diseases in the leukodystrophy family. The most severe, infantile forms lead to death before the age of 2 years. Salla disease, a more moderate form, is characterized by severe cognitive and motor deficits. There are also intermediate forms. These lysosomal storage diseases have been little studied, due to their very low frequency apart from certain isolates such as the Salla region in Finland. However, recently, it appeared that this pathology suffered from underdiagnoses caused by a lack of knowledge of the symptoms and a lack of systematic testing to detect it. Moreover, its distribution in the world has been found to be more generalized. This discovery aroused renewed interest in this pathology. In particular, a consortium of researchers has been created around a foundation of families of patients (STAR) in the USA.

Team A is interested in the lysosome, a cellular organelle whose roles are to eliminate and recycle “cellular waste” by breaking it down into small molecules, and to participate in cellular nutrition. It focuses mainly on the lysosomal transporters that enable small molecules to be evacuated. Since the early 2000s, part of the team has been studying sialin, the lysosomal transporter of a sugar, sialic acid, whose mutations (defects) can cause disease. In 2004, a publication made it possible to study its activity in the lysosome, as well as that of pathological mutants, a study continued in 2008. Subsequently, the team turned its attention to the search for molecules to understand the mechanisms involved, but also to pave the way for pharmacological treatment. This treatment was based on the idea that, for the most common mutation causing Salla disease, the sialin protein remained partially capable of fulfilling its role when present in the lysosome, but was only partially sent to the lysosome. This is probably due to a problem of “shape”, the folding of sialin that prevents its recognition by the cellular systems that guide proteins to their areas of function. The idea was therefore to look for small molecules that would help sialin take the right shape to be recognized. The first interesting compounds were described in 2012, and the first compound aimed at correcting the pathology in 2020 in collaboration with team B. However, while this compound provided proof of principle that the so-called “pharmacological chaperone” method could work to redirect sialin to the lysosome, it did not actually treat the pathology. This is due to its mode of action: it binds tightly to sialin at the same point as the sugar which sialin must remove from the lysosome; this sugar can no longer be taken up by sialin and accumulates instead of being removed.

The aim of this project is therefore to develop second-generation chaperone molecules. These molecules will target the misfolded sialin region without preventing sugar binding and transport. We have begun to build models of sialin and to understand the structural consequences of the “Salla” mutation. Based on these models, we will screen in silico very large databases of molecules (some of some already used in therapy). This virtual screening has the advantage of being very rapid in identifying the types of molecules that can help folding by “repairing” the structure destabilized by the mutation. As soon as a promising compound is identified, it will immediately be tested on cells to verify that it has the expected chaperone effect and enables sialin to be active. In a second phase, its effect will be evaluated on patient cells, showing that it can correct the accumulation of harmful sialic acid causing the pathology.