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 and still incurable genetic leukodystrophy characterised by a slowly progressive course leading to motor and cognitive deficits as well as epilepsy. The clinical condition of patients is often worsened after trauma or certain infections. Patient care requires intensive parental, educational and social support.

About 80% of people with MLC carry mutations in the MLC1 gene encoding a protein whose function is not yet fully understood; a minority of patients (around 15%) have mutations in the Hepacam / Glialcam gene which encodes a cell adhesion molecule.

These two proteins are very strongly expressed in a population of brain cells called astrocytes. Astrocytes are essential for homeostasis and brain function, including maintaining water and ion balance. Studies by our research group and others suggest that MLC1 may regulate the exchange of ions and water. We recently began to study the role of MLC1 in the intracellular processes controlling the response of astrocytes to stress conditions (osmotic, inflammatory and oxidative stress). The results obtained will provide us with fundamental knowledge to study how mutations in MLC1 alter the functionality of astrocytes and lead to brain damage.

For this, we obtained inducible pluripotent stem cells from skin fibroblasts of people suffering from MLC and we are currently in the process of differentiating them into astrocytes carrying pathological mutations of MLC. This model should allow us to gain new insights into molecules and pathways that may become pharmacological targets to restore astrocyte function(s) and ultimately correct neurological deficits, which would pave the way for the development of treatments that can cure MLC or improve the quality of life of people with it.

Marjo van der Knaap – 2021

The disease

CACH (Childhood Ataxia with Central Nervous System Hypomyelination) is a rare genetic disease of the hypomyelinating leukodystrophy family, also known as leukoencephalopathy with vanishing white matter (VWM). It is characterised by a progressive degradation of the white matter in the brain, leading to various cognitive disorders and muscle stiffness. These disorders may go unnoticed at first, making early diagnosis difficult. When suspicion is high, the diagnosis can be confirmed by genetic testing. The disease often manifests itself in early childhood, but some patients do not show symptoms until adulthood. There is currently no treatment, only symptomatic treatment is offered for the treatment.

Hope for families

Research teams have been working for years to speed up diagnosis, understand the mechanisms of the disease, find new markers, move towards new therapies, and improve patient management.
Marjo van der Knaap’s team at the VUmc (Center for White Matter Disorders of the VU University Medical Center in Amsterdam, the Netherlands) has been interested in leukodystrophies, but also specifically in CACH syndrome for several years. The gene associated with this disease was identified by the team in 2001 and for the past 20 years, with the support of ELA, researchers have focused on understanding the mechanisms of the disease. As a result of this research, a promising molecule has been identified that could improve the condition of these patients. This molecule, guanabenz, has been marketed for many years in the United States and Europe for the treatment of hypertension in adults. It acts on the cellular stress response (cell defence mechanism) which is involved in CACH syndrome.
The team of researchers led by Marjo van der Knaap (ms.vanderknaap@amsterdamumc.nl) has set up a clinical study with the aim of testing the effectiveness of the molecule in the disease as quickly as possible.

Who can take part in the trial?

A patient is eligible for participation in the trial if he/she meets the following criteria:

• genetically proven VWM
• brain MRI abnormalities consistent with VWM
• at the time of study entry, a maximum disease duration of 8 years
• VWM disease started before the age of 6 years
• able to stand up and walk at least 10 steps, with or without some support
• not suffering from another significant disease (eg, heart, liver or kidney disease)
• not participating in another medical-scientific study
• able to undergo MRI examination (ie, no presence of metal-containing implants, such as cochlea implant, neurostimulator or pacemaker)
• living within reasonable travel distance from Amsterdam

• When all of these eligibility criteria are met, we can start the process of evaluating whether the child can participate in the trial.

Parents/guardians or treating physicians can contact the clinical team at TreatVWM@amsterdamumc.nl to discuss whether a child can participate in the trial.

ELA International is supporting this trial and is contributing €500,000. This study has been open since 1 June and will be conducted for at least one year. It may be extended to 3 or 4 years depending on the progress of recruitment, which is expected to reach 20 patients.

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By supporting clinicians and researchers working on leukodystrophies, ELA is once again involved in the development of international research. Research must continue to improve the understanding of the disease and to develop specific treatments. This first clinical trial on CACH represents real hope for these patients and their families.

Leukodystrophies are a major source of handicap at all ages, but children are affected most. The team studies leukodystrophies since 1987. Initially their research was focused on describing new leukodystrophies and finding the underlying gene defects. Much of their research efforts have focused on the new leukodystrophy vanishing white matter (VWM), also called childhood ataxia with CNS hypomyelination (CACH). The disease may occur at all ages, but mainly affects young children (2-6 years). Children with VWM experience progressive neurological handicap and die early, usually a few years after diagnosis. There is no cure for VWM, but patients benefit from treatments that prevent fever and head trauma, as these events trigger a fast worsening of the disease.

Several years ago, the team founds that the gene defect for VWM lies in an enzyme complex that is crucial for protein synthesis. Since then, they study how the disease works (disease mechanisms), most of all to find openings for treatment. The group founds that cells in the white matter of the brain do not develop into mature cells that can execute their normal function of myelination and white matter repair properly. The problem with maturing in functional cells can well explain the severe white matter damage that is observed in patients. Their recent studies have demonstrated that a basic stress pathway is abnormally activated in VWM white matter cells. They have evidence that abnormal activation of this stress pathway may contribute to disease.

In the proposed study they will test the effects of three FDA-approved inhibitors of this stress pathway in representative disease models. The proposed work has the potential to open up new treatment options fast. Their vision on treatment of VWM is that effective cure of this complex disease is not achieved with any single therapeutic modality. The team believes that the treatment should target the disease at multiple levels, including reduction of stress pathways, reduction of the toxicity of the diseased white matter, provision of patient derived cured/healthy white matter cells (stem cell transplantation) and possibly gene therapy.

Project financed by ELA up to: 99 762 €

Leukodystrophies are a major source of handicap at all ages, but children are affected most. We have studied leukodystrophies since 1987. Initially, our research focused on describing new leukodystrophies and finding the underlying gene defects. Much of our subsequent research efforts concerned the new leukodystrophy vanishing white matter (VWM), also called childhood ataxia with CNS hypomyelination (CACH). The disease occurs at all ages, but mainly starts in young children (2-6 years). Children with VWM experience progressive neurological handicap that prevent fever and head trauma, as these events trigger a fast worsening of the disease.

Several years ago we found that the gene defect for VWM lies in an enzyme complex that is crucial for protein synthesis. Since then we have studied how the disease works (disease mechanisms), most of all to find openings for potential treatment. We found that cells in the white matter of the brain do not develop into mature cells that can execute their normal function of myelination and white matter repair properly. The problem with maturing into functional cells can well explain the severe white matter damage that we observe in patients. Our recent studies have demonstrated that a basic stress pathway is abnormally activated in VWM white matter cells. We have evidence that abnormal activation of this stress pathway causes the disease. In the proposed study we will target and inhibit an important and toxic component of this stress pathway with antisense oligonucleotides and test the effects in a representative disease model. The proposed work has the potential to open up new treatment options relatively fast.

Our vision on treatment of VWM is that effective treatment of this complex disease is most likely not achieved with any single therapeutic modality. We think that the treatment should target the disease at multiple levels, including reduction of stress pathways, reduction of the toxicity of the diseased white matter, provision of healthy white matter cells and possibly gene therapy.

Project financed by ELA up to: 50 000 €