Breakthrough trial offers first hope for children with Vanishing White Matter disease
核心洞察
A phase 1/2 trial found that the repurposed antihypertensive drug guanabenz may alter the course of vanishing white matter disease (搜索) (VWM), a rare childhood neurodegenerative disorder with no previously effective treatment.
Among 33 treated children compared with 66 matched historical controls, none died during the study, whereas deaths occurred in the untreated group, and treated children lost the ability to walk with support less frequently.
MRI scans showed less white matter deterioration in treated children, with the greatest benefit observed in those whose disease began at age 3 or later.
A team of researchers from the Amsterdam Leukodystrophy Center at Amsterdam UMC (搜索), led by Prof. Marjo van der Knaap, has published the first clinical evidence that the drug guanabenz may alter the course of vanishing white matter disease (搜索) (VWM), a devastating childhood neurodegenerative disorder for which no effective treatment previously existed. The findings from this phase 1/2 trial, conducted between 2021 and 2025, have now been published in The Lancet Neurology.
A devastating disease with no effective therapy
Vanishing white matter disease (搜索) is a rare inherited neurodegenerative disorder that usually begins between 1 and 6 years of age. Children with VWM progressively lose motor and cognitive abilities, develop severe disabilities, and often die at a young age. The disease is estimated to affect approximately 1 in 100,000 children worldwide. In the Netherlands, about 1.3 people per million are living with the condition.
The disease is caused by a genetic defect affecting eukaryotic initiation factor 2B (搜索) (eIF2B), a key regulator of the integrated stress response. For many years, researchers at the Amsterdam Leukodystrophy Center, within the department of Pediatric Neurology at Amsterdam UMC (搜索), have investigated the genetic and molecular basis of VWM. Under the leadership of Prof. Van der Knaap and Prof. Nicole Wolf, this work has led to the identification of underlying genetic mutations and the start of both preclinical and clinical studies.
The first clinical trial targeting the disease mechanism
The phase 1/2 trial was conducted with support of international patient recruitment. In total, 33 ambulatory children with VWM received guanabenz, a repurposed antihypertensive drug that inhibits the integrated stress response believed to drive VWM pathology. Guanabenz is no longer marketed for hypertension because newer blood-pressure medications are available, so Amsterdam UMC (搜索) arranged for the drug to be specially manufactured for children participating in the VWM study.
Outcomes in the treated children were compared with those of 66 matched historical controls from an international registry. The treatment was found to be safe and, after an initial period of side effects, generally well tolerated.
Significant clinical benefits
Compared with untreated controls, children receiving guanabenz had a significantly lower risk of losing the ability to walk with support. The difference in disability between treated and untreated children increased over four years. Notably, none of the treated children died during the study, whereas deaths occurred in the historical control group — five of the 66 children in the comparison group died during the study period.
Furthermore, MRI scans showed that treated children experienced less white matter deterioration, and in some cases no detectable progression, compared with untreated children. The positive effect of the medication was greatest in children whose disease began at age 3 or later, compared to children whose disease began before age 3.
"This demonstrates for the first time that this fatal brain disease in children can be influenced," said Marjo van der Knaap, the study's first author and a retired professor of pediatric neurology at Amsterdam UMC (搜索).
Side effects and tolerability
Side effects, including hallucinations, drowsiness, constipation and low blood pressure, occurred mainly during the first few months of treatment. After four to six months, the children generally tolerated the medication well, and none discontinued treatment because of side effects.
"Precisely because we are dealing with young children, it is important that side effects are recognizable, treatable and temporary," van der Knaap said.
What these findings mean
This study is the first to demonstrate a meaningful treatment to alter the course of VWM and suggests that patients with later-onset disease may benefit from therapy if treatment is started early. However, the researchers emphasize that guanabenz is not a cure. The beneficial effect is expected to stop when treatment is stopped, and the study did not include a concurrent untreated control group; instead, treated children were compared with previously registered patients.
"Nevertheless, this study marks an important turning point," Van der Knaap says.
Next steps toward longer-term treatment
In a follow-up study, children will be monitored for a longer period, and the effects of higher doses of guanabenz will be investigated. At present, guanabenz is available only within a research setting because it has not yet been approved by the European Medicines Agency (EMA) for the treatment of VWM. While the follow-up study continues, Amsterdam UMC (搜索) has begun the first steps toward obtaining EMA approval so that the treatment may eventually become available outside clinical research.