A Phase 1/2 trial suggests that the antihypertensive drug Guanabenz may alter the progression of vanishing white matter disease in children, offering new hope for a rare and devastating neurological disorder.
Guanabenz, an older antihypertensive medicine, may offer the first sign of a treatment that changes the course of vanishing white matter disease, a rare inherited brain disorder that mainly affects young children. In a phase 1/2 study published in The Lancet Neurology, children given the drug were far less likely to lose the ability to walk with support than similar patients who did not receive the treatment.
The trial, led by Margo van der Knaap at Amsterdam UMC, followed 33 children with genetically and MRI-confirmed disease. They were treated for up to four years, starting with a low dose that was gradually increased. Among the treated group, seven children lost walking ability with support, compared with 29 in a matched historical control group from the international Vanishing White Matter Registry. The researchers said this amounted to a 67% lower hazard of reaching that endpoint.
Vanishing white matter usually begins between the ages of 1 and 6 and steadily damages the brain’s white matter, often leading to severe disability and early death. The condition is caused by mutations in EIF2B genes, which trigger a harmful stress response in cells. Guanabenz appears to act on that pathway, and earlier animal studies suggested it could ease disease features.
The benefits looked strongest in children whose symptoms began at age 3 or later. In that subgroup, only one of 18 treated patients lost walking ability with support, versus 11 of 36 matched controls. The authors said the results suggest the drug may mainly slow further decline when started relatively early, while treatment begun even sooner could prove more effective.
Safety, however, remains an issue. The investigators said the adverse-effect profile was manageable, but hallucinations were common and often appeared in the first months of treatment. Other serious reactions included constipation and one episode of low blood pressure with marked sleepiness. No child stopped treatment because of side effects, and there were no deaths or life-threatening events.
Geneviève Bernard of McGill University, writing in a linked comment, said the findings are the first clinical evidence that a therapy might alter the disease course in vanishing white matter. She said larger studies with longer follow-up are needed to show whether the benefit lasts, and noted that other approaches, including gene therapy and combination treatment, may also help in future.
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