Vanishing White Matter Disease (VWMD)
Vanishing white matter (VWM) is a rare inherited neurological disease that mainly affects children. It damages the brain’s white matter, leading to progressive problems with movement, coordination, speech, and thinking. Even minor illnesses, fever, or head injuries can trigger sudden and irreversible worsening of symptoms. Studies in mice suggested that guanabenz, a medicine originally developed to treat high blood pressure, could protect brain cells affected by VWM. Before testing whether the drug is effective in children, researchers first needed to understand how it is processed by the body (pharmacokinetics) and how it affects the body (pharmacodynamics), helping to identify doses that are both safe and potentially beneficial. In this phase 1/2 clinical trial, 32 children with genetically confirmed VWM received guanabenz. The researchers measured drug levels in the blood, monitored blood pressure, heart rate and body temperature, and recorded any side effects. They also compared the results with computer models based on previous animal and adult studies to assess how accurately these models predicted drug exposure in children. The study found that the modelling approach predicted guanabenz concentrations reasonably well and that the doses used achieved blood levels thought to be potentially therapeutic. However, hallucinations emerged as an unexpected dose-limiting side effect, and larger reductions in blood pressure appeared to increase this risk. These findings suggest that blood pressure could help monitor treatment safety and that future studies may need to use lower or more carefully adjusted doses. Overall, this research provides valuable guidance for designing future clinical trials of guanabenz in children with VWM.