RATIONALE: Vanishing white matter (VWM) is a genetic brain disease, mainly affecting young children. Onset 4yr leads to rapid decline and death, onset at or >4yr to slower, more variable disease. Only for onset <4 yr, age of onset predicts the disease course. VWM is caused by a defect in eIF2B, an integrated stress response (ISR) regulator. Stresses reduce eIF2B activity, thereby activating the ISR. Mutant eIF2B has reduced activity and in VWM the ISR always activated. No curative therapy is available. Guanabenz, an old antihypertensivum, was found to also reduce ISR activation. In VWM mice, Guanabenz reduces ISR activation and ameliorates the disease clinically and pathologically. It is the first drug with potential for VWM patients.
HYPOTHESIS: Guanabenz ameliorates VWM.
STUDY DESIGN: International mono-center, open-label, non-randomized study with historical controls.
STUDY POPULATION: 20 VWM patients with onset <4yr, early in the disease course, before brain damage is irreparable.
INTERVENTION & COMPARATOR: Patients will be titrated to their maximum tolerated Guanabenz dose (1-10 mg/kg/d). All patients will remain in the study until the last has been followed 1yr. From our historical cohort (296 patients), strata will be predefined based on disease onset and degree of handicap at diagnosis. Each trial patient will have a control set of historical patients in the same stratum.
OUTCOME MEASURES: Guanabenz, has proven safety in adults and teenagers, but the trial concerns its first application in young children and relatively high doses may be needed. We will assess safety, tolerability, pharmacokinetics and –dynamics, and efficacy in terms of major effects. Annually, quantitative clinical and brain MRI parameters reflecting tissue integrity will be assessed.
SAMPLE SIZE: 20 is the max achievable in 3 years and sufficient to assess safety, tolerability, major clinical effects and reliable estimates of outcomes and standard deviations, important for future studies.