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Therapy Trial Design in Vanishing White Matter: An Expert Consortium Opinion
Marjo S van der Knaap1, Joshua L Bonkowsky1, Adeline Vanderver1
1Department of Pediatric Neurology (M.S.v.d.K., N.I.W.), Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers; Amsterdam Neuroscience (M.S.v.d.K., N.I.W.); Department of Functional Genomics (M.S.v.d.K.), Center for Neurogenomics and Cognitive Research, Vrije Universiteit, Amsterdam, the Netherlands; Division of Pediatric Neurology (J.L.B.), Department of Pediatrics, University of Utah School of Medicine; Primary Children's Hospital (J.L.B.), Intermountain Healthcare, Salt Lake City, UT; Division of Neurology (A.V.), Children's Hospital of Philadelphia; Department of Neurology (A.V.), Perelman School of Medicine, University of Pennsylvania, PA; 4D Molecular Therapeutics (R.S.), Emeryville, CA; Department of Developmental and Child Neurology (I.K.-M.), Social Pediatrics, University Children's Hospital Tübingen, Germany; Department of Neuroscience (E.B.), Unit of Neuromuscular and Neurodegenerative Diseases, Laboratory of Molecular Medicine, Genetics and Rare Diseases Research Division, IRCCS Ospedale Pediatrico Bambino Gesù, Rome 00146, Italy; Departments of Neurology and Neurosurgery (G.B.), Pediatrics and Human Genetics, McGill University; Department Specialized Medicine (G.B.), Division of Medical Genetics, McGill University Health Center; Child Health and Human Development Program (G.B.), Research Institute of the McGill University Health Center, Montreal, Canada; Kennedy Krieger Institute (S.A.F.), Johns Hopkins University, Baltimore, MD; Research Department (E.S.-V.), European Leukodystrophies Association International and European Leukodystrophies Association France, Paris, France; United Leukodystrophy Foundation (R.R.), DeKalb, IL; Vereniging Volwassenen, Kinderen en Stofwisselingsziekten (H.D.), Zwolle, the Netherlands; Industry Alliance Office (P.v.B., P.S.L.), Amsterdam Neuroscience, Amsterdam University Medical Centers; and Department of Epidemiology and Data Science (P.v.d.V.), Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam, the Netherlands.
Abstract:
Vanishing white matter (VWM) is a leukodystrophy caused by recessive variants in the genes EIF2B1-EIF2B5. It is characterized by chronic neurologic deterioration with superimposed stress-provoked episodes of rapid decline. Disease onset spans from the antenatal period through senescence. Age at onset predicts disease evolution for patients with early onset, whereas disease evolution is unpredictable for later onset; patients with infantile and early childhood onset consistently have severe disease with rapid neurologic decline and often early death, whereas patients with later onset have highly variable disease. VWM is rare, but likely underdiagnosed, particularly in adults. Apart from measures to prevent stressors that could provoke acute deteriorations, only symptomatic care is currently offered. With increased insight into VWM disease mechanisms, opportunities for treatment have emerged. EIF2B1-EIF2B5 encode the 5-subunit eukaryotic initiation factor 2B complex, which is essential for translation of mRNAs into proteins and is a principal regulator of the integrated stress response (ISR). ISR deregulation is central to VWM pathology. Targeting components of the ISR has proven beneficial in mutant VWM mouse models, and several drugs are now in clinical development. However, clinical trials in VWM pose considerable challenges: low numbers of known patients with VWM, unpredictable disease course for patients with onset after early childhood, absence of intermediate biomarkers, and novel first-in-human molecular targets. Given these challenges and considering the critical need to offer therapies, we have formulated recommendations for enhanced diagnosis, drug trial setup, and patient selection, based on our expert evaluation of molecular, laboratory, and clinical data.
