The impact of vanishing white matter on unaffected family members
Orphanet J Rare Dis 20, 456 (2025). https://doi.org/10.1186/s13023-025-03987-8
Guanabenz Clinical Trial - Data Management Plan (pdf)
A phase 1/2 clinical trial to Explore the Safety, Tolerability, Pharmacokinetic Profile, and Potential Efficacy of Guanabenz in Patients With Early Childhood Onset Vanishing White Matter (VWM)
Vanishing white matter (VWM) is caused by a genetic defect in eukaryotic translation initiation factor 2B, eIF2B. As a consequence, eIF2B activity is decreased, thereby constitutively activating the downstream integrated stress response (ISR). The drug Guanabenz has been shown to impact the ISR and to ameliorate the disease in VWM models. Guanabenz is a known α2-adrenergic antihypertensive drug with proven safety in adults and children above 12 years of age and therefore suitable for assessing the effect in VWM patients.
With CCMO / CTIS approval, we executed a clinical trial with the aim to evaluate the safety, tolerability and efficacy of Guanabenz in young children with VWM. For further details on the background and details of this study see the EU clinical trials register: https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-001438-25/NL.
The Guanabenz trial started May 31 2021 and ended May 31, 2025. Database lock is on August 1, 2025.
The Statistical Analysis Plan, Data Management Plan and Data Validation and Derivation plan are available.
Vanishing white matter (VWM) is caused by a genetic defect in eukaryotic translation initiation factor 2B, eIF2B. As a consequence, eIF2B activity is decreased, thereby constitutively activating the downstream integrated stress response (ISR). The drug Guanabenz has been shown to impact the ISR and to ameliorate the disease in VWM models. Guanabenz is a known α2-adrenergic antihypertensive drug with proven safety in adults and children above 12 years of age and therefore suitable for assessing the effect in VWM patients.
With CCMO / CTIS approval, we executed a clinical trial with the aim to evaluate the safety, tolerability and efficacy of Guanabenz in young children with VWM. For further details on the background and details of this study see the EU clinical trials register: https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-001438-25/NL.
The Guanabenz trial started May 31 2021 and ended May 31, 2025. Database lock is on August 1, 2025.
The Statistical Analysis Plan, Data Management Plan and Data Validation and Derivation plan are available.
Guanabenz Clinical Trial - Statistical analysis plan (pdf)
A phase 1/2 clinical trial to Explore the Safety, Tolerability, Pharmacokinetic Profile, and Potential Efficacy of Guanabenz in Patients With Early Childhood Onset Vanishing White Matter (VWM)
Vanishing white matter (VWM) is caused by a genetic defect in eukaryotic translation initiation factor 2B, eIF2B. As a consequence, eIF2B activity is decreased, thereby constitutively activating the downstream integrated stress response (ISR). The drug Guanabenz has been shown to impact the ISR and to ameliorate the disease in VWM models. Guanabenz is a known α2-adrenergic antihypertensive drug with proven safety in adults and children above 12 years of age and therefore suitable for assessing the effect in VWM patients.
With CCMO / CTIS approval, we executed a clinical trial with the aim to evaluate the safety, tolerability and efficacy of Guanabenz in young children with VWM. For further details on the background and details of this study see the EU clinical trials register: https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-001438-25/NL.
The Guanabenz trial started May 31 2021 and ended May 31, 2025. Database lock is on August 1, 2025.
The Statistical Analysis Plan, Data Management Plan and Data Validation and Derivation plan are available.
Vanishing white matter (VWM) is caused by a genetic defect in eukaryotic translation initiation factor 2B, eIF2B. As a consequence, eIF2B activity is decreased, thereby constitutively activating the downstream integrated stress response (ISR). The drug Guanabenz has been shown to impact the ISR and to ameliorate the disease in VWM models. Guanabenz is a known α2-adrenergic antihypertensive drug with proven safety in adults and children above 12 years of age and therefore suitable for assessing the effect in VWM patients.
With CCMO / CTIS approval, we executed a clinical trial with the aim to evaluate the safety, tolerability and efficacy of Guanabenz in young children with VWM. For further details on the background and details of this study see the EU clinical trials register: https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-001438-25/NL.
The Guanabenz trial started May 31 2021 and ended May 31, 2025. Database lock is on August 1, 2025.
The Statistical Analysis Plan, Data Management Plan and Data Validation and Derivation plan are available.
Guanabenz Clinical Trial - Data Validation and Derivation Plan (pdf)
A phase 1/2 clinical trial to Explore the Safety, Tolerability, Pharmacokinetic Profile, and Potential Efficacy of Guanabenz in Patients With Early Childhood Onset Vanishing White Matter (VWM)
Vanishing white matter (VWM) is caused by a genetic defect in eukaryotic translation initiation factor 2B, eIF2B. As a consequence, eIF2B activity is decreased, thereby constitutively activating the downstream integrated stress response (ISR). The drug Guanabenz has been shown to impact the ISR and to ameliorate the disease in VWM models. Guanabenz is a known α2-adrenergic antihypertensive drug with proven safety in adults and children above 12 years of age and therefore suitable for assessing the effect in VWM patients.
With CCMO / CTIS approval, we executed a clinical trial with the aim to evaluate the safety, tolerability and efficacy of Guanabenz in young children with VWM. For further details on the background and details of this study see the EU clinical trials register: https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-001438-25/NL.
The Guanabenz trial started May 31 2021 and ended May 31, 2025. Database lock is on August 1, 2025.
The Statistical Analysis Plan, Data Management Plan and Data Validation and Derivation plan are available.
Vanishing white matter (VWM) is caused by a genetic defect in eukaryotic translation initiation factor 2B, eIF2B. As a consequence, eIF2B activity is decreased, thereby constitutively activating the downstream integrated stress response (ISR). The drug Guanabenz has been shown to impact the ISR and to ameliorate the disease in VWM models. Guanabenz is a known α2-adrenergic antihypertensive drug with proven safety in adults and children above 12 years of age and therefore suitable for assessing the effect in VWM patients.
With CCMO / CTIS approval, we executed a clinical trial with the aim to evaluate the safety, tolerability and efficacy of Guanabenz in young children with VWM. For further details on the background and details of this study see the EU clinical trials register: https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-001438-25/NL.
The Guanabenz trial started May 31 2021 and ended May 31, 2025. Database lock is on August 1, 2025.
The Statistical Analysis Plan, Data Management Plan and Data Validation and Derivation plan are available.
Core protocol development for phase 2/3 clinical trials in the leukodystrophy Vanishing White Matter: a consensus statement by the VWM consortium and patient advocates
BMC Neurol 23, 305 (2023). https://doi.org/10.1186/s12883-023-03354-9
Therapy Trial Design in Vanishing White Matter - An Expert Consortium Opinion
Neurol Genet Apr 2022, 8 (2) e657; DOI: 10.1212/NXG.0000000000000657
Childhood Ataxia with Central Nervous System Hypomyelination / Vanishing White Matter
GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020. PMID: 20301435 Bookshelf ID: NBK1258
Vanishing white matter disease expression of truncated EIF2B5 activates induced stress response.
Elife. 2020 Dec 10;9:e56319. doi: 10.7554/eLife.56319. PMID: 33300869; PMCID: PMC7752137.
Vanishing white matter: Eukaryotic initiation factor 2B model and the impact of missense mutations
Mol Genet Genomic Med; 9(3):e1593. doi: 10.1002/mgg3.1593. Epub 2021 Jan 12.
Modeling vanishing white matter disease with patient-derived induced pluripotent stem cells reveals astrocytic dysfunction
CNS Neurosci Ther; 25(6):759-771. doi: 10.1111/cns.13107. Epub 2019 Feb 5. PMID: 30720246; PMCID: PMC6515702.