Vanishing White Matter (VWM) is an ultra-rare genetic condition that causes the deterioration of white matter in the brain and permanently affects the transmission of nerve signals to the rest of the body.
Individuals with VWM commonly have symptoms such as:
While symptoms often begin to appear between ages 2 and 6, the disease can present at any age. VWM is chronic and progressive, and stressors such as fever, infection, and mild head trauma may cause periods of faster deterioration.
VWM is an autosomal recessive disorder, meaning that both copies of the affected gene must be altered for the disease to manifest. There is currently no cure and no treatment approved for VWM.
VWM is caused by genetic variations in any of the five genes responsible for producing a protein complex called the eukaryotic translation initiation factor 2B (eIF2B). The activity of eIF2B is required for the production of new proteins in all our cells and is a key factor in the regulation of the integrated stress response (ISR). When the activity of eIF2B is reduced, protein production is also reduced and the ISR is turned on. When activated in the brain, a chronic ISR can cause the destruction of white matter.
In collaboration with AbbVie, Calico is investigating ABBV-CLS-7262 as a potential regulator of the ISR. ABBV-CLS-7262 directly targets eIF2B and increases the activity of both normal elF2B complexes and those carrying VWM variations. In preclinical studies, ABBV-CLS-7262 has demonstrated the ability to decrease the ISR in the brain and spinal cord in disease models that carry VWM variations and has been shown to improve coordination and movement problems. It is hypothesized that if proper function of the elF2B protein complex can be restored, brain white matter damage and loss may be prevented in people with VWM.
Calico has also partnered with the Vanishing White Matter Consortium to investigate the use of ABBV-CLS-7262 in treating VWM. For more information about this global consortium visit: www.vwmconsortium.org.
Calico has initiated enrollment of patients in a Phase 1b clinical trial of ABBV-CLS-7262 in people diagnosed with VWM (NCT05757141). ABBV-CLS-7262 is currently used only under clinical investigation and is not approved for any use in any markets at this time.
The most up to date information about this investigational study can be found by visiting www.clinicaltrials.gov and entering “NCT05757141” in the “Other terms” field.
For questions about potential trial participation and available travel support, please call: 1-833-250-9660 or send an email to: firstname.lastname@example.org.
Calico and our collaborative partners are committed to designing and conducting clinical studies with the highest integrity and ethical standards and we are devoted to the safety and well-being of the people who participate. All interventional clinical trials sponsored by Calico are designed in accordance with, and authorized by, the appropriate regulatory agencies. If you have additional questions, please contact us at: email@example.com.
Yao Liang Wong, et al. The small molecule ISRIB rescues the stability and activity of Vanishing White Matter Disease eIF2B mutant complexes. eLife 7:e32733 (2018). https://doi.org/10.7554/eLife.32733
Yao Liang Wong, et al. eIF2B activator prevents neurological defects caused by a chronic integrated stress response. eLife 8:e42940 (2019). https://doi.org/10.7554/eLife.42940
James J. Lee, et al. eIF2B Activator Rescues Neonatal Lethality of an eIF2Bα Sugar Phosphate Binding Mutation Associated with Vanishing White Matter Disease. bioRxiv 2023.05.06.539602 (2023). https://doi.org/10.1101/2023.05.06.539602