75. Trametinib Prevents Formation of Vascular Lesions in a MAP2k1-p.K57N Arteriovenous Malformation Mouse Model
Year: 2024
Type: article
Abstract: Purpose: Extracranial arteriovenous malformation (AVM) is caused by a MAP2K1 mutation in endothelial cells (ECs). We previously generated a mouse model of AVM by introducing the MAP2K1 p.K57N mutation into the ROSA (R26) locus genome. Activation of the mutation in ECs caused AVM-like vascular malformations most prominent in brain, and intestines. The goal of this study was to determine if pharmacotherapy using a MAP2K1 inhibitor would prevent the formation of vascular lesions in mutant mice. Methods: 12 R26GT-Map2k1-GFP/+; Tg-Cdh5CreER+/- mutant pups were treated topically on the dorsal skin of the left ear with 50 ug of 4-OH-tamoxifen at postnatal day 10 (P10) to generate vascular lesions. Six mice (Group 1) were not treated with a MAP2K1 inhibitor. Six mice (Group 2) were treated with the MAP2K1 inhibitor trametinib starting at P21 (weaning) (3 ug/ml ad libitum in drinking water). Both groups were followed for survival and development of vascular lesions. Results: Group 1 non-treated mice died between P30-P45. All animals contained vascular malformations in the brain and intestines. Group 2 mice all survived long-term and were analyzed at P52 for the presence of vascular anomalies. None of the mice treated with trametinib developed vascular malformations. Conclusion: A MAP2K1 inhibitor prevents formation of Map2k1-K57N induced vascular malformations in mice. These findings support the use of trametinib as a treatment for patients with extracranial AVM.
Institution: Boston Children's Hospital
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,195
OpenAlex ID: W4395028511