Genetically Guided Pharmacotherapy for Structural Neurovascular Lesions

Structural neurovascular lesions (SNVLs)-arteriovenous malformations, cavernous malformations, and vein of Galen aneurysmal malformations, among others-have historically been treated using neurosurgical, radiotherapeutic, and endovascular approaches. However, lesion size, location, and presence of high-risk angioarchitectural features preclude many patients from receiving these treatments. Advances in human genetics and cerebrovascular biology have redefined SNVLs as dynamic, genetically driven lesions where sporadic cases are caused by somatic variants. Intriguingly, many SNVL-causing variants are also oncogenic and active drug targets. These data provide the rationale for a genetically driven taxonomy to guide targeted therapeutic selection. In this commentary, we synthesize efforts toward pharmacologic treatments of SNVLs and highlight how variant-specific or pathway-modulating therapies may be investigated, incorporating key considerations in molecular diagnosis, cerebrovascular biology, and molecular and phenotypic outcome measures, in forthcoming clinical trials. Together, these advances support the investigation of pharmacologic treatment strategies in carefully selected patients with SNVLs.