Thalidomide Reverses Sporadic Arteriovenous Malformation in the Central Nervous System

Sporadic arteriovenous malformations of the central nervous system (CNS-AVMs) are caused by somatic activating mutations of KRAS within endothelial cells (ECs) of the brain and spinal cord. There is no approved drug for this disease because the lack of a clinically representative animal model has hindered drug discovery. Here, we developed a novel mouse model of sporadic brain AVM (BAVM) induced by intracerebral injection of AAV-BR1-KRASG12V. This model faithfully recapitulates the clinical manifestations, radiology, pathology, and transcriptomic profiles of human sporadic BAVM. Connectivity Map database analysis revealed thalidomide as a promising therapeutic. Preclinical experiments revealed that thalidomide can restore mural cell coverage with downregulating Angiopoietin 2 (ANGPT2) in ECs and inhibiting BAVM progression. This effect reduced hemorrhage and prolonged the survival of mice with BAVM. We then administered thalidomide to 30 patients with sporadic CNS-AVMs. Over a median treatment duration of 7.3 months, AVM lesions regressed in 60.7% of patients, while symptoms improved in 10.7%. Biopsies demonstrated that thalidomide increased mural cell coverage and decreased ANGPT2 expression in ECs within AVM lesions. In summary, we established a representative model of sporadic BAVM and provided promising evidence supporting the therapeutic potential of thalidomide for sporadic CNS-AVMs.