Repurposed drug thalidomide shows promise for hard-to-treat brain and spinal cord arteriovenous malformations
Science China Press
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This graphical abstract summarizes the study design and main findings. The researchers constructed a KRAS-driven mouse model of sporadic brain arteriovenous malformation, identified thalidomide through transcriptomic drug screening, and validated its therapeutic potential in mice and patients. Thalidomide may promote vascular stabilization by reducing ANGPT2 expression and restoring mural cell coverage.
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Central nervous system arteriovenous malformations, or CNS-AVMs, are abnormal tangles of blood vessels in the brain or spinal cord. They form direct high-flow connections between arteries and veins and can cause hemorrhagic stroke, seizures, headache, neurological deficits, or progressive disability, especially in children and young adults. Current treatments, including microsurgery, embolization, and stereotactic radiosurgery, can be effective but are invasive and may carry substantial risks for patients with complex lesions. This considerable therapeutic gap underscores the urgent need for effective pharmacological strategies against sporadic CNS-AVMs.
A research team led by investigators from Xuanwu Hospital, Capital Medical University, has reported preclinical and early clinical evidence that thalidomide may help stabilize and shrink sporadic CNS-AVMs.
A major obstacle to drug development for sporadic CNS-AVMs has been the lack of an animal model that closely resembles human disease. To address this challenge, the researchers developed a mouse model of sporadic brain arteriovenous malformation, or BAVM, driven by KRASG12V, a mutation associated with human sporadic CNS-AVMs. The model reproduced key features of human BAVM, including feeding arteries, a nidus, draining veins, high-flow vascular shunting, hemorrhagic changes, impaired vascular integrity, and reduced mural cell coverage.
The researchers then compared gene-expression profiles from human and mouse BAVMs and found strong cross-species similarity. Using the Connectivity Map platform, which predicts compounds that may reverse disease-associated molecular signatures, thalidomide emerged as a top candidate among FDA approved drugs.
In BAVM mice, thalidomide improved survival, reduced lesion growth, decreased hemorrhage, lowered abnormal blood-flow velocity, improved neuromuscular performance, and increased mural cell coverage around malformed vessels. These findings suggest that thalidomide may help convert fragile, unstable vessels into more mature and stable vascular structures.
The researchers also found the therapeutic mechanism of thalidomide in sporadic CNS-AVMs. Thalidomide reduced endothelial angiopoietin 2, or ANGPT2, a molecule associated with vascular destabilization and abnormal endothelial-mural cell communication. Blocking ANGPT2 with a neutralizing antibody produced key therapeutic effects similar to those of thalidomide in the mouse model, supporting ANGPT2 as a potential mediator of the drug’s benefit.
To evaluate clinical relevance, the team conducted a proof-of-concept clinical study involving patients with refractory sporadic brain or spinal cord arteriovenous malformations who were refractory invasive treatment. Among 28 patients who completed thalidomide therapy and follow-up digital subtraction angiography, no lesion growth was observed. Eleven patients had stable lesions, while 17 showed lesion regression. Some patients showed shrinkage of the nidus, feeding arteries, draining veins, or aneurysms. Adverse events were mild to moderate, with no grade 3 or higher events reported.
Human tissue analysis further supported the proposed mechanism. In cutaneous arteriovenous malformation samples from patients with metameric spinal cord arteriovenous malformations, thalidomide treatment increased mural cell coverage and reduced endothelial ANGPT2 expression, consistent with the findings in mice.
The authors emphasize that the clinical study was exploratory, single-arm, and limited by its small sample size and relatively short follow-up. Larger controlled studies are needed to confirm efficacy, determine optimal dosing, and evaluate long-term safety. Nevertheless, the findings provide a potential pharmacological strategy for patients with complex sporadic CNS-AVMs, particularly those who are poor candidates for invasive treatment or may benefit from preoperative lesion regression.
“This study provides a representative experimental model for sporadic brain arteriovenous malformations and offers early evidence that thalidomide may promote vascular stabilization through ANGPT2 downregulation and mural cell restoration,” the authors said. “These findings open a new direction for developing medical therapies for these challenging vascular disorders.”
