A team at Xuanwu Hospital, Capital Medical University, has identified thalidomide as a potential treatment for sporadic central nervous system arteriovenous malformations using a novel KRASG12V-driven mouse model and exploratory clinical data from 28 patients.
Researchers at Xuanwu Hospital, Capital Medical University have reported encouraging preclinical and early clinical evidence that thalidomide may help stabilise and reduce rare vascular malformations affecting the brain and spinal cord.
Central nervous system arteriovenous malformations (CNS-AVMs) are abnormal tangles of blood vessels that create direct, high-flow connections between arteries and veins. These lesions can lead to haemorrhagic stroke, seizures, headaches, neurological impairment and progressive disability, particularly in children and young adults.
While treatments such as microsurgery, embolisation and stereotactic radiosurgery can be effective, they are invasive and may carry significant risks, especially for patients with complex lesions. As a result, a safe and effective drug-based therapy is needed.
New disease model enables drug discovery
One of the biggest barriers to developing medicines for sporadic CNS-AVMs has been the lack of animal models that accurately reflect the human disease.
To overcome this, the researchers developed a mouse model of brain arteriovenous malformation driven by the KRASG12V mutation, which is associated with sporadic CNS-AVMs in humans.
The model successfully reproduced many of the key characteristics of the disease, including feeding arteries, a central vascular nidus, draining veins, abnormal blood flow, haemorrhagic changes and impaired vessel integrity.
One of the biggest barriers to developing medicines for sporadic CNS-AVMs has been the lack of animal models that accurately reflect the human disease
By comparing gene-expression profiles from both human and mouse lesions, the team identified strong similarities between the two. They then used the Connectivity Map platform, a tool that predicts compounds capable of reversing disease-related molecular signatures.
Among approved medicines, thalidomide emerged as one of the most promising candidates.
Improved survival and reduced lesion growth
When administered to mice with brain arteriovenous malformations, thalidomide produced a range of beneficial effects.
The treatment improved survival rates, reduced lesion growth and haemorrhage, lowered abnormal blood-flow velocity and improved neuromuscular function. Researchers also observed increased coverage of malformed blood vessels by mural cells, which play a key role in maintaining vascular stability.
The findings suggest that thalidomide may help transform fragile and unstable blood vessels into more mature vascular structures.
The treatment improved survival rates, reduced lesion growth and haemorrhage, lowered abnormal blood-flow velocity and improved neuromuscular function
Further investigation revealed a possible mechanism behind these effects. The drug reduced levels of angiopoietin 2 (ANGPT2), a molecule associated with vascular instability and abnormal communication between endothelial and mural cells.
Blocking ANGPT2 directly with a neutralising antibody produced similar therapeutic benefits in the mouse model, reinforcing the molecule’s potential role in disease progression.
Early clinical results show encouraging signs
To explore whether the findings might translate to patients, the researchers conducted an exploratory clinical study involving individuals with refractory brain or spinal cord arteriovenous malformations who were not suitable candidates for invasive treatment.
Among the 28 patients who completed treatment and follow-up imaging, no lesion growth was observed. Eleven patients showed stable disease, while 17 experienced some degree of lesion regression.
Among the 28 patients who completed treatment and follow-up imaging, no lesion growth was observed
In several cases, reductions were observed in the size of the nidus, feeding arteries, draining veins or associated aneurysms. Reported side effects were mild to moderate and no severe treatment-related adverse events were recorded.
Analysis of human tissue samples further supported the proposed mechanism, showing increased mural cell coverage and reduced ANGPT2 expression following treatment.
Whats next?
The researchers caution that the study was exploratory and involved a relatively small number of patients with limited follow-up. Larger controlled trials will be required to establish long-term safety, determine optimal dosing and confirm efficacy.
Nevertheless, the findings represent a potentially important step towards developing the first pharmacological treatment for sporadic CNS-AVMs.
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