Cheaper and Safer: A New Effective Treatment for Abnormal Blood Vessel Formations



Thalidomide's anti-angiogenesis (blocking of blood vessel development) features, which led to birth abnormalities when it was given to pregnant women, are the same characteristics that have spurred interest in its therapeutic potential in other fields.

At the annual meeting of the European Society for Human Genetics on Sunday, Professor Miikka Vikkula of the de Duve Institute, Université Catholique de Louvain, Brussels, Belgium, presented findings from a study on the use of thalidomide in patients with severe arteriovenous malformations (AVMs). These results show a significant reduction in symptoms and an improvement in quality of life as a result, and were just published in Nature Cardiovascular Research.

AVMs are aberrant blood vessel clusters that connect veins and arteries and alter regular blood flow. They cause cardiac problems, severe discomfort, bleeding, and deformities of the affected bodily portion. They are typically congenital and frequently don't show until a person matures and reaches adolescent or old age. When treating severe cases, surgery or embolization (the injection of a material that locally destroys blood vessels, generating scar tissue) are frequently utilized, despite the fact that these treatments are rarely totally effective and sometimes further worsen the situation.

Although some people with AVMs can lead reasonably normal lives, there is always a chance that the aberrant blood vessel tangles in the brain could burst, leading to a stroke. Annually, one hundred AVM patients experience a stroke.

For 30 years, Professor Vikkula's team has been researching the causes of vascular anomalies. "We have discovered a number of genetic reasons and have demonstrated that specific mutations trigger signaling within blood vessel wall cells, promoting aberrant blood vessel creation" (angiogenesis). This made us consider whether thalidomide may be used to prevent the creation of aberrant blood vessels.

Professor Laurence Boon from the Centre for Vascular Anomalies at Saint Luc University Hospital in Brussels, who has been working with Professor Vikkula for 30 years, recruited 18 patients with AVMs to a study of the use of thalidomide in their condition after demonstrating that a vascular malformation could be corrected in a mouse model.

They ranged in age from 19 to 70 and all had significant abnormalities that were resistant to treatment by traditional methods. Prior to starting thalidomide treatment and for four weeks after finishing it, patients had to consent to using contraception for at least four weeks. Men also had to consent to using condoms during intercourse because thalidomide is found in semen.

For a period of two to 52 months, patients were given either 50 mg, 100 mg, or 200 mg of thalidomide every day. Eight AVMs remained stable after an average of 54 months without thalidomide, while four returned after an average of 11.5 months. Five patients were able to reduce their thalidomide dosage to 50mg per day thanks to a combination treatment that also included embolization, in which arteries or veins within the AVM are plugged by a substance that kills vascular wall cells.

According to Professor Vikkula, it was crucial to lower the dose whenever possible because a higher dose was linked to adverse effects, particularly fatigue and peripheral neuropathy, which is damage to the nerves outside the brain and spinal cord and causes weakness and numbness, especially in the hands and feet.

According to Professor Vikkula, "all the patients reported a quick reduction in pain, together with the cessation of bleeding and the healing of ulcers where these were present." "After 19 months of thalidomide treatment and an eight-year follow-up, the three patients with heart failure also experienced difficulties being treated, and one AVM appeared to be totally cured.

Vascular endothelial growth factor (VEGF), a signaling protein that encourages the creation of new blood vessels, is one of the ways that thalidomide functions, as is well known. Due to the high VEGF levels found in vascular anomalies like AVMs, it is likely that thalidomide inhibits signaling through angiogenesis-promoting pathways. Despite the limited size of our study, the results are compelling, and we anticipate that larger studies will support them.

The low cost of thalidomide therapy for AVMs is an additional benefit. Two more medications, which cost up to twelve times as much and also have a long list of negative effects, are being investigated to treat AVMs and were recently created for use in oncology.

Our findings were not unexpected because we had predicted that thalidomide would be effective in these patients, but it was wonderful to receive clinical proof that we were correct, says Professor Vikkula. According to us, this is a ground-breaking discovery that offers a strong foundation for the creation of molecular therapies for AVMs.

"This study highlights not only the healthcare and economic benefits of repurposing pharmaceuticals - even the most reviled - but also how genetic research can lead to significant advances in therapy for difficult-to-treat, unpleasant disorders," said Professor Alexandre Reymond, the conference's chair.

Case report study of thalidomide treatment in 18 patients with severe arteriovenous malformations by Laurence M. Boon, Valérie Dekeuleneer, Julien Coulie, Liliane Marot, Anne-Christine Bataille, Frank Hammer, Philippe Clapuyt, Anne Jeanjean, Anne Dompmartin, and Miikka Vikkula published in Nature Cardiovascular Research on June 10, 2022.

By EUROPEAN SOCIETY OF HUMAN GENETICS

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