Thalidomide is infamous for causing tragic birth defects in the late 1950s and early 1960s, when it was marketed as a sedative and treatment for morning sickness in pregnant women.
The drug inhibits the formation of blood vessel (angiogenesis), but there’s now interest in whether thalidomide could be used therapeutically when inhibition of this process could be beneficial.
A small study in 18 patients with severe arteriovenous malformations (AVMs) has now shown that treatment with thalidomide can result in a striking reduction in symptoms and a subsequent improvement of quality of life.
The research has been published in Nature Cardiovascular Research and will be presented on June 12 at the annual conference of the European Society for Human Genetics in Vienna, Austria.
“Our group has been studying the causes of vascular abnormalities for 30 years. We have identified several genetic causes and have been able to show that certain mutations activate the signalling inside the blood vessel wall cells, and this promotes the abnormal formation of blood vessels,” says Miikka Vikkula, professor of human genetics at the De Duve Institute at the Catholic University of Louvain, Belgium.
“This led us to wonder about the possibility of using thalidomide to inhibit abnormal blood vessel formation.”
This is because thalidomide inhibits the expression of vascular endothelial growth factor (VEGF), a signalling protein that promotes the growth of new blood vessels.
“VEGF levels are high in vascular abnormalities such as AVMs and it is therefore likely that thalidomide reduces signalling via the angiogenesis-promoting pathways.”
Thalidomide inhibits the growth of blood vessels
AVMs are abnormal tangles of the blood vessels connecting arteries and veins that alter normal blood flow. They are very painful, and cause bleeding and deformation of the affected body part as well as cardiac problems.
Severe cases are usually treated through surgery or embolism (the injection of an agent that destroys the blood vessels locally) but this causes scar tissue to form, is rarely totally effective, and can even make the problem worse.
After having shown that it could work in a mouse model, the researchers recruited 18 patients aged between 19 and 70 years of age – with AVMs that could not be treated by conventional approaches – to receive doses of either 50, 100 or 200 milligrams of thalidomide per day for between 2 and 52 months.
They all had to agree to use contraception for at least four weeks before and after finishing treatment.
“All the patients experienced a rapid reduction of pain, together with cessation of bleeding and the healing of ulcers where these were present,” says Vikkula. “The three patients with cardiac failure also saw their problems resolved, and one AVM appeared to be completely cured after 19 months of thalidomide and an eight-year follow-up.”
Combining the treatment with embolism allowed the dosage of thalidomide to be reduced to 50mg per day, which was important as a higher dose was associated with side-effects like tiredness and peripheral neuropathy – damage to the nerves located outside the brain and spinal cord that causes weakness and numbness, particularly in the hands and feet.
“We had hypothesised that thalidomide should work in these patients, so our results did not come as a surprise, but it was great to have clinical confirmation that we were right,” concludes Vikkula. “In our view, this is a breakthrough finding and provides a solid basis for the development of molecular treatments for AVMs.”
Professor Alexandre Reymond, chair of the conference, adds: “This study shows not only the healthcare and economic benefits of repurposing drugs – even the most maligned – but also how genetic research can lead to real breakthroughs in therapies for difficult to treat, distressing conditions.”