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New targets and orphan drugs for rare diseases

Scientists at the Centro de Investigaciones Biológicas (CIB) of the CSIC work to find out the genetic diagnosis of rare diseases related to vascular disorders and tumors, as well as to find new therapies. Their research has focused mainly on the HHT disease and the Von Hippel-Lindau syndrome, and they have found out three orphan molecules for treating the HHT disease and one for the treatment of VHL.

Members of the Translational research in rare diseases with vascular involvement team. From left to right, Ángel Cuesta Martínez, postdoctoral researcher; Luisa María Botella Cubells, CSIC researcher and group leader; Isabel de Rojas de Pablo, Master student; and Lucia Recio Poveda, predoctoral researcher.The HHT disease (which stands for Hereditary hemorrhagic telangiectasia) is a rare hereditary disorder, which affects the blood vessel formation. It affects 1 in 6,000 people and the symptoms are mainly nosebleeds, telangiectasias or arteriovenous malformations (AVMs) on the skin, as well as  anemia. AVMs can also appear in internal organs, which can trigger other more severe complications. HHT has no cure and the treatment is focused on monitoring the new and worsening AVMs, and early interventions when it is necessary.

At the biological research centre, Centro de Investigaciones Biológicas (CIB), of the CSIC, the team led by Luisa Maria Botella has identified treatments for reducing the nose haemorragias in HHT patients. This unit (Translational research in rare diseases with vascular involvement), is focused on studying vascular rare diseases. Their goals are understanding the molecular mechanisms of the disease, in order to find out new targets, and to find treatments based on drugs that now have other uses in Medicine. Their work includes translating the research from the laboratories to the doctors and patients, so they collaborate with Medical units specialized in these diseases.

"On 2002, we establish contact to patients of this disease and their doctors throughout Spain, in order to get samples for studying the genetic diagnosis of the disease". Afterwards, the scientists try to find among commercial molecules with other applicattions which ones could be applied to the rare disease. If assays in the laboratory are successful, they initiate the process for obtaining the orphan drug designation. This is what is technically named drug “repositioning” and is what this research group has done with etamsyilate, an antihaemorragic drug commercialized for being injected. The scientists found out that it can be topically administered with good results for HHT nose bleeding.

After several assays, the scientists at the CIB saw that topically administered etamsylate can significantly reduce the bleeding nose of HHT patients, which improves a lot their quality of life. Now, the scientists have achieved the orphan drug designation for etamsylate topically administered.

“But etamsylate in glass vials can not be found in Spain, so for keeping on with the research, we need to find a company that sintetizes etamsylate and makes the necessary assays requested by the European Medicines Agency”, say the scientist. So, there is still a lot of work to do.

The team also works to find treatment for another rare disease, the von-Hippel-Lindau syndrome, characterized by the formation of tumors in many different parts of the body throughout life, and which affects 1 per 35.000 people.

To inhibit the onset of tumors, patients could be treated with propranolol, which is effective but has cardiovascular side effects, as it alters the heart rate and blood pressure. CIB scientists have identified a molecule, called ICI 118,551, which can be a better alternative. Experiments on murine model have shown that ICI 118,551 inhibits tumors without the adverse effects of propranolol.

"The molecule is a very specific since it only blocks the beta2 adrenergic receptor, which is associated with the antitumor effect, according to our ‘in vitro’ experiments, whereas propranolol blocks not only the beta2 receptor but also beta1, related to the heart rate", says Luisa Maria Botella. In this case, ICI 118,551 is a new finding, that is, it is not a drug repositioning as in the previous case. Scientists have patented the molecule and licensed the patent to a company, which will continue with the development.