Sildenafil – an active ingredient also marketed as Viagra – improves symptoms in patients with Leigh syndrome. This has now been reported on Cell journal by researchers at Charité – Universitätsmedizin Berlin, together with teams from Heinrich Heine University Düsseldorf (HHU), University Hospital Düsseldorf (UKD) and the Fraunhofer Institute for Translational Medicine and Pharmacology ITMP in Hamburg. Leigh syndrome is a rare, previously untreatable metabolic disorder that occurs in childhood and causes severe neurological and muscular symptoms. In a pilot study involving six patients, sildenafil showed a positive effect on the course of the disease.
Leigh syndrome is a congenital brain and muscle disorder caused by a defective energy metabolism, often manifesting in infancy or early childhood. The disorder develops slowly and is accompanied by severe symptoms such as seizures, muscle weakness and paralysis, and mental development can also be impaired. Patients with Leigh syndrome have a significantly lower life expectancy and there is currently no approved drug treatment.
A real surprise: The activity drug turns out to be effective
Now, however, a research team has identified a drug candidate that showed promising results in a pilot study—and that may seem surprising at first glance: sildenafil, a so-called PDE-5 inhibitor. The drug is best known as a treatment for erectile dysfunction in adults. However, thanks to its vasodilating action, it is also used in the treatment of pulmonary hypertension in infants. The study involved the continuous administration of sildenafil to six patients with Leigh syndrome aged between 9 months and 38 years. Within just a few months, their muscle strength improved greatly and in some cases neurological symptoms disappeared. In addition, they recovered more quickly from metabolic crises, i.e. overloading of energy metabolism, which can suddenly worsen the course of this disorder.
“For example, in the case of a child treated with sildenafil, the walking distance increased tenfold, from 500 to 5,000 meters,” explains Professor Markus Schuelke. “In another child, the treatment completely suppressed the metabolic seizures that occurred almost every month, while another patient no longer suffered from seizures.” Markus Schuelke is a physician and scientist in the Department of Pediatric Neurology at the Charité and one of the lead authors of the newly published study. He went on to emphasize: “Such effects significantly improve the quality of life of patients with Leigh syndrome. While we will need to confirm these initial observations in a more comprehensive study, we are very pleased to have found a promising drug to treat this serious inherited disease.”
Why finding cures for rare diseases is hard
Such success cannot be taken for granted as Leigh syndrome is rare and affects only one in 36,000 children. “The low numbers of cases make it difficult to research the disease and present some obstacles in our urgent search for effective treatments,” explains Markus Schuelke. With such a small number of patients, large-scale studies are almost impossible, which means that specialists from different centers must collaborate internationally. Furthermore, it is not possible to simply remove the brain or nerve tissue from patients in order to investigate the causes of the disease.
In order to identify sildenafil as a potentially effective drug, researchers had to resort to some methodological tricks. In an initial step, they took skin cells from patients and used them to produce so-called induced pluripotent stem cells in the lab – cells that are capable of developing into many different cell types. From the stem cells, they grew nerve cells whose metabolism exhibited the same defective functionality as that of the patients. In the next step, the researchers selected more than 5,500 active substances that were already approved for the treatment of other diseases or for which there was extensive safety and efficacy data and tested their effect on cultured nerve cells.
Positive effect in cells, animal models and patients
This is the largest drug trial for the treatment of Leigh syndrome to date. It showed that sildenafil, among other drugs, improved the electrical functionality of nerve cells.”
Dr. Ole Pless, lead author of the study from the ITMP
Additional laboratory tests supported the results obtained at the cellular level: In 3D miniature replicas of the brain, known as organoids, sildenafil enhanced the growth of nerve cells, for example. The drug also improved energy metabolism and increased life expectancy in animal models.
“Based on these results, we decided to administer the drug as part of an individual treatment trial in six patients with Leigh syndrome,” said Professor Alessandro Prigione, lead author from the Department of General Paediatrics, Neonatology and Pediatric Cardiology at UKD. “Another determining factor was the fact that detailed safety data were available for the long-term use of sildenafil in children, as the active ingredient is already approved for other pediatric disorders.” The first Leigh syndrome patient was treated at the Charité. Following positive results, additional patients were treated in Dusseldorf, Munich and Bologna. All patients tolerated the drug well overall.
A comprehensive clinical study was designed
Based on the results now being published, the European Medicines Agency (EMA) has granted sildenafil orphan drug (ODD) status, meaning drug for rare diseases. Such medicines can be put through a simplified approval process, which aims to support the development of treatments for rare diseases. In order to validate the new findings and – since the previous observations were confirmed – to prepare for the approval of sildenafil for Leigh syndrome, the research team is planning a pan-European placebo-controlled clinical trial as a next step. The trial will be conducted within the SIMPATHIC EU project.
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