Sildenafil, the active ingredient in Viagra, may offer new hope for people living with Leigh syndrome, a rare and severe childhood disease. Researchers from Berlin’s Charité University are conducting the study in collaboration with collaborators from Düsseldorf’s Heinrich-Heine University (HHU), Düsseldorf University Hospital (UKD), and Hamburg’s Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, the journal reported. cell The drug improved symptoms in a small group of patients.
Leigh syndrome is a rare metabolic disease that affects the brain and muscles and usually begins in infancy or early childhood. In a pilot study of six patients, sildenafil treatment was associated with measurable improvements in disease progression.
A rare and devastating childhood disorder
Leigh syndrome is caused by a defect in cellular energy production. The brain and muscles are particularly affected because the cells cannot produce enough energy. Symptoms often include seizures, muscle weakness, paralysis, and developmental delays. Over time, the disease worsens and life expectancy is significantly reduced. There are currently no approved drug treatments.
Unexpected uses of well-known drugs
Researchers identified sildenafil, the PDE-5 inhibitor best known for treating erectile dysfunction, as a potential treatment. Because this drug widens blood vessels, it is also used to treat pulmonary hypertension in infants.
In this study, six patients, ranging in age from 9 months to 38 years, received continuous sildenafil treatment. Within a few months, many showed stronger muscles and some experienced improvement in neurological symptoms. Patients also recovered faster from metabolic crisis, an overload of energy metabolism that can suddenly worsen the course of the disease.
“For example, in children treated with sildenafil, the walking distance increased tenfold, from 500 meters to 5,000 meters,” explains Professor Markus Schuelke. “In another child, this therapy completely suppressed a metabolic crisis that occurred almost every month, and in another patient, the patient no longer suffers from epileptic seizures.”
Markus Schuelke, a physician-scientist in the Department of Pediatric Neurology at Charité and one of the study’s lead authors, added: “Such an effect significantly improves the quality of life for patients with Leigh syndrome. Although these initial observations need to be confirmed in more comprehensive studies, we are very pleased to have found a promising drug candidate for the treatment of this serious genetic disorder.”
Why are rare diseases difficult to treat?
Leigh syndrome affects approximately 1 in 36,000 children and is particularly difficult to study. “The small number of cases makes it difficult to study this disease and poses some obstacles in the urgent search for effective treatments,” explains Markus Schuelke.
Large-scale clinical trials are difficult to conduct because the number of patients available is very small. Researchers often need to collaborate across multiple centers and countries. Additionally, studying the disease directly is complicated by the inability to easily harvest brain and nerve tissue from patients.
Screening thousands of drugs to find solutions
To find a possible treatment, scientists used an innovative approach. They collected skin cells from patients and reprogrammed them into induced pluripotent stem cells that can grow into many different cell types. These then transformed into nerve cells that mimic the same metabolic abnormalities seen in Leigh syndrome.
Researchers tested more than 5,500 compounds that were already approved or had strong safety data. They evaluated how each substance affected affected nerve cells and identified sildenafil as a promising candidate.
Benefits seen in cells, animal models, and patients
“This is the largest drug screen for the treatment of Leigh syndrome to date,” emphasizes Dr. Ole Press, lead author of the ITMP study. “It showed that sildenafil, among other drugs, improved the electrical function of nerve cells.”
Further experiments confirmed these findings. In brain organoids, small three-dimensional models of brain tissue, sildenafil promoted the growth of nerve cells. In animal models, energy metabolism was improved and lifespan was extended.
Professor Alessandro Prigione, from UKD’s Department of General Pediatrics, Neonatology and Pediatric Cardiology, said: “Based on these results, we decided to administer the drug as part of an individual treatment trial to six patients with Leigh syndrome.” “Another deciding factor was the fact that detailed safety data on long-term use of sildenafil in children were available, as the active ingredient in sildenafil is already approved for other pediatric diseases.”
The first patient was treated at Charité, followed by additional patients in Düsseldorf, Munich and Bologna. Overall, the treatment was well tolerated.
Large-scale clinical trials are planned
Following these encouraging results, the European Medicines Agency (EMA) has granted sildenafil Orphan Drug (ODD) status for rare diseases. This designation helps speed up the development and approval process.
The researchers are now planning to run a large-scale, placebo-controlled clinical trial across Europe as part of the SIMPATHIC EU project. This next step will determine whether the initial findings can be confirmed in a broader group of patients.
Understanding Leigh syndrome
Leigh syndrome belongs to a group of conditions known as mitochondrial disorders, which involve problems with energy production within cells. Mitochondria act as the energy generators of cells, and when mitochondria do not function properly, energy-intensive tissues such as the brain are damaged.
Symptoms include muscle weakness, difficulty swallowing, breathing, seizures, and delayed mental development. The disease is hereditary and currently incurable, with many children dying within a few years of diagnosis. Leigh syndrome has an incidence of 1 in 36,000 live births and is classified as a rare disease by European guidelines.
Research collaboration and funding
The research was led by Charité (Professor Markus Schuelke), HHU and UKD (Professor Alessandro Prigione), ITMP (Dr Ole Pless), University of Luxembourg (Professor Antonio del Sol) and University of Verona (Dr Emanuela Bottani). Additional research groups from Germany, Austria, Finland, the Netherlands, Poland, Italy, Greece, and the United States contributed.
Funding was provided by the German Research Foundation (DFG), the German Federal Ministry of Education and Research, the German Federal and State Government Excellence Strategy (NeuroCure Cluster of Excellence), and the European Commission.
