This Viagra ingredient just did something remarkable for a deadly childhood disease

Leigh syndrome is a rare metabolic condition that affects the brain and muscles, usually appearing in infancy or early childhood. In a pilot study of six patients, sildenafil treatment was linked to measurable improvements in disease progression.

A Rare and Devastating Childhood Disorder

Leigh syndrome is caused by defects in cellular energy production. Because cells cannot generate enough energy, the brain and muscles are particularly affected. Symptoms often include seizures, muscle weakness, paralysis, and delayed development. Over time, the disease worsens, and life expectancy is significantly reduced. At present, there are no approved drug treatments.

An Unexpected Use for a Well-Known Drug

Researchers identified sildenafil, a PDE-5 inhibitor best known for treating erectile dysfunction, as a potential therapy. The drug is also used in infants to treat pulmonary hypertension due to its ability to widen blood vessels.

In the study, six patients between 9 months and 38 years old received continuous sildenafil treatment. Within a few months, many showed stronger muscles, and some experienced improvements in neurological symptoms. Patients also recovered more quickly from metabolic crises, i.e., overloads of the energy metabolism, which can suddenly worsen the course of this disorder.

"For example, in the case of a child undergoing sildenafil treatment, the walking distance increased tenfold, from 500 to 5,000 meters," as Prof. Markus Schuelke explains. "In another child, the therapy completely suppressed metabolic crises that occurred almost monthly, while another patient no longer suffered from epileptic seizures."

Markus Schuelke, a physician and scientist at Charité's Department of Pediatric Neurology and one of the study's lead authors, added: "Such effects significantly improve the quality of life of Leigh syndrome patients. While we will have to confirm these initial observations in a more comprehensive study, we are very pleased to have found a promising drug candidate for the treatment of this serious hereditary disease."

Why Rare Diseases Are Difficult to Treat

Leigh syndrome affects about one in 36,000 children, making research especially challenging. "The low case numbers make it difficult to research the disease and present some obstacles in our urgent search for effective therapies," explains Markus Schuelke.

Because so few patients are available, large clinical trials are difficult to conduct. Researchers often need to collaborate across multiple centers and countries. In addition, studying the disease directly is complicated, since brain or nerve tissue cannot easily be collected from patients.

Screening Thousands of Drugs for a Solution

To find potential treatments, scientists used an innovative approach. They collected skin cells from patients and reprogrammed them into induced pluripotent stem cells, which can develop into many different cell types. These were then turned into nerve cells that mimicked the same metabolic defects 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 the diseased nerve cells, leading to the identification of sildenafil as a promising candidate.

Benefits Seen in Cells, Animal Models, and Patients

"This is the largest drug screening for the treatment of Leigh syndrome to date," emphasizes Dr. Ole Pless, lead author of the study from ITMP. "It showed that sildenafil, among other drugs, improved the electrical functionality of the nerve cells."

Further experiments supported these findings. In brain organoids, which are miniature three dimensional models of brain tissue, sildenafil promoted nerve cell growth. In animal models, it improved energy metabolism and extended lifespan.

"Based on these results, we decided to administer the drug as part of an individual therapeutic trial in six patients with Leigh syndrome," as Prof. Alessandro Prigione from the Department of General Pediatrics, Neonatology, and Pediatric Cardiology at the UKD stated. "Another decisive factor was the fact that detailed safety data was available for the long-term use of sildenafil in children, as the active ingredient is already approved for other pediatric disorders."

The first patient was treated at Charité, followed by additional patients in Düsseldorf, Munich, and Bologna. Overall, the treatment was well tolerated.

Larger Clinical Trials Planned

Following these encouraging results, the European Medicines Agency (EMA) has granted sildenafil orphan drug (ODD) status for rare diseases. This designation can help speed up the development and approval process.

Researchers now plan to conduct a larger, placebo controlled clinical trial across Europe as part of the SIMPATHIC EU project. This next step will determine whether the early findings can be confirmed in a broader group of patients.

Understanding Leigh Syndrome

Leigh syndrome belongs to a group of conditions known as mitochondriopathies, which involve problems with energy production in cells. Mitochondria act as the cell's energy generators, and when they do not function properly, tissues that require high energy, such as the brain, are damaged.

Symptoms can include muscle weakness, difficulty swallowing, breathing problems, seizures, and delayed mental development. The disease is inherited and currently incurable, with many children dying within a few years of diagnosis. With an incidence of one in 36,000 births, Leigh syndrome is classified as a rare disease under European guidelines.

Study Collaboration and Funding

The study was led by Charité (Prof. Markus Schuelke), HHU and UKD (Prof. Alessandro Prigione), ITMP (Dr. Ole Pless), Université du Luxembourg (Prof. Antonio del Sol), and Università di Verona (Dr. Emanuela Bottani). Additional research groups from Germany, Austria, Finland, the Netherlands, Poland, Italy, Greece, and the USA contributed.

Funding was provided by the German Research Foundation (DFG), the German Federal Ministry of Education and Research, the Excellence Strategy of the German federal & state governments (NeuroCure Cluster of Excellence), and the European Commission.