A diagnosis of Leigh syndrome is often devastating for families. The rare genetic disorder steadily robs the brain and muscles of energy, slowly shutting down the body with no chance of a cure. Many affected children die within a few years of diagnosis, although the course varies widely.

In a new study, researchers used patient-derived cells to screen thousands of existing drugs and surprisingly identified sildenafil—the active ingredient in Viagra—as a candidate treatment. The drug improved disease-related measures in lab-grown cells and animal models, and six patients treated off-label later showed encouraging clinical gains. But because those human results come from a tiny, uncontrolled group, the findings still need to be tested in a proper trial.

A Desperate Search Meets a Surprising Molecule
Leigh syndrome affects roughly one in 36,000 to 40,000 births. The disease attacks the mitochondria—the double-membrane-bound organelles found in most eukaryotic cells, known as the “powerhouses” of the cell because they generate over 90% of the body’s energy in the form of adenosine triphosphate (ATP). When these cellular engines fail, tissues that demand the highest amounts of energy suffer first. This means the brain and muscles begin to starve. Children endure seizures, severe muscle weakness, and developmental regression.

Finding a treatment for such a rare condition presents steep hurdles. Large clinical trials are nearly impossible to organize. Furthermore, researchers cannot easily extract living brain tissue from affected children to study the disease up close.

To overcome this, an international research team thought outside the box. They took skin cells from Leigh syndrome patients and coaxed them into becoming stem cells. The team then turned those cells into neurons that reproduced key metabolic defects seen in Leigh syndrome.

With a working model of the disease alive in a petri dish, the scientists tested over 5,500 approved drugs. They hunted for anything that might restore the electrical balance within the affected cells.

“This is the largest drug screening for the treatment of Leigh syndrome to date,” Dr. Ole Pless, a lead author of the study from the Fraunhofer Institute for Translational Medicine and Pharmacology, said in a statement.

One compound stood out. Sildenafil inhibits an enzyme called PDE5. While adults recognize it as a treatment for erectile dysfunction, pediatricians already use its blood-vessel-widening properties to treat infants with pulmonary hypertension. It has a well-documented safety record in children. In fact, sildenafil was initially developed by Pfizer to treat cardiovascular issues, specifically angina pectoris (chest pain) and hypertension (high blood pressure).

Extending Life
The researchers next brought the drug out of the dish and into animal models. They tested sildenafil in mouse and pig models carrying Leigh-syndrome-associated mutations.

In mice, sildenafil moderately increased lifespan and alleviated muscle weakness. In a pig model, the results appeared even more striking. The disease usually kills these animals within weeks. Yet, one treated pig remained stable for over six months.

“This is a genuinely exciting paper,” Vivian Gama, a cell biologist at Vanderbilt University who was not involved in the work, told Science. She praised the unusually detailed research and multiple lines of evidence, adding that sildenafil could be a “really promising compound … for one of the most devastating childhood rare diseases.”

Bolstered by the animal data and the drug’s known safety profile in pediatric care, doctors initiated off-label treatments for six Leigh syndrome patients. The group ranged in age from nine months to 38 years.

Within a few months, the clinical results mirrored the laboratory successes.

Patients regained muscle strength. Some neurological symptoms vanished entirely, and the patients recovered much faster from metabolic crises—sudden, dangerous overloads of their broken energy systems.

“For example, in the case of a child undergoing sildenafil treatment, the walking distance increased tenfold, from 500 to 5,000 meters,” Prof. Markus Schuelke, a physician and scientist at Charité’s Department of Pediatric Neurology, explained. “In another child, the therapy completely suppressed metabolic crises that occurred almost monthly, while another patient no longer suffered from epileptic seizures.”

Navigating the Complexities of Rare Diseases

Schuelke observed that these clinical changes drastically upgrade daily life for affected families. “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,” he added.

Despite the thrilling progress, some researchers urge caution. Simon Johnson, a Leigh syndrome researcher at Northumbria University, pointed out that the disease often progresses unpredictably. Patients can experience sudden, temporary downturns followed by periods of stability, making it hard to measure a drug’s true impact in a small group.

The research team recognizes these limitations. Sildenafil has received orphan-drug designation in Europe for Leigh syndrome, a status that can provide regulatory support and incentives for developing therapies for rare diseases. The team says it is planning a Europe-wide, placebo-controlled clinical trial through the SIMPATHIC project.

In the meantime, the scientists strongly advise against families experimenting with the medication independently. “If a patient or physician wants to use it, we are happy to collaborate,” Alessandro Prigione, a stem cell researcher at Heinrich Heine University, stressed. The safety and specific dosing must remain under strict medical supervision.

The study was published in the journal Cell.