The first patient Markus Schuelke treated with sildenafil was a teenager in Berlin whose symptoms were worsening fast enough that his doctors were considering moving him to palliative care. That was more than seven years ago. The boy is still alive, still taking the drug, and his symptoms have stabilized on clinical scales — not reversed, not cured, but measurably improved. Schuelke, a pediatric neurologist at Charité university hospital, calls it a turning point in a disease that mostly runs in one direction.
That patient is one of six people with Leigh syndrome who have now received continuous sildenafil treatment as part of an off-label compassionate use program, and the results are described today in a paper published in Cell by researchers at Charité, Heinrich Heine University Düsseldorf, and collaborators. The study traces a path from a library of more than 5,600 compounds screened in patient-derived stem cells, through organoid and animal validation, to the patients who are living with the drug today, according to EurekAlert.
Leigh syndrome is a mitochondrial disease — one of a broad class of disorders caused by defective energy metabolism in cells. Mitochondria generate most of the body's chemical energy, and when they malfunction, tissues with high energy demands suffer most: the brain, muscles, and nervous system. In Leigh syndrome, that dysfunction leads to progressive neurological and muscular decline, often beginning in infancy. Most children with the condition die before age three. There are no approved therapies, according to EurekAlert.
The research team, led by Alessandro Prigione at Heinrich Heine University and Schuelke at Charité, started with a drug repurposing screen: they took skin cells from Leigh syndrome patients, reverted them to a stem cell state, then coaxed those into neural cells that mimicked the patients' metabolic defects. They then tested 5,632 compounds already approved for other conditions or with established safety profiles — the largest such screen attempted for Leigh syndrome, according to EurekAlert. PDE5 inhibitors emerged as the most consistent hits. Sildenafil, already approved for erectile dysfunction and pediatric pulmonary hypertension, was the frontrunner, according to PubMed.
"The drug does look safe — that is the good news," said Simon Johnson, a Leigh syndrome researcher at Northumbria University who was not involved in the work, in comments reported by Science. "The evidence for beneficial effects, he argues, is not so compelling."
Johnson's caution reflects a real challenge in rare disease research. Some forms of Leigh syndrome are episodic: patients can experience sudden temporary worsening of symptoms followed by partial recovery, making it difficult to separate drug effects from the disease's natural course. The effects seen in animal experiments were also modest. Sildenafil moderately extended lifespan in mice with a Leigh syndrome mutation, according to Science. In pigs with another mutation — typically fatal within weeks — two of seven treated animals survived more than two months and one remained stable for six months, according to Science.
In the six patients, outcomes varied. One had to stop the drug because of a rash, according to Science. The other five tolerated it, with four showing improvement in movement ability and two showing small gains in cognitive domains such as language perception, according to Science. One child's walking distance increased tenfold, from 500 to 5,000 meters, according to EurekAlert. In another patient, metabolic crises that had occurred almost monthly stopped entirely, according to EurekAlert. A third no longer experienced epileptic seizures, according to EurekAlert.
The drug's mechanism is not fully established, but the researchers propose that sildenafil may help normalize the electrical charge across mitochondrial membranes — a property that neural stem cells in Leigh syndrome patients tend to lose. The compound is a phosphodiesterase type 5 (PDE5) inhibitor: it blocks an enzyme that regulates blood vessel dilation and, the researchers suspect, mitochondrial function in certain cell types.
Vivian Gama, a cell biologist at Vanderbilt University who studies rare diseases and was not involved in the work, called the paper "genuinely exciting" in comments reported by Science. She noted the unusual depth of the evidence — spanning cell, organoid, and animal models — and said the results in pigs were "remarkable," according to Science.
The researchers filed patent applications for sildenafil in mitochondrial disease treatment and have received orphan drug designation for Leigh syndrome from the European Medicines Agency, according to PubMed. A placebo-controlled trial is being planned under the SIMPATHIC EU project, with enrollment of 60 to 70 patients across multiple European countries, pending protocol finalization and ethical approval, according to PubMed.
Johnson and others note that alternative approaches are being pursued. Low-oxygen treatment is in testing in mouse models. The gap between animal data and human patients remains substantial, and the natural variability of Leigh syndrome means early human data requires careful interpretation. For a disease with no approved drugs and a median survival measured in years, even a modestly effective therapy would fill an enormous gap.
"Patients and physicians should not self-administer," Prigione said in a statement reported by EurekAlert. "If a patient or physician wants to use it, we are happy to collaborate."
