Sildenafil may help treat Leigh syndrome

Sildenafil could prove to be an unexpected ally in the fight against Leigh syndrome, a rare genetic disorder that usually manifests itself before the second birthday and often takes its victims within a few years.

In pre-clinical trials, the molecule better known by its trade name Viagra made it possible to correct certain abnormalities in cells carrying a genetic variant associated with the disease.

It also slightly extended lifespan in rodents and pigs with other mutations linked to this syndrome.

Preliminary results published by American and European researchers finally reveal that sildenafil may have relieved the symptoms of some patients.

“(The researchers) have seen an improvement in several characteristics, so it’s very encouraging, but there is still a lot to measure,” said Dr. Grant Mitchell, who is a geneticist at the CHU Sainte-Justine.

Leigh syndrome is a severe and incurable form of mitochondrial disease that leads to psychomotor regression and metabolic crises.

Mitochondrial diseases refer to a set of inherited disorders affecting the functioning of mitochondria, structures whose task is to make energy from the food we eat.

Most affected children quickly develop difficulty breathing and swallowing, but symptoms, in some cases, do not appear until adolescence or even later.

Several defective genes can be implicated in Leigh syndrome, Dr. Mitchell pointed out.

“There are multiple forms of Leigh syndrome and it is not certain that all forms would respond in the same way to sildenafil treatment,” he said. There is a form of the syndrome that is more common in Quebec than elsewhere because of a historical genetic founder effect. Neither this form, nor the gene responsible, was mentioned in the published study.”

Researchers discovered several years ago that the MT-ATP6 gene appears to be responsible for an abnormal electrical charge in the mitochondrial membrane.

The authors of the new study sifted through nearly 6,000 molecules. They found that sildenafil was particularly effective in restoring a normal electrical charge.

Other in vitro and in vivo tests have testified to the molecule’s potential to correct some of the problems associated with the disease.

The researchers also prescribed sildenafil to six patients. One of them, a 16-year-old, was deteriorating rapidly and hospitalization in palliative care was being considered. Seven years later, his symptoms are improving, although he still can’t walk without help.

“How the drug produced the effects is speculative,” Dr. Mitchell said. The drug is known to dilate blood vessels, but there may be other effects. It is not clear how taking sildenafil is related to the (beneficial) effects. But overall, the effects are very encouraging.”

One of the other five patients had to stop treatment due to side effects, but there was a modest improvement in the condition of the other four.

“It was over a short period of time, it was analyzed with only one (form of) the disease, so you can’t get too optimistic, but yes, if everything keeps going like this,” Mitchell said. The authors have made a big leap forward, it’s a very complex and very detailed paper.”

Finally, independent experts point out that Leigh syndrome can be episodic, with a sudden improvement or deterioration of symptoms. This can make it difficult to distinguish the effect of the drug from the normal progression of the disease.

The findings of the new study were published by the medical journal Cell.

–This report by La Presse Canadienne was translated by CityNews