A new study published in the journal Cell opens therapeutic perspectives for Leigh syndromea serious pediatric genetic disease so far without effective treatments. The research was coordinated by Alessandro Prigione ofUniversity of Düsseldorf and involved Italian researchers fromUniversity of Milandell’ICarlo Besta Neurological Institute and of theUniversity of Verona, including Dario Brunetti ed Emanuela Bottani. The work was developed within the European CureMILS consortium, funded by the European Joint Program on Rare Diseases with approximately 2.4 million euros, involving numerous research centers in Europe and the United States.
A rare and devastating disease
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Leigh syndrome is a progressive genetic disorder that affects the central nervous system and impairs energy production in cells due to defects in the mitochondria. Symptoms often appear in the first years of life and include delayed psychomotor development, muscle weakness, metabolic crises and breathing difficulties. In the most severe cases, the disease progresses rapidly and can lead to death in the first years of life. Until now, there were no therapies capable of modifying its course.
From patient cells to the discovery of a possible treatment
The study used a translational medicine approach. The researchers got it induced pluripotent stem cells (iPSC) starting from patients’ skin cells and transformed them into nerve cells affected by the disease, thus recreating the model of the pathology in the laboratory. A high-capacity screening of over 5,600 existing drugs was carried out on these cells, with the aim of identifying reusable molecules. Among the most promising candidates have emerged phosphodiesterase type 5 inhibitors, in particular Sildenafil, known commercially as Viagra, it is therefore already used in the clinical field for other indications. The drug has been shown to improve energy metabolism and function of cells affected by the disease, correcting defects in mitochondrial function and restoring nervous system development programs in cell models and brain organoids.
From testing to the first patients
The results were subsequently confirmed in animal models, including mouse and pig models developed with the contribution of the biotech company Avantea. In experimental models, the treatment improved signs of the disease and significantly prolonged survival. Based on these data, the drug was also administered to a small group of patients with Leigh syndrome as part of compassionate use. A. was observed in treated patients good tolerability of the drug and preliminary signs of clinical benefitincluding improvements in motor functions and greater resistance to metabolic crises.
Towards clinical trials
According to the researchers, the study represents the first concrete evidence of a potential treatment for Leigh syndrome and demonstrates how the integration between human cellular models, advanced animal models and clinical observations can accelerate the development of therapies for rare diseases. The European Medicines Agency has already granted sildenafil Orphan Drug Designation for this pathology, a step that facilitates the clinical development of new treatments for rare diseases. Clinical studies are now underway to evaluate its safety and effectiveness on a larger number of patients. The research was supported by various bodies and foundations, including the Telethon Foundation, the Regional Foundation for Biomedical Research, the Mariani Foundation and the Mitocon patient association.
The study
