Researchers report that sildenafil may slow neurological decline and improve symptoms in patients with Leigh syndrome, a severe mitochondrial disease related to thymidine kinase 2 deficiency (TK2d).
In a study published recently in Cell, the drug improved cellular function, extended lifespan in animal models and produced clinical benefits in six individuals with the disorder, suggesting a potential treatment strategy for mitochondrial diseases that currently lack effective therapies.
Leigh syndrome is a rare inherited neurological condition that typically begins in infancy or childhood and causes psychomotor regression, muscle weakness and life-threatening metabolic crises. Similar to TK2d, the disease arises from defects that impair mitochondrial energy production. To search for potential treatments, researchers screened 5,632 repurposable compounds in neural cells derived from patients with Leigh syndrome using induced pluripotent stem cell technology.
The screening identified drugs known as phosphodiesterase type 5 inhibitors as promising candidates. Among them, sildenafil was prioritized because of its established safety record in children treated for pulmonary arterial hypertension.
“In addition to its neurological impact, sildenafil might induce mitochondrial biogenesis and oxygen consumption,” explained this study’s authors.
Read more about treatment and care of TK2d
In neural precursor cells from patients carrying variants in the mitochondrial gene MT-ATP6, sildenafil normalized abnormal mitochondrial membrane potential by about 16% without toxicity. The treatment also increased cellular ATP levels, restored mitochondrial DNA copy number and normalized the NAD+/NADH balance.
Further experiments showed that sildenafil reversed several molecular signatures of the disease. Multi-omics analyses revealed that the drug corrected 724 of 2,160 dysregulated molecules, or about 33.5%.
Pathways involved in neuronal development and mitochondrial function improved, including genes linked to axon formation and nervous system development. In brain organoids modeling early brain development, sildenafil restored the balance between neural progenitor cells and early neurons and reduced abnormal calcium surges during metabolic stress.
Animal studies provided additional evidence. In mice lacking the Ndufs4 gene, a model of Leigh syndrome, sildenafil treatment starting at day 25 extended lifespan and improved muscle strength and coordination. In pigs with a mutation in a relevant gene called SURF1, the drug improved responsiveness, mobility and feeding behavior, with some animals surviving beyond day 261 despite reduced body weight. Researchers also confirmed that sildenafil can cross the blood-brain barrier, an essential feature for treating neurological disease.
The most immediate implications for patients came from individual off-label treatment in six people with Leigh syndrome caused by MT-ATP6 variants. Using low or medium doses ranging from 0.66 to 3.00 mg/kg/day, clinicians observed improved motor function and development in most participants. Overall disease severity scores, measured with the Newcastle Pediatric Mitochondrial Disease Scale or the Newcastle Mitochondrial Disease Adult Scale, either decreased or increased more slowly during treatment.
For patients and families facing disorders such as Leigh syndrome and related mitochondrial diseases such as TK2d, the findings suggest that a widely available medication could eventually help stabilize symptoms, reduce metabolic crises and potentially slow disease progression if confirmed in larger clinical studies.
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