Ultrasound-assisted gene therapy mitigates Leigh syndrome pathology

Leigh syndrome (LS) is a fatal neurometabolic disease caused by mutations in genes involved in mitochondrial energy harvesting. While there is currently no cure for this disease, pre-clinical studies showed that gene therapy can afford a therapeutic benefit in a relevant model of LS, the Ndufs4-knockout (KO) mouse. However, similar results need to be obtained using methods that can be translated into patients. Here, we combined two tools that are approved for clinical interventions. We used low-intensity focused ultrasound (FUS) to transiently permeabilize the blood-brain barrier and thereby facilitate the passage of an adeno-associated virus serotype 9 (AAV9) vector. This approach resulted in transgene expression in the brain and peripheral organs. When applied to 1-month-old Ndufs4-KO mice, this gene replacement strategy significantly extended the survival of the animals and ameliorated brain and cardiac function. These improvements were associated with the restoration of protein expression and mitochondrial function. These findings support the potential of combining FUS with AAV-mediated gene delivery to treat LS, and they warrant further clinical translation. This study also provides the first evidence that ultrasound-assisted gene replacement can exert a therapeutic effect in a condition affecting the CNS.