Leigh syndrome: Ultrasound-assisted gene therapy, a promising strategy

Leigh syndrome is a severe pediatric mitochondrial disorder, notably linked to mutations in the NDUFS4 gene. The absence of this protein disrupts the function of mitochondrial complex I, leading to progressive energy failure in the brain. Affected children may experience developmental delay, muscle weakness, movement disorders and respiratory difficulties. To date, no curative treatment exists.

Crossing the blood–brain barrier without surgery

Any gene therapy targeting the central nervous system faces a major obstacle: the nearly impermeable blood–brain barrier, which protects the brain.

To overcome this challenge, scientists from the “Brain Aging and Repair” team led by Michael Decressac combined an intravenous injection of an AAV9 viral vector carrying a functional copy of the NDUFS4 gene with the transcranial application of low-intensity focused ultrasound (FUS), enabling a transient and controlled opening of the blood–brain barrier.

“NDUFS4 is an almost ideal candidate gene for gene therapy: it is small, easily fits into a viral vector, and does not cause toxicity when overexpressed,” explains Michael Decressac.

Demonstrated therapeutic benefit

In one-month-old Ndufs4-KO mice, a murine model of Leigh syndrome, the scientists observed that this strategy restores NDUFS4 protein expression and improves mitochondrial function, while also correcting cerebral and cardiac alterations and, most importantly, significantly extending the animals’ survival.
This is the first demonstration that ultrasound-assisted gene replacement can exert a therapeutic effect in a pathology affecting the central nervous system.
“Our aim is not to cure mice,” emphasizes Michael Decressac. “It is to develop an approach that can truly be translated to patients. We wanted to demonstrate that a strategy compatible with clinical application could produce a meaningful therapeutic effect.”

Towards clinical applications

Focused ultrasound is already used in humans for certain neurological applications, and AAV9 has received regulatory approval in other indications. Their combination could therefore pave the way for non-invasive gene therapy strategies targeting central nervous system diseases.

Further studies are underway to optimize blood–brain barrier opening parameters at larger scales and to assess safety and biodistribution in advanced preclinical models.
 

Reference: 
Ultrasound-assisted gene therapy mitigates Leigh syndrome pathology
Mathilde Faideau, Romain Clément, Sébastien Rigollet, Giorgia Benegiamo, Cassandra Cresson, Béatrice Blot, Robin Reynaud-Dulaurier, Sara Yjjou, Fanny Aprahamian, Sylvère Durand, Anthony Delalande, Emmanuel L Barbier, Vasile Stupar, Johan Auwerx, Michael Decressac
Brain, 2026 Jan 23.
doi: 10.1093/brain/awag026. Online ahead of print.