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Home > Focused Ultrasound: the brain finally accessible to gene therapy for Leigh Syndrome

Focused Ultrasound: the brain finally accessible to gene therapy for Leigh Syndrome

The main obstacle to treating Leigh syndrome is the blood–brain barrier, the brain’s ultra-selective protective shield. The team led by Michael Decressac at the Grenoble Institute of Neurosciences has just demonstrated that focused ultrasound can transiently open this barrier, making the brain accessible to gene therapy. This major breakthrough, published in Brain and supported by AFM-Téléthon, could ultimately be relevant for other rare diseases. Explanation by Michael Decressac.

Today, what is the main hurdle facing a potential gene therapy for Leigh syndrome?

Michael Decressac: Above all, the ability to deliver the healthy gene to the entire brain. The brain is protected by the blood–brain barrier, which notably prevents viruses circulating in the bloodstream from entering. It is extremely effective — and that’s a good thing… except when we need viral gene therapy vectors to reach the whole brain. However, this obstacle could be overcome using low-intensity focused ultrasound (FUS), as we have just demonstrated in mouse models of Leigh syndrome associated with mutations in the nuclear gene NDUFS4.

What does this focused ultrasound technique involve?

M.D.: Microbubbles are injected into the bloodstream. When they reach an area where ultrasound is applied, they “vibrate” and relax the vessel wall. The blood–brain barrier then becomes temporarily permeable — but not to everything. It allows only small elements such as viruses to pass through, and certainly not blood cells, which are fortunately 200 times larger.

It had already been shown that this technique can be used with viral vectors carrying a sequence encoding a fluorescent protein. With our work, a new milestone has been reached. This is the first proof of concept of its feasibility and relevance for delivering a gene therapy targeting a disease.

What results did you obtain?

M.D.: The mouse models of Leigh syndrome that received the AAV vector (adeno-associated virus) carrying the healthy NDUFS4 gene together with focused ultrasound showed improved mitochondrial function in the brain. This improvement correlated with a slowdown in neuronal loss, particularly of Purkinje cells in the cerebellum, resulting in increased lifespan. Their lifespan was almost tripled compared with untreated pups!

Moreover, although our primary objective was to treat the brain, we observed that the vector also reached the liver and the heart, where cardiomyopathy was partially reduced. However, it did not correct the muscles, as it does not penetrate them, nor the retina, which has its own barrier and where we did not apply ultrasound.

In fact, would correcting the brain, liver, and heart through gene therapy be sufficient?

M.D. : I believe this triad is the most important for Leigh syndrome, bearing in mind that treating the brain remains absolutely central. In our previous study using a viral vector that spontaneously crosses the blood–brain barrier – but cannot be used in humans – we demonstrated that massively correcting the brain produced positive collateral effects. The mice gained weight and muscle mass even though the muscles themselves were not treated. In other words, when the brain improves, other organs improve as well.

What is your strategy going forward?

M.D. : We are focusing on scaling up focused ultrasound. Today, it is being evaluated in patients to allow large molecules to enter the brain for the treatment of brain cancers. It is also being considered in Alzheimer’s disease. But in both cases, only a small part of the brain is targeted. For Leigh syndrome, however, we will need to apply ultrasound to the entire brain. This is an unprecedented and essential scaling challenge that will notably require adapting the technique to animal models whose brain volume is closer to that of a child — much larger than the one-cubic-centimeter brain of a mouse.

Will the gene therapy itself also need optimization?

M.D. : No, because we chose to work deliberately with the vector developed by Martine Barkats at Genethon, which is used clinically in Zolgensma® for spinal muscular atrophy. This vector has proven effective in correcting the brain, its potential side effects are well known, and it is approved by health authorities. So we are not starting from scratch. In the same spirit, the ultrasound used is the same as in standard imaging procedures, and the microbubbles are small lipid sacs filled with an inert gas that are rapidly degraded and completely harmless to the body. In other words, we have positioned ourselves so that we only have one development to carry out: large-scale focused ultrasound.

Could scaling up this technique be of interest for other gene therapies?

M.D. : Absolutely — and that is precisely the broader challenge of our work. Intravenous injection of microbubbles and treatment is less invasive than administering therapy directly into the brain. Moreover, for example, even though the Zolgensma® viral vector crosses the blood–brain barrier, only a small fraction actually reaches the brain. A very high dose must therefore be injected for it to be effective. By applying focused ultrasound, the optimal dose can be reduced tenfold, meaning lower potential toxicity and a significant reduction in treatment costs. Finally, more efficient and promising vectors are under study, but their clinical development will still take many years. For all these reasons, our focused ultrasound approach is of great interest to AFM-Téléthon, which will continue to support us.

Interview conducted by MitoGether

Leigh Syndrome: dozens of genes involved

Leigh syndrome is the most common pediatric mitochondrial disease, with an estimated prevalence of approximately one in 36,000 births. Its progression is generally severe and progressive, and there is currently no curative treatment.

To date, about 113 genes have been identified as responsible for this pathology. Some are located in mitochondrial DNA, others in nuclear DNA, including NDUFS4, which encodes one of the subunits of complex I of the mitochondrial respiratory chain.

Mice deficient in ndufs4, the murine version of the gene, faithfully reproduce the main symptoms of the human disease, particularly brain involvement, which is central in Leigh syndrome.

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