Alexandre Carpentier

The SonoSLA project, supported by the French Ministry of Health and MSDAvenir, aims to “temporarily open the brain's blood barrier to treat Charcot disease”. This research program represents the world's first clinical trial on patients suffering from Charcot disease.

After studying at the Lycée Louis le Grand, Professor Alexandre Carpentier devoted himself to medicine, obtaining his doctorate at Paris VI, followed by a doctorate in science between Paris VI and Yale University. His clinical activities at the Pitié Salpêtrière Hospital - AP-HP.Sorbonne University are mainly dedicated to the treatment of brain tumors and epilepsy. He performs almost two hundred neurosurgical procedures a year as part of the largest team in France, which he has been in charge of since 2017.

His fundamental and translational research activities focus on the interface between physics and biology. His research includes pioneering studies in diagnostic functional MRI and the exploration of interactions between laser light and brain tissue. In 2006, he set up his own laboratory, carrying out the world's first laser treatments of closed-skull brain tumors. By 2010, Professor Alexandre Carpentier was exploring the use of ultrasound to open the blood-brain barrier, leading to significant advances published in renowned journals such as Science Translational Medicine, Clinical Cancer Research and The Lancet Oncology.

He also founded the university start-up CarThera to promote his discoveries and make them accessible to patients worldwide. He was elected Chairman of the Pitié Salpêtrière hospital group's Research and Innovation Commission in 2011, and sits on the board of the International Society for Therapeutic Ultrasound, while actively participating in numerous international congresses. Today, he is pursuing his research into ultrasound applied to other brain pathologies, such as Amyotrophic Lateral Sclerosis (ALS), convinced that innovation and collaboration are essential to progress in neurosurgery.

1) Could you explain the innovative protocol proposed by the SonoSLA research project and how it differs from traditional pharmaceutical approaches to treating Charcot disease/ALS?

Alexandre Carpentier: With this protocol, we explore a novel approach to the treatment of ALS: the temporary permeabilization of cerebral vessels using low-intensity ultrasound. Brain vessels play a crucial role in sealing the brain, but this limits the penetration of our immune defenses and most drugs into the brain, posing a major challenge in the treatment of neurological diseases. With just four minutes of ultrasound emission, we are able to permeabilize these vessels for 2-3 hours in a reversible and non-toxic manner.

This approach has already been successfully tested on over 100 of our patients with brain tumors, where it improved survival by facilitating chemotherapy penetration. In the case of Charcot's disease, our preliminary studies on ALS mice have shown that this temporary permeabilization of cerebral vessels improves survival by allowing the entry of regulatory lymphocytes, thereby reducing the inflammation associated with the disease. Ultimately, we will be able to couple this action with the previously impossible penetration of drugs.
We have therefore undertaken to initiate a clinical trial to extend this approach to ALS. We will start with a study on 12 patients to confirm the absence of toxicity, and then on a further 11 patients to assess efficacy on clinical symptoms, survival and disease biomarkers. The low-intensity pulsed ultrasound we use does not damage or heat tissues, but it does temporarily open the blood-brain barrier, allowing the entry of our immune system and therapeutic substances. This biophysical approach, combining biology and ultrasound, represents a potentially major advance in the treatment of neurological diseases.

By developing this method, we have shown that temporarily permeabilizing the blood-brain barrier does not present toxic risks, thus opening the way to new treatments for a wide range of neurological diseases. We continue our research with enthusiasm, hoping to offer new therapeutic perspectives to those who need them most.

2) What are the main therapeutic obstacles facing patients with Lou Gehrig's disease/ALS, and why is it important to find new therapeutic avenues for this disease?

Current treatments for ALS are inadequate, with patients living an average of only 24 to 48 months after diagnosis. These treatments focus primarily on reducing symptoms rather than addressing the cause of the disease, which remains uncertain and under debate.

Riluzole is the only drug since 1996 whose effectiveness is recognized. Its action is a replacement of neurotransmitters, providing a survival of 2 months, but having no therapeutic effect on the cause of the disease itself. Other drugs exist but their effectiveness remains uncertain.

While there are many theoretical candidate drugs to treat ALS, this problem of treatment penetration into the brain is very limiting. It is indeed a very specific property of cerebral vessels to limit the penetration of 99% of drugs in order to protect it from any potential toxicity. We are talking about the blood-brain barrier (BBB). Protective effect, but an insurmountable barrier in the event of a need for treatment! The failure of current treatments for many brain pathologies (tumors, ALS, Alzheimer's, etc.) is largely due to this BBB.

3) What do you hope to achieve at the end of your research project on Charcot's disease?

We first seek to confirm that our technique is non-toxic for fragile patients with Charcot's disease, in particular by evaluating the tolerance of the surgical procedure of implantation of the ultrasound transmitter under local anesthesia.

We hope to observe a sign of efficacy, whether clinical (survival and motor function of patients), or on blood biomarkers. This would allow us to determine the optimal number of patients for a possible phase 3, in order to obtain irrefutable statistical proof of the efficacy of our approach.

In the event of no detected efficacy, our protocol will nevertheless open the possibility of considering a combination of “ultrasound + medication” to potentiate the effect of the medication.

4)  If this clinical trial on Charcot's disease is positive, what will be the next steps and what can we hope for in the treatment of this currently incurable disease?

If this trial is positive then we will move on to a phase 3 where patients will be randomly divided into two groups: one receiving the ultrasound treatment and the other not.

This phase 3 trial, which will involve a large patient population, will aim to provide robust statistical proof of the efficacy of our approach and its benefit for patients. If phase 3 is also conclusive, the technique will then be proposed in routine practice, with regular monitoring.

5) MSDAvenir and the Ministry of Health (PHRC) are supporting the SonoSLA project. What does this support mean for your project?

This is a great show of confidence. We are the first in the world in the treatment of brain tumors with BBB opening by ultrasound, with proof of non-toxicity and strong signals of efficacy published in excellent scientific journals. It is pleasing to see that a program as disruptive as ours was able to generate interest from the selection committees. We thank them very much for their open-mindedness.