Antibiotherapy

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Antibio-therapy and autism: hypothesis and intuition are not enough 

We are living in a period with countless propositions of therapeutical solutions, in particular to treat Autism, that resemble more « fake news » and scientific pollution than actual possible treatments. It is important to remember the principles of well-established protocols on drug discovery, and to help parents navigate the unofficial announcements of possible future treatments. 

A good hunch is not enough. A Nobel prize winner in the need for publicity that in addition has no experience in the field of Autism, nor neurological or psychiatric diseases, postulates that has found the solution to cure Autism. The trials that are in favor of the beneficial effects of the antibio-therapy are followed by rumors saying that the treatment works, and 1000 kids have been tested successfully, even if these trials do not follow regulatory clinical protocols and are based on isolated cases. Yet, the steps needed to be achieved in order to perform these types of trials have been known for years. Starting with a hypothesis, preclinical experimental trials in animal models should be done, followed by proof-of-concept pilot trials that are controlled, randomized and double-blind. Then, when this first trial turns out positive, the next step is to perform in multiple centers randomized, double-blind phase 2 clinical trials aimed at determining the right dose of the treatment that leads to the best benefit/risk ratio. The final step is to perform a controlled phase 3 clinical trial that will confirm the efficiency of the treatment in a large population, meaning a population that present not-only the pathology but common co-morbidities (the closest possible to the population for which the treatment will be prescribed). To the best of our knowledge, there are no publications that attest the existence of these type of data or trials showing that antibio-therapy, such as the use of probiotics, has positive effects. The mandatory rules and the respect of the proper steps to follow, should be reminded before the making of public and media declarations. The example of the statements made on possible treatments for Covid19 based on badly conducted trials or very small populations show the danger of skipping the necessary steps to find proper treatments. In our humble personal experience, it took several decades of experimental research for one of us (Y B-A) to be able to understand the alterations in brain inhibition during development and brain disorders notably in Autism. After this, it took one decade for both of us to perform clinical trials with pilot studies, followed by double-bind, randomized, controlled trials with positive outcomes that were confirmed by other teams. At this stage, and in partnership with the pharmaceutical company Servier, we are conducting a final phase 3 pediatric trial. If this trial confirms our previous results, we will be able, after more than 15 years, to propose a treatment. The path is long, the administrative and financial hurdles enormous, the demands of the health authorities cumbersome, slow and expensive, but that is the price to pay. Chi va piano, va sano!

Concerning the development of treatments, we have been promised for at least 4 decades that thanks to genetic and big data (such as the Blue Brain project), brain disorders will be soon resolved and removed from the medical agenda. Yet, this is clearly not the case. Why? I think that the lack of genuine innovation bears a big responsibility, the genuine innovation that does not follow the usual paths. To understand and treat Autism, maternity must be at the core of our thoughts, as the disorder is “born” in utero. The complex questions that we must resolve are to better understand how the inaugural insult, whether genetic or environmental, perturbs developmental sequences leading to the pathology. This is capital as the therapeutic target is not any more the inaugurating insult but its remaining signature. The concept of Neuroarcheology posits that misplaced or misconnected neuronal ensembles, generated due to the original insult, remain immature leading to aberrant activity that perturb and prevent the operation of behaviorally relevant oscillations. Our therapeutic approach in the last 10 years has been to treat these aberrant patterns by blocking selectively their operation relying on their immature features. The “genocenteric” approach, namely identifying more novel genetic mutations, is inoperant in a therapeutic perspective for that reason (even if the transfection and the genetic repair were possible, it would not resolve the problem). The core of the agenda must be to diagnose as early as possible, and to be able to use behavioral treatments coupled with a therapeutic approach using drugs that selectively block immature currents.

To conclude, pilot administration of drugs and approaches based on intuition without experimental data and a global concept are doomed to fail. In addition, to raise false hopes in parents who have already an incredibly heavy burden and are prone to believe any charlatan who promises a miracle, is uncalled for. We need order and method, global concepts associated with experimental data. To determine what is impacted early experimentally we should use tools that nowadays are considered out of fashion such as electrophysiology, anatomy, good pathways tracing and 3D brain imaging associated with global body analysis in experimental models. Furthermore, epidemiological investigations on maternity associated with imaging in utero will allow us to better define the announcing modifications and their possible relation with Autism and its heterogeneity. The sooner the better, as prevention and early interventions are and remain the best way to stop the disease and attenuate its severity. The aims are more modest, to attenuate not to cure, as this might be out of reach often.

Yehezkel Ben-Ari & Eric Lemonnier
Y B-A : CEO Neurochlore, Président de IBEN
E L : CHU Limoges

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