Basic science: In 1989 we discovered that adult and immature neurons have different electrical activity with notably much lower intracellular concentrations of chloride in the former than in the latter. High levels of chloride lead to a reduced brain inhibition and increased excitation, and are observed in immature neurons of all animal species and brain structures studied. They are needed for essential developmental processes including proliferation, migration and synapse formation. The developmentally regulated abrupt reduction of intracellular chloride concentration is instrumental as adult neurons are vulnerable to high chloride levels and resulting excitation. However, a wide range of brain disorders produce a “return to an immature state” with persistent high intracellular chloride levels. This has been reported in a wide range of brain disorders, including Autism Spectrum Disorders (ASD) and other Developmental disorders (DDs). The Neuroarcheology concept suggested 13 years ago posits that the initial genetic or environmental triggering insult modifies proliferation, migration and other essential processes leading to aberrant neuronal ensembles endowed with “immature” properties. These generate signals that perturb brain activity and are the direct cause of the disease, suggesting that treating the initial cause will not lead to adequate treatments. This however open a possibility of treating DDs with selective antagonists of these immature neurons to produce a sort of pharmaceutical surgery. This concept has been validated in preclinical studies performed on animal models of DDs and more recently in clinical trials.
Clinical trials: Bumetanide is a selective antagonist of the principal neuronal chloride importer and has been shown to efficiently reduce intracellular chloride levels. In animal models, it also attenuates many DDs including ASD and various types of infantile epilepsies. Ten years ago we started clinical studies with a pilot trial using Bumetanide to treat ASD (5 children)1. The encouraging results led to a double-blind randomized Phase 2a trial (60 children) 2 followed by and a Phase 2b trial (88 children) 3. The latter was multicentric and covered the entire pediatric population (2-18 years old) testing 3 dosages to select an optimal one with minimal side effects. We observed a significant amelioration of the core symptoms of ASD after treatment with Bumetanide, particularly on social communication and restricted interests. Our observations were recently confirmed by 2 independent trials in China using the same dosage and treatment duration 4,5. Other smaller trials in Sweden 9 and in Tunisia 10 also brought interesting insights on the efficacy of Bumetanide in the treatment of ASD. In addition, a study by a Dutch group reported significant amelioration of repetitive behavior but not in the Social Responsive Scale, although interview by many parents suggested a significant amelioration of the symptoms 6. The efficacy of the treatment was also validated for a genetic form of ASD -Tuberous Sclerosis- 7 and a case report of a child with Fragile X syndrome 8. Our Phase 2b trial is part of a Pediatric Investigation Plan reviewed by the European Medicine Agency and was recognized as pivotal 3. It allowed to go on with two large international final Phase 3 trials which are presently performed by the French Pharma Servier and Neurochlore (a startup dedicated to treat ASD)
https://clinicaltrials.gov/ct2/show/NCT03715153?term=servier&cond=ASD&draw=2&rank=1
https://clinicaltrials.gov/ct2/show/NCT03715166?term=servier&cond=ASD&draw=2&rank=2
These trials are using a Bumetanide pediatric formulation adapted to children and allowing a dose to weight adaptation. All our trials characterized the pharmacokinetics of this Bumetanide oral liquid formulation into the full age range of children and adolescents (2 to 18 years old). This is crucial to ensure that children of all ages have access to a safe and accurate dosage depending also of their co-morbidities and concomitant medications (https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-formulations-choice-paediatric-population). If the Phase 3 is successful and the product registered, its access to reimbursement will be possible according to the medical care regulation of each European country.
Conclusions: Basic science can lead to the discovery of treatments of disorders that are medically unmet, but this requires innovative concepts. In spite of the genetic and molecular revolution, we have no successful treatments for most DDs. The main reason is that DDs are born in the womb and the initial insult deviates developmental sequences leading to neuronal ensembles that fail to mature correctly. Clearly not taking into account the dynamic impact of an in-utero insult and treating only the triggering cause is bound not to provide innovative treatments. Also, clinical trials and approval by the authorities are crucial to avoid inappropriate use of treatments. It is only once our trials are finalized, and the results approved by the authorities, that the treatment will be valid to be prescribed by doctors in well-controlled conditions.
Yehezkel Ben-Ari & Eric Lemonnier
Y B-A : CEO Neurochlore, Président de IBEN
E L : CHU Limoges
Références :
- Lemonnier, E. & Ben-Ari, Y. The diuretic bumetanide decreases autistic behaviour in five infants treated during 3 months with no side effects. Acta Paediatr. Int. J. Paediatr.99, 1885–1888 (2010).
- Lemonnier, E. et al. A randomised controlled trial of bumetanide in the treatment of autism in children. Translational Psychiatry (2012).
- Lemonnier, E. et al. Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders. Transl. Psychiatry (2017) doi:10.1038/tp.2017.10.
- Zhang, L. et al. Symptom improvement in children with autism spectrum disorder following bumetanide administration is associated with decreased GABA/glutamate ratios. Transl. Psychiatry (2020) doi:10.1038/s41398-020-0692-2.
- Du, L. et al. A Pilot Study on the Combination of Applied Behavior Analysis and Bumetanide Treatment for Children with Autism. J. Child Adolesc. Psychopharmacol. 25, 585–588 (2015).
- D., M. van A. et al. Behavioural and Neurophysiological Outcomes of the Bumetanide in Autism Medication and Biomarker (BAMBI) Trial. Biol. Psychiatry (2019) doi:10.1016/j.biopsych.2019.03.235 LK
- Van Andel, D. M. et al. Effects of bumetanide on neurodevelopmental impairments in patients with tuberous sclerosis complex: An open-label pilot study. Mol. Autism (2020) doi:10.1186/s13229-020-00335-4.
- Lemonnier, E. et al. Treating Fragile X syndrome with the diuretic bumetanide: A case report. Acta Paediatr. Int. J. Paediatr.102, 2007–2009 (2013).
- Fernell, E. et al. Bumetanide for autism: open-label trial in six children. Acta Paediatr. (2020) https://doi.org/10.1111/apa.15723
- Hajri, M. et al. Bumetanide in the management of autism. Tunisian experience in Razi Hospital. La Tunisie Medicale (2019) 97, 08/09, 971-977.
