Prof. Yehezkel Ben-Ari will participate in BIO Europe meeting in Stockholm early November to develop partnerships with Pharma’s & investors to treat autism and brain tumors.
The Co-transporter NKCC1 that regulates GABAergic inhibition and cell volume is overactive in many brain disorders including autism, fragile X and Rett syndrome, brain trauma, epilepsies, brain traumas cerebro-vascular infarcts, Parkinson, Huntington &Alzheimer disease, various cancers & tumors, chronic pain, etc. Our efforts are centered on autism & brain tumors relying on a 1st and 2nd generation developments.
I. Autism
1st generation : The generic specific NKCC1 inhibitor restores inhibition in experimental conditions (Y. Ben-Ari et al. 2007)(Tyzio et al. 2006) and attenuates autism severity in 9 double blind randomized trials phase 2 trials (>1030 children) performed in different countries (Yehezkel Ben-Ari 2017)(Xiao et al. 2024). Bumetanide ameliorates visual interactions, identification of emotive figures and functional MRI alterations (Hadjikhani et al. 2018). Yet, our phase 3 trial failed (Fuentes et al. 2023) ; it used as a principal criterion CARS2 – a mean of 15 different items- and second criterion SRS – a mean of 65 different items, in addition to DSM. We tested the hypothesis that analysis of subscales might reveal bumetanide responders. Indeed, 30-40% of bumetanide responder children can be identified in a phase 3 Machine Learning re-analysis of all subscales. This identification is now patent protected. We are seeking partnership/investors to perform a phase 3 using these inclusion characteristics.
2nd generation : We have synthetized, and patent protected over 120 novel NKCC1 inhibitors some even more potent than Bumetanide. We are now seeking partnership/investors to bring our inhibitors to IND-enabling studies and clinical phase 1. Considering the large number of disorders susceptible to treatment by NKCC1 inhibitors, our large collection of proprietary drugs is highly valuable.
II. Brain Tumors & Glioblastoma
1st generation : Extensive evidence suggests that the generic Bumetanide (Algharabil et al. 2012)(Cuddapah and Sontheimer 2011)(Garzon-Muvdi et al. 2012) like the anthelminthic agent Mebendazole reduce brain tumors including Glioblastoma (Jordan and Wilson 2004)(Gallia et al. 2021). Using human glioblastoma cell lines and tumoroids extracted from surgically resected material, we show that both agents can act synergistically: inefficient low dosages of Meb and Bum reduce migration and enhance apoptosis when combined. In a pilot trial, the combo (Meb +Bum) ameliorates clinical conditions & increases survival without generating novel side effects. We are proceeding with a larger trial (10 patients). The combo has been patent protected. We are seeking partnership/ investors to perform a phase 3 designed to put the combo in the market.
2nd generation. We have synthetized and patent protected over 120 novel NKCC1 inhibitors, some even more potent than Bumetanide. In human glioblastoma cell lines and tumoroids extracted from surgically resected material, some of these new NKCC1 inhibitors block migration and enhance apoptosis without impacting cultures of fibroblasts. In rodent hippocampal slices, they enhance GABAergic inhibition and reduce seizures without affecting synaptic and voltage gated currents. We are now seeking partnership/investors to bring our inhibitors to IND-enabling studies and clinical phase 1.
References
Algharabil, Jehad, Douglas B. Kintner, Qiwei Wang, Gulnaz Begum, Paul A. Clark, Sung Sen Yang, Shih Hua Lin, Kristopher T. Kahle, John S. Kuo, and Dandan Sun. 2012. “Inhibition of Na-K + -2Cl – Cotransporter Isoform 1 Accelerates Temozolomidemediated Apoptosis in Glioblastoma Cancer Cells.” Cellular Physiology and Biochemistry. https://doi.org/10.1159/000339047.
Ben-Ari, Y., J.-L. Gaiarsa, R. Tyzio, and R. Khazipov. 2007. “GABA: A Pioneer Transmitter That Excites Immature Neurons and Generates Primitive Oscillations.” Physiological Reviews 87 (4): 1215–68. https://doi.org/10.1152/physrev.00017.2006.
Ben-Ari, Yehezkel. 2017. “NKCC1 Chloride Importer Antagonists Attenuate Many Neurological and Psychiatric Disorders.” Trends in Neurosciences 40 (9): 536–54. https://doi.org/10.1016/j.tins.2017.07.001.
Cuddapah, Vishnu Anand, and Harald Sontheimer. 2011. “Ion Channels and Tranporters in Cancer. 2. Ion Channels and the Control of Cancer Cell Migration.” American Journal of Physiology – Cell Physiology 301 (3): 1–16. https://doi.org/10.1152/ajpcell.00102.2011.
Fuentes, Joaquin, Mara Parellada, Christina Georgoula, Guiomar Oliveira, Stéphane Marret, Véronique Crutel, Cristina Albarran, et al. 2023. “Bumetanide Oral Solution for the Treatment of Children and Adolescents with Autism Spectrum Disorder: Results from Two Randomized Phase III Studies.” Autism Research, no. July: 1–14. https://doi.org/10.1002/aur.3005.
Gallia, Gary L, Matthias Holdhoff, Henry Brem, Avadhut D Joshi, Christine L Hann, Ren-yuan Bai, Verena Staedtke, et al. 2021. “Neuro-Oncology Advances Diagnosed High-Grade Gliomas : Results of a Phase 1.” Neuro-Oncology Advances 3 (November 2020): 1–8. https://doi.org/10.1093/noajnl/vdaa154.
Garzon-Muvdi, Tomas, Paula Schiapparelli, Colette ap Rhys, Hugo Guerrero-Cazares, Christopher Smith, Deok Ho Kim, Lyonell Kone, et al. 2012. “Regulation of Brain Tumor Dispersal by NKCC1 through a Novel Role in Focal Adhesion Regulation.” PLoS Biology 10 (5). https://doi.org/10.1371/journal.pbio.1001320.
Hadjikhani, N., J. Åsberg Johnels, A. Lassalle, N.R. Zürcher, L. Hippolyte, C. Gillberg, E. Lemonnier, and Y. Ben-Ari. 2018. “Bumetanide for Autism: More Eye Contact, Less Amygdala Activation.” Scientific Reports 8 (1): 1–8. https://doi.org/10.1038/s41598-018-21958-x.
Jordan, Mary Ann, and Leslie Wilson. 2004. “Microtubules As a Target For” 4 (April). https://doi.org/10.1038/nr1317.
Tyzio, Roman, Rosa Cossart, Ilgam Khalilov, Marat Minlebaev, Christian A. Hübner, Alfonso Represa, Yehezkel Ben-Ari, and Rustem Khazipov. 2006. “Maternal Oxytocin Triggers a Transient Inhibitory Switch in GABA Signaling in the Fetal Brain during Delivery.” Science 314 (5806): 1788–92. https://doi.org/10.1126/science.1133212.
Xiao, Hong Li, Han Zhu, Jia Qi Jing, Si Jia Jia, Su Hong Yu, and Chang Jiang Yang. 2024. “Can Bumetanide Be a Miraculous Medicine for Autism Spectrum Disorder: Meta-Analysis Evidence from Randomized Controlled Trials.” Research in Autism Spectrum Disorders 114 (February): 102363. https://doi.org/10.1016/j.rasd.2024.102363.
