CERES aspires to revolutionize the treatment paradigm for neurological diseases characterized by bioenergetic deficiencies

INTEGRATIVE TECHNOLOGY TO PROVIDE
BRAIN CELLS WITH CREATINE

Ceres relies on its distinctive and innovative Creatine-to-Neurons™ approach to supply brain cells with creatine. This approach consists of creatine prodrugs, a highly innovative and adaptable formulation ensuring the stability and sprayability of the prodrugs, and intra-nasal delivery to target the Nose-to-Brain pathway and finally the brain, particularly neurons.

As of today, Ceres Brain Therapeutics stands as the sole entity capable of delivering creatine to cerebral neurons. This groundbreaking method opens the door to a myriad of clinical applications, including rare genetic diseases characterized by a primary lack of cerebral creatine, conditions related to mitochondrial deficiencies, epigenetic diseases, and broader societal health issues

Creatine

Creatine is a naturally occurring compound within cells, playing a crucial role in cellular energy production. It is synthesized in the body from the amino acids arginine, glycine, and methionine, primarily in the kidneys and liver.

Additionally, creatine is also present in certain animal-derived foods such as meat and fish. On a cellular scale, creatine is converted into creatine phosphate, a molecule that rapidly stores and releases energy, facilitating the regeneration of ATP, the primary cellular energy source.

Creatine has garnered increasing interest in the field of neurological diseases due to its potential neuroprotective properties. Studies show that creatine exert beneficial effects on cellular health by reducing oxidative stress and modulating various cellular signaling pathways.

Furthermore, it appears to possess neuroprotective properties, holding potential in the treatment of certain neurologic diseases such as degenerative diseases, traumatic brain injuries, stroke, age-related loss of cognitive function and more generaly cognitive impairments.

Creatine, although naturally occurring in the body, may face challenges in crossing blood-brain barrier due to the creatine transporter that can be saturated, impaired or lacking. Dopaminergic neurons, which produce the neurotransmitter dopamine, are particularly sensitive to this access restriction.

Platform

« Nose-to-Neurons » Ceres Brain’s platform

The Ceres Brain's 'Nose-to-Neurons' platform allows for the transition from a hit compound to a drug candidate that has demonstrated its ability to reach the brain, particularly the neurons, in preclinical models. 

This is made possible through:

  • Possible chemical optimization of the hit to make it more suitable for nasal administration, ensuring its stability and its capability to cross biological membranes,

  • the use of a unique formulation adaptable to a wide variety of drugs,

  • the application of protocols in rodents and non-rodents to demonstrate the Nose-to-Brain passage to the brain, particularly to the neurons, and to study its pharmacological effects,

  • measurement of concentrations at the site of action (the brain and possibly the neurons). 

Publications

Impaired brain glucose metabolism as a biomarker for evaluation of dodecyl creatine ester in creatine transporter deficiency: Insights from patient brain-derived organoids and in vivo [18F]FDG PET imaging in a mouse model.
Disdier C, Soyer A, Broca-Brisson L, Goutal S, Guyot AC, Ziani N, Breuil L, Winkeler A, Hugon G, Joudinaud T, Bénech H, Armengaud J, Skelton MR, Harati R, Hamoudi RA, Tournier N, Mabondzo A. Neurobiol Dis. 2024 Nov;202:106720. doi: 10.1016/j.nbd.2024.106720. Epub 2024 Oct 26.

Dodecyl creatine ester therapy: from promise to reality.
Aloïse Mabondzo, Jiddeke van de Kamp, Saadet Mercimek‑Andrews.
Cellular and Molecular Life Sciences (2024) 81:186.

Dodecyl creatine ester, a promising treatment to deliver creatine to neurons, achieves pharmacology efficacy in creatine transporter deficiency
Disdier C, Lhotellier C, Guyot AC, Costa N, Théoodoro F, Pruvost A, Skelton MR, Joudinaud T, Mabondzo A, Bénech H. European Journal of Medicinal Chemistry 284 (2025) 117195 »

Deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiency. 
Broca-Brisson L, Harati R, Disdier C, Mozner O, Gaston-Breton R, Maïza A, Costa N, Guyot AC, Sarkadi B, Apati A, Skelton MR, Madrange L, Yates F, Armengaud J, Hamoudi R, Mabondzo A. Elife. 2023 Oct 13;12:RP88459. doi: 10.7554/eLife.88459.

Dodecyl creatine ester improves cognitive function and identifies key protein drivers including KIF1A and PLCB1 in a mouse model of creatine transporter deficiency. 
Mabondzo A, Harati R, Broca-Brisson L, Guyot AC, Costa N, Cacciante F, Putignano E, Baroncelli L, Skelton MR, Saab C, Martini E, Benech H, Joudinaud T, Gaillard JC, Armengaud J, Hamoudi R. Front Mol Neurosci. 2023 Mar 24;16:1118707. doi: 10.3389/fnmol.2023.1118707

Dodecyl creatine ester-loaded nanoemulsion as a promising therapy for creatine transporter deficiency. 
Ullio-Gamboa G, Udobi KC, Dezard S, Perna MK, Miles KN, Costa N, Taran F, Pruvost A, Benoit JP, Skelton MR, Lonlay P, Mabondzo A. Nanomedicine (Lond). 2019 Jun;14(12):1579-1593. doi: 10.2217/nnm-2019-0059. Epub 2019 Apr 30.

Cognitive deficits and increases in creatine precursors in a brain-specific knockout of the creatine transporter gene Slc6a8. 
Udobi KC, Kokenge AN, Hautman ER, Ullio G, Coene J, Williams MT, Vorhees CV, Mabondzo A, Skelton MR. Genes Brain Behav. 2018 Jul;17(6):e12461. doi: 10.1111/gbb.12461. Epub 2018 Feb 20.

Dodecyl creatine ester and lipid nanocapsule: a double strategy for the treatment of creatine transporter deficiency. 
Trotier-Faurion A, Passirani C, Béjaud J, Dézard S, Valayannopoulos V, Taran F, de Lonlay P, Benoit JP, Mabondzo A. Nanomedicine (Lond). 2015 Jan;10(2):185-91. doi: 10.2217/nnm.13.205. Epub 2014 Feb 21.

Synthesis and biological evaluation of new creatine fatty esters revealed dodecyl creatine ester as a promising drug candidate for the treatment of the creatine transporter deficiency. 
Trotier-Faurion A, Dézard S, Taran F, Valayannopoulos V, de Lonlay P, Mabondzo A. J Med Chem. 2013 Jun 27;56(12):5173-81. doi: 10.1021/jm400545n. Epub 2013 Jun 7.

Communications

  • T. Joudinaud. CBT101 development: Steeple chase race toward clinical trials. Xtraordinaire Symposium, 2023 Sept 30th 2023, Paris, France

  • T.  Joudinaud. Advancements towards clinical trial of CBT101. ACD virtual conference 2023, August 25-26, 2023

  • A. Mabondzo. Development of cerebral brain organoids from CTD patients. ACD virtual conference 2023, August 25-26, 2023

  • Disdier C, Benech H, Callebert J, Joudinaud T , Mabondzo A. CBT101, a creatine ester prodrug, secures energy supply and boosts mitochondrial dynamics in the 6OHDA rat model. 14th congress targeting mitochondria. October 2023 Berlin, Germany.

  • Kengne Kamkui L, Herbet A, Disdier C , Hautiere M , Costa N , Joudinaud T , Benech H , Mabondzo A , Boquet D. Nose-to-brain delivery of biotherapeutics. An approach to treat brain metastases. 14th conference of Cerebrovascular Biology June 2023 Uppsala, Sweden.

  • Soyer A. et al Evaluation of brain F-18-FDG-PET imaging as a translational biomarker for therapeutic monitoring in creatine transporter deficiency. the 35th Annual Congress of the European Association of Nuclear Medicine October 2022, Barcelona Spain. 

  • Bénech H. et al CBT101, a creatine ester prodrug, shows promising results in mitochondrial diseases preclinical models. Mitonice September 2022, Nice France.