Dodecyl creatine ester, a promising treatment to deliver creatine to neurons for CTD

Abstract: Dodecyl creatine ester (DCE) is a creatine prodrug currently developed for brain diseases, including creatine transporter deficiency (CTD), an incurable rare genetic disease. A dual strategy combining a prodrug to bypass the non-functional creatine transporter and its delivery via the nose-to-brain pathway has been proposed to replenish creatine levels in cerebral cells, particularly in neurons of CTD patients. In vitro and in vivo studies in various animal models, including wild-type non-human primates and creatine transporter deficient mice, show that formulated DCE, when administered intranasally, achieves significant cerebral distribution up to the target cells, the neurons, and modulates the expression of neuronal markers related to cognitive function at doses intended for patients. These compelling results contribute to a better understanding of the pharmacokinetics and pharmacodynamics of DCE after nasal administration, with a particular focus on the crucial role of the nose-to-brain pathway in DCE distribution.

Parent Summary: Currently, giving creatine to creatine transporter deficiency patients by mouth is ineffective, because creatine does not pass the blood-brain barrier without a working creatine transporter. Scientists are developing a new drug called dodecyl creatine ester (DCE) as a potential solution. DCE is a modified form of creatine that is designed to cross cell membranes more easily, even without a transporter. Once inside the brain cells, DCE can be converted back into the active form of creatine.
In this paper, DCE was given through the nose to deliver it to the brain without being injected into the bloodstream (DCE is not stable in blood because it readily converts into creatinine which the body quickly removes). The researchers showed that DCE given intranasally quickly converted to creatine and could be detected in the brains of monkeys and CTD mice. In CTD mice, the low doses of nasal DCE were able to change certain markers in the brain that are linked to cognitive function. This suggests that DCE treatment could help improve brain function in patients with CTD. The results of this study provide a foundation for further development of nasal DCE as a potential treatment for CTD patients.

Link to article: https://www.sciencedirect.com/science/article/abs/pii/S0223523424010778

PubMed: https://pubmed.ncbi.nlm.nih.gov/39733481/

Authors: Clémence Disdier, Clara Lhotellier, Anne-Cécile Guyot, Narciso Costa, Frédéric Théodoro, Alain Pruvost, Matthew R. Skelton, Thomas Joudinaud, Aloïse Mabondzo, Henri Bénech

Key Terms: CTD, Animal Study, Small Molecule Therapy, In vitro, Basic Science, Therapeutics