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

Creatine transporter deficiency (CTD) is an inborn error of creatine (Cr) metabolism in which Cr is not properly distributed to the brain due to a mutation in the Cr transporter (CrT) SLC6A8 gene. CTD is associated with developmental delays and with neurological disability in children. Dodecyl creatine ester (DCE), as a Cr prodrug, is a promising drug to treat CTD after administration by the nasal route, taking advantage of the nose-to-brain pathway. In this study, the potential adaptive response to energy imbalance in glucose metabolism was investigated in CTD using both SLC6A8-deficient mice (CrT KO) and brain organoids derived from CTD patient cells. Longitudinal brain [18F]FDG PET imaging in CrT KO mice compared to wild-type mice demonstrated that CTD was associated with a significant loss and decline in brain glucose metabolism. In CrT KO mice, intranasal supplementation with DCE for a month significantly mitigated the decline in brain glucose metabolism compared to untreated (vehicle) animals. Mechanistic investigations in CrT KO mice and cerebral organoids derived from CTD patient cells suggest that intracellular trafficking of glucose transporter (Glut) may be altered by lack of activation of AMP-activated protein kinase (AMPK). Consistency between observations in the CrT KO mouse model and cerebral organoids derived from CTD patient cells supports the value of this new model for drug discovery and development. In addition, these results suggest that [18F]FDG PET imaging may offer a unique and minimally-invasive biomarker to monitor the impact of investigational treatment on CTD pathophysiology, with translational perspectives.