Researchers at CEA-Joliot have confirmed that a drug candidate could be used to treat creatine congenital deficit syndrome, a neurological childhood disease responsible for delayed development and cognitive deficits.
Creatine transporter deficiency is a rare metabolic and genetic disease, with currently no cure. It leads to autistic disorders, moderate to serious intellectual deficits, and major communication and developmental disorders, such as psychomotor disorders. Many affected children also suffer from epileptic seizures. This pathology, which mainly affect boys, was first described at the beginning of this century, and it could represent 1 to 2% of all cases of delayed development whose cause is unknown. While a rare disease, it is still largely under-diagnosed and is very debilitating. It is caused by a gene alteration that can be inherited and which leads to the absence of functionality of the creatine transporter (SLC6A8), involved in cellular energy regulation loops.
Researchers are working on the development of pharmaceutical-grade paediatric drugs that would increase the level of brain creatine in children affected by the disease to reduce or even eliminate their neuro-cognitive disorders. Such drugs could also help treat affected adults.
For several years now, two teams from CEA-Joliot have been working on the development of new creatine prodrugs that could be considered as potential drug candidates. In 2015, the researchers described an in vitro therapeutic strategy based on the use of a creatine dodecyclic ester (EDC) incorporated in lipid nanocapsules.
In their new study, they have developed a new galenic formula in the form of a microemulsion to deliver the EDC, which thus protected can be administered nasally. Tested in mice, it “short-circuits” the blood-brain barrier and can passively enter the parenchymal cells of the brain areas by retrograde transport via the olfactory and trigeminal nerves. The ester will then be cleaved by intracellular enzymes and creatine will be released.
The researchers observed an increase in creatine levels in the striatum, cerebellum, hippocampus and cortex following intranasal administration of these microspheres to the animal model. They also saw an improvement in cognitive functions as measured by the New Object Recognition Test (NOR) in treated animals. Finally, they demonstrated an increase in the transcription of genes encoding markers involved in post-synaptic functions, neuronal plasticity, memory process formation and neuroprotection in the striatum.
These results confirm the potential of creatine dodecyl ester in the treatment of creatine transporter deficiency. The next step in the research: preclinical and clinical developments that should ultimately lead to a drug that will treat children suffering from creatine congenital deficit syndrome.
Reference: Dodecyl creatine ester-loaded nanoemulsion as a promising therapy for creatine transporter deficiency, Gabriela Ullio-Gamboa et al., Nanomedicine.
Translated by LABNAUT.