A novel strategy to deliver glucose to the brain under conditions of glucose transporter deficiency

Glucose transporter type 1 deficiency syndrome is caused by a gene mutation. This disease will impair the transport of glucose into the brain. As a result, glucose is absent or severely decreased in the brain, and the latter suffers a severe energy impairment. The symptoms may vary, however the most characteristic manifestations of the classical form include untreatable epileptic seizures, usually with onset in infancy, delayed cognitive and motor development, and microcephaly. The classical form of the syndrome occurs during the first year of life, manifesting as developmental delay, impaired motor control and deceleration of skull growth (microcephaly). The onset of seizures generally occurs when the child is between three weeks and four months old, manifesting as spasms in the arms and/or legs, staring or rolling eye movements, short episodes of pallor, absent gaze or nodding.The child may also have recurrent episodes of symptoms unrelated to the seizures, including balance and coordination problems (ataxia), confusion, headaches, or sleep disturbances. All children develop some form of motor control problems, including shaking movements, ataxia and spasticity. Our objective will be to provide a pharmacological way to carry glucose across the blood brain barrier (into the brain) even in the absence of GLUT1. In turn, this may be the first step toward a cure for GLUT1 deficiency syndrome. One way to carry molecules into the brain is to bind them to a molecule having a specific cerebral transporter. In the brain the combined molecule should then revert to its components. We used this approach for creatine transporter deficiency where creatine, lacking its transporter, does not enter the brain. In preliminary experiments we had encouraging results by binding creatine to ascorbate, a molecule having its own transporter, and by using the commercially available creatine-gluconate, gluconic acid being supposedly carried by the glucose transporter (a specific gluconate transporter exists only in prokariotes). The encouraging preliminary results we had made us think that the same principle may be used to transport glucose in Glut1 DS. To verify blood brain barrier crossing, we will use radioactively labeled deoxy-glucose. The latter is often used in glucose research because it is not metabolized into different compounds, thus assuring that any measured radioactivity does not originate from glucose metabolites (they could, in theory, cross the blood brain barrier independently). We will inject the experimental compounds intraperitoneally into mice lacking the glucose transporter, which we will receive from Dr. De Vivo who created them. We will sacrifice the animals 30', 60', 120' and 180' after injection, measuring radioactivity at each time point. As controls we will use two groups of the same transporter-deficient mice, one injected with creatine and C14-deoxy-glucose separately, the other with C14-deoxy-glucose only. Our intention is to make an important contribution to research to "De Vivo disease". We want to find a drug to be proposed for this disease.