Novel pharmacological approaches to increase ketone bodies availability in GLUT1 Deficiency Syndrome

The overall objective of this project is to identify new therapies that improve the quality of life of patients affected by GLUT1 Deficiency Syndrome (GLUT1 DS). GLUT1 DS is a genetic disease caused by mutations in the gene encoding GLUT1, a transporter that allows glucose to enter the brain to provide adequate energy supply. GLUT1 DS patients suffer from epileptic encephalopathy and motor incoordination. The only treatment is a tight dietary regimen rich in fat and low in sugars, designed to allow the production of ketone bodies as the alternative source of energy for the brain. This diet, called “ketogenic diet”, limits the choice of ingredients to avoid exceeding glucose concentrations in the blood. New therapeutic approaches would be highly desirable to improve health condition and quality of life. The production of ketone bodies physiologically increases during fasted state and is regulated by receptors called peroxisome proliferators-activated receptors (PPARs), which can be considered “molecular switches” controlling specific biological processes. Fibroblast growth factor 21 (FGF21) also stimulates the production of ketone bodies, by acting as a “signal molecule” targeting distinct physiologic functions. The specific aims of this project are: 1. to investigate whether activation of PPARs with specific molecules or administration of FGF21 to experimental models of GLUT1 DS can increase the production of ketone bodies and 2. to evaluate the effects of these molecules on neurologic functions in GLUT1 deficiency. Our results may represent a proof-of-concept for new treatments to reduce the symptoms of the disease and alleviate the stringency of ketogenic diet. Of note, the hypolipidemic drugs “fibrates” selectively activate PPARs and have been widely prescribed for many years, showing a safe profile. Therefore, the added value of this project is the proximity to find a new therapy with drugs that have already been extensively characterized.