D-099
Targeting Astrocytes to Help Meet Brain Energy Demands in GLUT1 Deficiency Syndrome
Julia Dimundo1, Sebastián Bairo1, Deborah Holstein2, James Lechleiter2, Mariana Bollo1, R. Sebastián Miranda Morales1,3
  1. Instituto M. M. Ferreyra, INIMEC-CONICET-UNC. Córdoba, Argentina 
  2. Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
  3. Facultad de Psicología, UNC, Córdoba, Argentina
Presenting Author:
Julia Dimundo
jdimundo@immf.uncor.edu
Glucose transport across the blood-brain barrier and into astrocytes relies on the glucose transporter type 1 (GLUT1). Heterozygous mutations in SLC2A1 cause GLUT1 Deficiency Syndrome (GLUT1-DS), a rare disorder that affects brain energy metabolism and development. Despite the genetic cause being identified over three decades ago, no therapies beyond the ketogenic diet exist. A US-based biotechnology company has been developing a small molecule that boosts astrocytic mitochondrial ATP production; its name is withheld due to an ongoing patent application. We aim to evaluate this compound as a candidate therapy for GLUT1-DS. To mimic GLUT1-DS, primary human astrocytes were incubated in glucose-free medium and treated with the compound, β-hydroxybutyrate (βHB), or their combination. These treatments significantly increased intracellular ATP individually and had a synergistic effect when combined. Mitochondrial membrane potential was also enhanced with either treatment. Additionally, intracellular calcium imaging revealed that the compound further increased Ca²⁺ fluctuations in reactive astrocytes versus controls, suggesting enhanced responsiveness under pathological conditions. These results support the potential of this compound as a pharmacological therapy to enhance astrocyte metabolism in GLUT1-DS. Next, we will test it in hiPSC-derived astrocytes modeling SLC2A1 haploinsufficiency and in transgenic mice to generate translational preclinical evidence.