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A therapeutic role for a regulatory glucose transporter1 (GLUT1)-associated lncRNA in GLUT1-deficient mice

Maoxue Tang,¹ Sasa Teng,¹ Yueqing Peng,¹ Ashley Y. Kim,¹ Yoon-Ra Her,¹ Peter Canoll,² Jeffrey N. Bruce,³ Phyllis L. Faust,² Kailash Adhikari,⁴ Darryl C. De Vivo,¹ and Umrao R. Monani¹

Published March 5, 2026 - More info

The mammalian brain relies primarily on glucose for its energy needs. Delivery of this nutrient to the brain is mediated by the glucose transporter-1 (GLUT1) protein. Low GLUT1 thwarts glucose entry into the brain, causing an energy crisis and, triggering, in one instance, the debilitating neurodevelopmental condition – GLUT1 deﬁciency syndrome (GLUT1DS). Current treatments for GLUT1DS are sub-optimal, as none address the root cause – low GLUT1 – of the condition. Levels of this transporter must respond rapidly to the brain’s changing energy requirements. This necessitates ﬁne-tuning its expression. Here we describe a long-noncoding RNA (lncRNA) antisense to GLUT1 (SLC2A1) and show that it is involved in such regulation. Raising levels of the lncRNA had a concordant effect on GLUT1 in cultured human cells and transgenic mice; reducing levels elicited the opposite effect. Delivering the lncRNA to GLUT1DS model mice via viral vectors induced GLUT1 expression, enhancing brain glucose levels to mitigate disease. Direct delivery of such a lncRNA to combat disease has not been reported previously and constitutes, to our knowledge, a unique therapeutic paradigm. Moreover, considering the importance of maintaining homeostatic GLUT1 levels, calibrating transporter expression via the lncRNA could become broadly relevant to myriad conditions, including Alzheimer’s disease, wherein GLUT1 is perturbed.

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