Therapeutic strategies for glucose transporter 1 deficiency syndrome

Abstract

Proper development and function of the mammalian brain is critically dependent on a steady supply of its chief energy source, glucose. Such supply is mediated by the glucose transporter 1 (Glut1) protein. Paucity of the protein stemming from mutations in the associated SLC2A1 gene deprives the brain of glucose and triggers the infantile‐onset neurodevelopmental disorder, Glut1 deficiency syndrome (Glut1 DS). Considering the monogenic nature of Glut1 DS, the disease is relatively straightforward to model and thus study. Accordingly, Glut1 DS serves as a convenient paradigm to investigate the more general cellular and molecular consequences of brain energy failure. Here, we review how Glut1 DS models have informed the biology of a prototypical brain energy failure syndrome, how these models are facilitating the development of promising new treatments for the human disease, and how important insights might emerge from the study of Glut1 DS to illuminate the myriad conditions involving the Glut1 protein.

Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group

“…The finding of impaired cerebral angiogenesis during development in Glut1DS model mice emphasizes the importance of early diagnosis and proactive treatment to prevent irreversible brain damage. Future therapies for Glut1DS are focusing on supplemental brain metabolic fuels, SLC2A1 transfer, and small molecules designed to enhance Glut1 expression or activity 82 …”

“…Peer‐reviewed National Institutes of Health funded studies using standard clinical trial criteria also are currently underway (NCT03041363, NCT03181399, NCT03301532). Novel approaches are ongoing, targeting small molecules and other biologics to enhance Glut1 expression and function 82 . Anecdotal reports have described individual benefits of acetazolamide and L‐DOPA as treatment for paroxysmal movement disorders in Glut1DS 83–85 …”

“…Glut1 haploinsufficiency arrests brain angiogenesis during brain development, and the diminished brain capillary network further aggravates neuroglycopenia 95 . Approaches to restore Glut1 protein content and function include upregulation of the normal SLC2A1 allele using small molecule strategies or gene transfer strategies whereby a normal SLC2A1 gene is delivered in a suitable viral vector to the Glut1‐deficient patient 82 . Preclinical experiments in Glut1DS model mice using AAV9 vectors have demonstrated that gene replacement is effective and durable: Brain Glut1 expression and CSF glucose concentrations increase, brain growth and volume are maintained during development, motor performance is preserved, seizure activity is controlled, and brain angiogenesis proceeds normally 82,95,96 .…”

“…Approaches to restore Glut1 protein content and function include upregulation of the normal SLC2A1 allele using small molecule strategies or gene transfer strategies whereby a normal SLC2A1 gene is delivered in a suitable viral vector to the Glut1‐deficient patient 82 . Preclinical experiments in Glut1DS model mice using AAV9 vectors have demonstrated that gene replacement is effective and durable: Brain Glut1 expression and CSF glucose concentrations increase, brain growth and volume are maintained during development, motor performance is preserved, seizure activity is controlled, and brain angiogenesis proceeds normally 82,95,96 . In contrast to successful presymptomatic or early symptomatic treatment, gene replacement in adult mice failed to improve symptoms, suggesting a therapeutic window of opportunity.…”

Reduction of Glut1 in retinal neurons but not the RPE alleviates polyol accumulation and normalizes early characteristics of diabetic retinopathy

“…We demonstrated here by ERG and histological analysis that no changes in retinal function or morphology of the retina are found in Glut1 +/mice, a model of Slc2a1 haploinsufficiency and Glut1 deficiency syndrome (Wang et al, 2006). Although neuroinflammation and microvascular changes occur in the brain of Glut1 +/mice (Tang et al, 2017;Tang et al, 2019)), Glut1 +/retinas are normal. Likewise, inactivation of one Slc2a1 allele in the retina (Crx Glut1-CKD) or the RPE (VMD2 Glut1-CKD) also maintained normal electroretinography and histology, with lower levels of Glut1 in these cell types but no compensation by other glucose transporters (RT-qPCR; other glucose transporters are undetected in the retina by western blot or immunohistochemistry).…”