Therapeutic strategies for glucose transporter 1 deficiency syndrome

Tang, Maoxue; Park, Sarah H.; Vivo, Darryl C. De; Monani, Umrao R.

doi:10.1002/acn3.50881

Cited by 56 publications

(48 citation statements)

References 83 publications

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“…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 …”

Section: Discussionmentioning

confidence: 99%

“…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 …”

Section: State Of the Art In Glut1ds And Consensus Recommendationsmentioning

confidence: 99%

“…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 .…”

Section: State Of the Art In Glut1ds And Consensus Recommendationsmentioning

confidence: 99%

“…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.…”

Section: State Of the Art In Glut1ds And Consensus Recommendationsmentioning

confidence: 99%

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

et al. 2020

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Glut1 deficiency syndrome (Glut1DS) is a brain energy failure syndrome caused by impaired glucose transport across brain tissue barriers. Glucose diffusion across tissue barriers is facilitated by a family of proteins including glucose transporter type 1 (Glut1). Patients are treated effectively with ketogenic diet therapies (KDT) that provide a supplemental fuel, namely ketone bodies, for brain energy metabolism. The increasing complexity of Glut1DS, since its original description in 1991, now demands an international consensus statement regarding diagnosis and treatment. International experts (n = 23) developed a consensus statement utilizing their collective professional experience, responses to a standardized questionnaire, and serial discussions of wide‐ranging issues related to Glut1DS. Key clinical features signaling the onset of Glut1DS are eye‐head movement abnormalities, seizures, neurodevelopmental impairment, deceleration of head growth, and movement disorders. Diagnosis is confirmed by the presence of these clinical signs, hypoglycorrhachia documented by lumbar puncture, and genetic analysis showing pathogenic SLC2A1 variants. KDT represent standard choices with Glut1DS‐specific recommendations regarding duration, composition, and management. Ongoing research has identified future interventions to restore Glut1 protein content and function. Clinical manifestations are influenced by patient age, genetic complexity, and novel therapeutic interventions. All clinical phenotypes will benefit from a better understanding of Glut1DS natural history throughout the life cycle and from improved guidelines facilitating early diagnosis and prompt treatment. Often, the presenting seizures are treated initially with antiseizure drugs before the cause of the epilepsy is ascertained and appropriate KDT are initiated. Initial drug treatment fails to treat the underlying metabolic disturbance during early brain development, contributing to the long‐term disease burden. Impaired development of the brain microvasculature is one such complication of delayed Glut1DS treatment in the postnatal period. This international consensus statement should facilitate prompt diagnosis and guide best standard of care for Glut1DS throughout the life cycle.

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Section: Discussionmentioning

confidence: 99%

Section: State Of the Art In Glut1ds And Consensus Recommendationsmentioning

confidence: 99%

Section: State Of the Art In Glut1ds And Consensus Recommendationsmentioning

confidence: 99%

Section: State Of the Art In Glut1ds And Consensus Recommendationsmentioning

confidence: 99%

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

et al. 2020

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“…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).…”

Section: Reduction Of Glut1 In Retinal Neurons Reduces Polyol Accumulmentioning

confidence: 75%

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

Holoman

Aiello

Trobenter

et al. 2020

Preprint

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Hyperglycemia is a key determinant for development of diabetic retinopathy (DR). Inadequate glycemic control exacerbates retinopathy, while normalization of glucose levels delays its progression. In hyperglycemia, hexokinase is saturated and excess glucose is metabolized to sorbitol by aldose reductase via the polyol pathway. Therapies to reduce retinal polyol accumulation for the prevention of DR have been elusive due to low sorbitol dehydrogenase levels in the retina and inadequate inhibition of aldose reductase. Using systemic and conditional genetic inactivation, we targeted the primary facilitative glucose transporter in the retina, Glut1, as a preventative therapeutic in diabetic male and female mice. Unlike wildtype diabetics, diabetic Glut1+/− mice did not display elevated Glut1 levels in the retina. Furthermore, diabetic Glut1+/− mice exhibited ameliorated ERG defects, inflammation and oxidative stress, which was correlated with a significant reduction in retinal sorbitol accumulation. RPE-specific reduction of Glut1 did not prevent an increase in retinal sorbitol content or early hallmarks of DR. However, like diabetic Glut1+/− mice, reduction of Glut1 specifically in retinal neurons mitigated polyol accumulation and completely prevented retinal dysfunction and the elevation of markers for oxidative stress and inflammation associated with diabetes. These results suggest that modulation of retinal polyol accumulation via Glut1 in photoreceptors can circumvent the difficulties in regulating systemic glucose metabolism and be exploited to prevent DR.SignificanceDiabetic retinopathy (DR) affects one third of diabetic patients and is the primary cause of vision loss in adults aged 20-74. While anti-VEGF and photocoagulation treatments for the late-stage vision threatening complications can prevent vision loss, a significant proportion of patients do not respond to anti-VEGF therapies and mechanisms to stop progression of early-stage symptoms remain elusive. Glut1 is the primary facilitative glucose transporter for the retina. We determined that a moderate reduction in Glut1 levels, specifically in retinal neurons, but not the RPE, was sufficient to prevent retinal polyol accumulation and the earliest functional defects to be identified in the diabetic retina. Our study defines modulation of Glut1 in retinal neurons as a targetable molecule for prevention of DR.

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Organoselenium Compounds in Medicinal Chemistry

Gallo‐Rodriguez,

Rodriguez

2024

ChemMedChem

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The chemical and biological interest in this element and the molecules bearing selenium has been exponentially growing over the years. Selenium, formerly designated as a toxin, becomes a vital trace element for life that appears as selenocysteine and its dimeric form, selenocystine, in the active sites of selenoproteins, which catalyze a wide variety of reactions, including the detoxification of reactive oxygen species and modulation of redox activities. From the point of view of drug developments, organoselenium drugs are isosteres of sulfur‐containing and oxygen—containing drugs with the advantage that the presence of the selenium atom confers antioxidant properties and high lipophilicity, which would increase cell membrane permeation leading to better oral bioavailability. This statement is the paramount relevance considering the big number of clinically employed compounds bearing sulfur or oxygen atoms if their structures including nucleosides and carbohydrates. Thus, in this article we have focused on the relevant features of the application of selenium in medicinal chemistry. With the increasing interest in selenium chemistry, we have attempted to highlight the most significant published data on this subject, mainly concentrating the analysis on the last years. In consequence, the recent advances of relevant pharmacological organoselenium compounds are discussed.

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Therapeutic strategies for glucose transporter 1 deficiency syndrome

Cited by 56 publications

References 83 publications

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

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

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

Organoselenium Compounds in Medicinal Chemistry

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