Gene therapy for <i>Glut1</i>‐deficient mouse using an adeno‐associated virus vector with the human intrinsic GLUT1 promoter

Nakamura, Shigeo; Muramatsu, Satoru; Takino, Naomi; Ito, Mika; Jimbo, Eriko F.; Shimazaki, Kuniko; Onaka, Tatsushi; Ohtsuki, Sumio; Yamagata, Takanori; Osaka, Hitoshi

doi:10.1002/jgm.3013

Cited by 21 publications

(11 citation statements)

References 32 publications

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“…GLUT1 is largely expressed in red blood cells and endothelial cells, including brain microvessels [48,49]. No alterations in GLUT1 immunoreactivity is found in CJD microvessels; reduction of GLUT1 mRNA correlates with decreased GLUT1 immunoreactivity in the neuropil in CJD.…”

Section: Discussionmentioning

confidence: 96%

Altered gene transcription linked to astrocytes and oligodendrocytes in frontal cortex in Creutzfeldt-Jakob disease

Benito

Gonzalez

Ferrer

2018

Prion

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Targeted expression of genes coding for proteins specific to astrocytes, oligodendrocytes and myelin was performed in frontal cortex area 8 of Creutzfeldt-Jakob disease methionine/methionine and valine/valine (CJD MM1 and VV2, respectively) compared with controls. GFAP (glial fibrillary acidic protein) mRNA was up-regulated whereas SLC1A2 (solute carrier family 1 member 2, coding for glutamate transporter 1: GLT1), AQ4 (aquaporin 4), MPC1 (mitochondrial pyruvate carrier 1) and UCP5 (mitochondrial uncoupled protein 5) mRNAs were significantly down-regulated in CJD MM1 and CJD VV2, and GJA1 (connexin 43) in CJD VV2. OLIG1 and OLIG2 (oligodendocyte transcription factor 1 and 2, respectively), SOX10 (SRY-Box10) and oligodendroglial precursor cell (OPC) marker NG2 (neuronal/glial antigen) 2 were preserved, but GALC (coding for galactosylceramidase), SLC2A1 (solute carrier family 2 member 1: glucose transporter member 1: GLUT1) and MCT1 (monocarboxylic acid transporter 1) mRNA expression levels were significantly reduced in CJD MM1 and CJD VV2. Expression levels of most genes linked to myelin were not altered in the cerebral cortex in CJD. Immunohistochemistry to selected proteins disclosed individual variations but GFAP, Olig-2, AQ4 and GLUT1 correlated with mRNA levels, whereas GLT1 was subjected to individual variations. However, MPC1, UCP5 and MCT1 decrease was more closely related to the respective reduced neuronal immunostaining. These observations support the idea that molecular deficits linked to energy metabolism and solute transport in astrocytes and oligodendrocytes, in addition to neurons, are relevant in the pathogenesis of cortical lesions in CJD.

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Section: Discussionmentioning

confidence: 96%

Altered gene transcription linked to astrocytes and oligodendrocytes in frontal cortex in Creutzfeldt-Jakob disease

Benito

Gonzalez

Ferrer

2018

Prion

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“…This study also delineates the temporal requirements for the Glut1 protein, critical to implementing future treatments for Glut1 DS and ensuring optimal therapeutic outcomes. Such information is especially pertinent considering the results of pre-clinical studies that raise the prospect of gene replacement as a means of treating the human condition (12,36). Consistent with the pediatric nature of Glut1 DS and reminiscent of the outcome of similar studies (37, 38) on another infantile-onset disease, spinal muscular atrophy, the earlier we effected Glut1 haploinsufficiency in our conditional mutants, the more closely we were able to mimic disease in constitutively haploinsufficient mutants and in human patients.…”

Section: Discussionmentioning

confidence: 99%

An early endothelial cell–specific requirement for Glut1 is revealed in Glut1 deficiency syndrome model mice

Tang¹,

Park²,

Petri³

et al. 2021

JCI Insight

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Paucity of the glucose transporter-1 (Glut1) protein resulting from haploinsufficiency of the SLC2A1 gene arrests cerebral angiogenesis and disrupts brain function to cause Glut1 deficiency syndrome (Glut1 DS). Restoring Glut1 to Glut1 DS model mice prevents disease, but the precise cellular sites of action of the transporter, its temporal requirements, and the mechanisms linking scarcity of the protein to brain cell dysfunction remain poorly understood. Here, we show that Glut1 functions in a cell-autonomous manner in the cerebral microvasculature to affect endothelial tip cells and, thus, brain angiogenesis. Moreover, brain endothelial cell–specific Glut1 depletion not only triggers a severe neuroinflammatory response in the Glut1 DS brain, but also reduces levels of brain-derived neurotrophic factor (BDNF) and causes overt disease. Reduced BDNF correlated with fewer neurons in the Glut1 DS brain. Controlled depletion of the protein demonstrated that brain pathology and disease severity was greatest when Glut1 scarcity was induced neonatally, during brain angiogenesis. Reducing Glut1 at later stages had mild or little effect. Our results suggest that targeting brain endothelial cells during early development is important to ensure proper brain angiogenesis, prevent neuroinflammation, maintain BDNF levels, and preserve neuron numbers. This requirement will be essential for any disease-modifying therapeutic strategy for Glut1 DS.

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“…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%

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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Gene therapy for Glut1‐deficient mouse using an adeno‐associated virus vector with the human intrinsic GLUT1 promoter

Abstract: Exogenous GLUT1 expression after AAV-GLUT1 injection approximated that of physiological human GLUT1 expression. Local central nervous system administration of AAV-GLUT1 improved CSF glucose levels and motor function of GLUT1-deficient mice and minimized off-target effects.

Cited by 21 publications

References 32 publications

Altered gene transcription linked to astrocytes and oligodendrocytes in frontal cortex in Creutzfeldt-Jakob disease

Altered gene transcription linked to astrocytes and oligodendrocytes in frontal cortex in Creutzfeldt-Jakob disease

An early endothelial cell–specific requirement for Glut1 is revealed in Glut1 deficiency syndrome model mice

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

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