DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for GLUT1 deficiency syndrome — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleGLUT1 deficiency syndrome maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
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Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for glut1 deficiency syndrome is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
solute carrier family 2 member 1 (SLC2A1) — SLC2A1 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet bngdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6THA · 2.4 Å · ligand nonyl beta-D-glucopyranoside (BNG). Experimental structure, not a prediction.
What the evidence adds up to
GLUT1 deficiency syndrome can be inherited as an autosomal recessive trait, not only as a dominant one. In two families described in 2010, a severely affected boy inherited a mutated allele from his asymptomatic heterozygous mother and acquired a de novo mutation on the paternal allele, while two mildly affected sisters inherited mutations from their asymptomatic heterozygous consanguineous parents. Red blood cell glucose uptake residual activity, a surrogate of haploinsufficiency, correlated with clinical severity. The clinical pattern of inheritance is determined by the relative pathogenicity of the mutation and the resulting degree of haploinsufficiency.
A 2019 study of 13 patients meeting clinical and biochemical criteria for GLUT1 deficiency syndrome found that six were positive for SLC2A1 mutations, and in five of the SLC2A1-negative patients another genetic defect was identified. No significant differences were observed between the two groups for age of onset, clinical presentation, microcephaly, intellectual disability, or response to ketogenic diet. Patients with SLC2A1 mutations had significantly lower CSF glucose (34.5 mg/dL vs. 46 mg/dL, p = 0.04) and a lower CSF/serum glucose ratio (0.4 vs. 0.48, p < 0.05). The study concluded that GLUT1 deficiency syndrome may be caused by mutations to genes other than SLC2A1 in patients with compatible phenotype, low CSF glucose, and good response to the ketogenic diet.
A 2015 case report described a nine-year-old boy with refractory epilepsy due to GLUT1 deficiency. By the 10th day from the beginning of the ketogenic diet, complete relief of epileptic seizures and EEG abnormalities was achieved. After three months, positive signs in cognitive and speech development were noted. Antiepileptic drugs were withdrawn due to stable remission. The patient continued the diet for one year and three months, and the improvement was maintained. The report called the ketogenic diet a highly effective and perhaps exclusive method for GLUT1 treatment.
A 2006 study proposed using aminoglycosides to pharmacologically decrease translational fidelity in patient cellular cultures haploinsufficient for Glut1, based on the known ability of certain aminoglycosides to read through premature termination codons. No clinical results in patients were reported. What is still missing is a randomised controlled trial of any drug therapy for GLUT1 deficiency syndrome, systematic patient stratification by genetic subtype, and funding for such trials.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Annals of Neurology · 2010 · 96 citations · open access
Glut1 deficiency: Inheritance pattern determined by haploinsufficiency
AbstractTwo families manifesting Glut1 deficiency syndrome (DS) as an autosomal recessive trait are described. In 1 family, a severely affected boy inherited a mutated allele from his asymptomatic heterozygous mother. A de novo mutation developed in the paternal allele, producing compound heterozygosity. In another family, 2 mildly affected sisters inherited mutations from their asymptomatic heterozygous consanguineous parents. Red blood cell glucose uptake residual activity, a surrogate of haploinsufficiency, correlated with the clinical severity. These cases demonstrate that Glut1 DS may present as an autosomal recessive trait. The clinical pattern of inheritance is determined by the relative pathogenicity of the mutation and the resulting degree of haploinsufficiency.
Journal of Pathology and Translational Medicine · 2017 · 23 citations · open access
GLUT1 as a Prognostic Factor for Classical Hodgkin’s Lymphoma: Correlation with PD-L1 and PD-L2 Expression
AbstractBACKGROUND: Glucose transporter type 1 (GLUT1) expression is linked to glucose metabolism and tissue hypoxia. A recent study reported that GLUT1 was significantly associated with programmed death ligand 1 (PD-L1) as a therapeutic target in relapsed or refractory classical Hodgkin's lymphoma (cHL). The purpose of this study was to measure the expression of GLUT1 and assess its prognostic significance and potential relationships with PD-L1, programmed death ligand 2 (PD-L2), and programmed death-1 (PD-1) expressions in cHL. METHODS: Diagnostic tissues from 125 patients with cHL treated with doxorubicin, bleomycin, vinblastine, and dacarbazine were evaluated retrospectively via immunohistochemical analysis of GLUT1, PD-L1, PD-L2, and PD-1 expression. RESULTS: The median follow-up time was 4.83 years (range, 0.08 to 17.33 years). GLUT1, PD-L1, PD-L2, and PD-1 were expressed in 44.8%, 63.2%, 9.6%, and 13.6% of the specimens, respectively. Positive correlations were found between GLUT1 and PD-L1 expression (p = .004) and between GLUT1 and PD-L2 expression (p = .031). GLUT1 expression in Hodgkin/Reed-Sternberg (HRS) cells was not associated with overall survival or event-free survival (EFS) in the entire cohort (p = .299 and p = .143, respectively). A subgroup analysis according to the Ann Arbor stage illustrated that GLUT1 expression in HRS cells was associated with better EFS in advanced-stage disease (p = .029). A multivariate analysis identified GLUT1 as a marginally significant prognostic factor for EFS (p = .068). CONCLUSIONS: This study suggests that GLUT1 expression is associated with better clinical outcomes in advanced-stage cHL and is significantly associated with PD-L1 and PD-L2 expressions.
Prospective Multicenter Validation of a Simple Blood Test for the Diagnosis of Glut1 Deficiency Syndrome
AbstractObjective GLUT1 deficiency syndrome (Glut1DS) is a treatable neurometabolic disease that causes a wide range of neurological symptoms in children and adults. However, its diagnosis relies on an invasive test, i.e., a lumbar puncture (LP) to measure glycorrhachia, and, sometimes complex, molecular analyses of the <i>SLC2A1</i> gene. This procedure limits the number of patients able to receive the standard of care. We wished to validate the diagnostic performance of METAglut1™, a simple blood test that quantifies GLUT1 at the erythrocyte surface. Methods We performed a multicenter validation study in France, involving 33 centers. We studied two patient cohorts: a prospective cohort, consisting of patients with a clinical suspicion of Glut1DS explored through the reference strategy, i.e., LP and analyses of the <i>SLC2A1</i> gene; a retrospective cohort that included patients previously diagnosed with Glut1DS. All patients were blind-tested with METAglut1™. Results We analyzed 428 patients in the prospective cohort, including 15 patients newly diagnosed with Glut1DS, and 67 patients in the retrospective cohort. METAglut1™ was 80% sensitive and >99% specific for the diagnosis of Glut1DS. Concordance analyses showed a substantial agreement between METAglut1™ and glycorrhachia. In the prospective cohort, the positive predictive value of METAglut1™ was slightly higher than that of glycorrhachia. METAglut1™ succeeded to identify patients with Glut1DS with <i>SCL2A1</i> mosaicism and variants of unknown significance. Interpretation METAglut1™ is an easily performed, robust and non-invasive diagnostic test for the diagnosis of Glut1DS, which allows a wide screening of children and adults, including those with atypical forms of this treatable condition. Classification of Evidence This study provides class I evidence that a positive METAglut1™ test accurately distinguishes patients with suspected GLUT1 deficiency syndrome from other neurological syndromes as compared to invasive and genetic testing.
Saudi Journal of Gastroenterology · 2017 · 8 citations · open access
Validity and clinical impact of glucose transporter 1 expression in colorectal cancer
AbstractBACKGROUND/AIM: There is no doubt that colorectal cancer (CRC) poses a major threat to public health worldwide, and despite improvement in managements, prognosis still remains an irritating question with no definite answer. Being a fundamental player in cancer metabolism, glucose transporter 1 (GLUT1) could be utilized as a prognostic biomarker that could fuel development of new treatment strategies. The aim of this study was to assess the validity of GLUT1 expression as a prognostic biomarker and to elucidate to what extent it is immersed in poor clinical outcome among CRC patients. PATIENTS AND METHODS: GLUT1 expression in peripheral blood specimens was analyzed by quantitative real-time polymerase chain reaction in 47 CRC patients and 20 healthy controls. RESULTS: There was significantly elevated GLUT1 expression in peripheral blood of CRC patients than in controls (P < 0.001). The cutoff value of 0.605 provided 98% sensitivity and 100% specificity. There were significantly higher values of GLUT1 expression in patients under 50 years (P = 0.003), performance status 2 (P = 0.009), stage IV (P < 0.001), and presence of metastasis (P < 0.001). GLUT1 expression showed nonsignificant association with overall survival (P = 0.068), while tumor stage (P = 0.01) and metastasis (P = 0.009) were significantly associated with lower overall survival. CONCLUSION: GLUT1 is sensitive and specific marker for CRC. It is overexpressed in young age patients, poor performance status, and stage IV patients. Although this was not statistically significant, GLUT 1 showed higher expression level in patients with lesser survival.
Estudio de pacientes pediátricos con fenotipo clínico y bioquímico de síndrome de déficit de transportador de glucosa cerebral (GLUT-1)
AbstractEl síndrome de déficit del transportador de glucosa cerebral (GLUT1DS) puede presentar fenotipos variados, incluyendo epilepsia, déficit intelectual y trastorno del movimiento. La mayoría presenta hipoglucorraquia y/o defectos en el gen SLC2A1, aunque existen pacientes sin hipoglucorraquia y otros con genética de SLC2A1-negativa, o con defectos en otros genes y fenotipo compatible. Describir las características clínicas, bioquímicas y genéticas y realizar un análisis univariante de un grupo de pacientes con fenotipo clínico y bioquímico de GLUT1DS, con o sin genética SLC2A1-positiva. Se incluyeron 13 pacientes con criterios clínico-bioquímicos de GLUT1DS. Se realizó secuenciación de SLC2A1 y MLPA. En los casos negativos se realizó exoma clínico. Seis presentaron fenotipo clásico, 2 discinesia paroxística, 2 trastornos del movimiento complejo, 2 ausencias precoces y otro presentó epilepsia con ausencias infantiles refractaria a farmacoterapia. Seis fueron SLC2A1-positivos. Y en 5 de los SLC2A1-negativos se identificó otro defecto genético. No hubo diferencias significativas entre los dos grupos en edad de inicio, presentación clínica, microcefalia, discapacidad intelectual ni respuesta a dieta cetogénica. De forma no significativa, los pacientes SCL2A1-positivos presentaron más cambios clínicos en relación con la ingesta (66,7% vs. 28,6%) y mayor persistencia de síntomas motores (66% vs. 28,6%). De forma significativa, presentaron menor glucorraquia (34,5 mg/dl vs. 46 mg/dl, p = 0,04) e índice glucorraquia/glucemia más bajo (0,4 vs. 0,48, p = 0,05) que los SLC2A1-negativos. GLUT1DS puede ser causado por defectos genéticos en otros genes diferentes de SLC2A1 en pacientes con fenotipo compatible, hipoglucorraquia y buena respuesta a dieta cetogénica. Glucose transporter type 1 (GLUT1) deficiency syndrome may present a range of phenotypes, including epilepsy, intellectual disability, and movement disorders. The majority of patients present low CSF glucose levels and/or defects in the SLC2A1 gene; however, some patients do not present low CSF glucose or SLC2A1 mutations, and may have other mutations in other genes with compatible phenotypes. We describe the clinical, biochemical, and genetic characteristics of the disease and perform a univariate analysis of a group of patients with clinical and biochemical phenotype of GLUT1 deficiency syndrome, with or without SLC2A1 mutations. The study included 13 patients meeting clinical and biochemical criteria for GLUT1 deficiency syndrome. SLC2A1 sequencing and multiplex ligation-dependent probe amplification were performed; exome sequencing was performed for patients with negative results. Six patients presented the classic phenotype; 2 paroxysmal dyskinesia, 2 complex movement disorders, 2 early-onset absence seizures, and one presented drug-resistant childhood absence epilepsy. Six patients were positive for SLC2A1 mutations; in the other 5, another genetic defect was identified. No significant differences were observed between the 2 groups for age of onset, clinical presentation, microcephaly, intellectual disability, or response to ketogenic diet. Patients with SLC2A1 mutations presented more clinical changes in relation to diet (66.7% vs. 28.6% in the SLC2A1-negative group) and greater persistence of motor symptoms (66% vs. 28.6%); these differences were not statistically significant. Significant differences were observed for CSF glucose level (34.5 vs. 46 mg/dL, P = .04) and CSF/serum glucose ratio (0.4 vs. 0.48, P < .05). GLUT1 deficiency syndrome may be caused by mutations to genes other than SLC2A1 in patients with compatible phenotype, low CSF glucose level, and good response to the ketogenic diet.
S S Korsakov Journal of Neurology and Psychiatry · 2015 · 3 citations
Experience of using ketogenic diet in a patient with glucose transporter 1 deficiency syndrome (a case report)
AbstractUNLABELLED: We present the experience of using the ketogenic diet (KD) in the treatment of pharmacoresistant epilepsy in a patient with glucose transporter deficiency syndrome type I (GLUT1). We observed a nine-year-old boy with refractory epilepsy with frequent multiple myoclonic seizures due to GLUT1. The high effectiveness of KD in the treatment of GLUT1 was demonstrated. By the 10th day from the beginning of KD, a complete relief of epileptic seizures and EEG abnormalities was achieved. After 3 months, we noticed positive signs in cognitive and speech development of the child. Antiepileptic drugs were withdrawn due to the stable remission. Subsequently there was a further positive dynamics in intelligence, psycho-emotional sphere; the child began attending a special school. By this time the patient continued the diet for 1 year and 3 months. A significant improvement in the patient's condition is maintained, observation is being continued. IN CONCLUSION: the ketogenic diet seems to be a highly effective and, perhaps, exclusive method for GLUT1 treatment.
AMINOGLYCOSIDE ENHANCEMENT OF GLUCOSE TRANSPORT IN GLUT1 DEFICIENCY SYNDROME
AbstractObjectives: To ameliorate GLUT1 deficiency by pharmacologically decreasing translational fidelity in a series of patient cellular cultures haploinsufficient for Glut1. It has been known for over 20 years that premature termination codons can be 'read through' in the presence of certain aminoglycosides, and certain derivatives are now being proposed for use in selected human diseases.
GLUT1-DS in a Girl with Transitory Abnormal Eye Movements and Seizures Responding to Carbamazepine
AbstractIntroduction: Diagnosing GLUT1 deficiency syndrome (GLUT1-DS) is sometimes challenging because of its broad clinical spectrum. The diagnosis may be delayed when the first manifestations are considered as less typical for the disease. It is usually assumed, for instance, that seizures will be resistant to conventional antiepileptic drugs. Other clinical manifestations, such as early-onset abnormal eye movements, are probably under-recognized as a suggestive feature.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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