DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for creatine transporter deficiency — 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 moduleCreatine transporter deficiency 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
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
approvedCreatineApproved drug
Structures already discussed alongside creatine transporter deficiency in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
creatininase-product complex — Creatine has a real, experimentally solved structure in complex with this target (PDB 1V7Z, 1.6 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet crndrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1V7Z · 1.6 Å · ligand Creatine (CRN). Experimental structure, not a prediction.
What the evidence adds up to
Creatine transporter deficiency is an X-linked disorder caused by mutations in the SLC6A8 gene, first identified in 2001. The hallmarks are X-linked mental retardation, expressive speech and language delay, epilepsy, developmental delay, and autistic behaviour. In about half of female carriers, learning disabilities of varying degrees have been noted. By 2003, at least 7 unrelated families (13 male patients and 13 carriers) had been identified, with four families from one metropolitan area, suggesting the incidence may be relatively high. A 2007 study introduced 13 SLC6A8 variants into deficient fibroblasts and proved that nine were pathogenic and four were nonpathogenic, providing an improved diagnostic tool for classifying sequence variants of unknown significance.
A 2021 case report treated a child with creatine transporter deficiency using high-dose creatine supplementation: 400 mg/kg/day for one month, then 800 mg/kg/day for two months, and finally 1200 mg/kg/day for three months. The patient tolerated treatment well and showed improvements in muscle mass and strength when the dose reached 1200 mg/kg/day. However, brain creatine concentration measured by proton magnetic resonance spectroscopy did not increase, and there was no improvement in speech or neurodevelopmental symptoms. The authors concluded that high-dose creatine supplementation alone improved muscular symptoms but did not improve cognitive symptoms or brain creatine concentration.
A 2020 study reviewed 498 urine creatine metabolite panel tests on 413 patients with neurodevelopmental disorders. Two new patients (one female, one male) were diagnosed with creatine transporter deficiency, both with markedly elevated urine creatine. The diagnostic yield was 0.67% (2/297). Among patients who underwent screening or monitoring for cerebral creatine deficiency disorders, the prevalence of creatine transporter deficiency was 2.64%. The study noted that many neurodevelopmental disorders are not caused by cerebral creatine deficiency disorders.
A 2022 study on renal tubular transport of creatinine found that OCT2 mediates the renal tubular secretion of creatinine with low affinity (Km 3.1 mM) and is a minor contributor to creatinine secretion. The OCT2 inhibitor cimetidine significantly reduced renal excretion of d3-creatinine in mice without affecting glomerular filtration rate. The study identified TYR362 and GLN242 as important sites for the OCT2-creatinine interaction. This work does not directly address creatine transporter deficiency but concerns the handling of creatinine, a related metabolite. What remains missing are treatments that can raise brain creatine levels and improve cognitive outcomes; current strategies have not achieved this, and no clinical trial has demonstrated efficacy for neurodevelopmental symptoms.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Inherited Metabolic Disease · 2003 · 173 citations
X‐linked creatine transporter defect: An overview
AbstractIn 2001 we identified a new inborn error of metabolism caused by a defect in the X-linked creatine transporter SLC6A8 gene mapped at Xq28 (SLC6A8 deficiency, McKusick 300352). An X-linked creatine transporter defect was presumed because of (1) the absence of creatine in the brain as indicated by proton magnetic resonance spectroscopy (MRS); (2) the elevated creatine levels in urine and normal guanidinoacetate levels in plasma, ruling out a creatine biosynthesis defect; (3) the absence of an improvement on creatine supplementation; and (4) the fact that the pedigree suggested an X-linked disease. Our hypothesis was proved by the presence of a hemizygous nonsense mutation in the male index patient and by the impaired creatine uptake by cultured fibroblasts. Currently, at least 7 unrelated families (13 male patients and 13 carriers) with a SLC6A8 deficiency have been identified. Four families come from one metropolitan area. This suggests that SLC6A8 deficiency may have a relatively high incidence. The hallmarks of the disorder are X-linked mental retardation, expressive speech and language delay, epilepsy, developmental delay and autistic behaviour. In approximately 50% of the female carriers, learning disabilities of varying degrees have been noted.
Functional characterization of missense variants in the creatine transporter gene (SLC6A8): improved diagnostic application
AbstractCreatine transporter deficiency is an X-linked mental retardation disorder caused by mutations in the creatine transporter gene (SLC6A8). So far, 20 mutations in the SLC6A8 gene have been described. We have developed a diagnostic assay to test creatine uptake in fibroblasts. Additionally, we expanded the assay to characterize novel SLC6A8 missense variants. A total of 13 variants were introduced in the SLC6A8 cDNA by site-directed mutagenesis. All variants were transiently transfected in SLC6A8-deficient fibroblasts and tested for restoration of creatine uptake in deficient primary fibroblasts. Thus, we proved that nine variants (p.Gly87Arg, p.Phe107del, p.Tyr317X, p.Asn336del, p.Cys337Trp, p.Ile347del, p.Pro390Leu, p.Arg391Trp, and p.Pro554Leu) are pathogenic mutations and four variants (p.Lys4Arg, p.Gly26Arg, p.Met560Val, and p.Val629Ile) are nonpathogenic. The present study provides an improved diagnostic tool to classify sequence variants of unknown significance.
European Journal of Pharmaceutical Sciences · 2022 · 14 citations · open access
Characterization of the renal tubular transport of creatinine by activity-based protein profiling and transport kinetics
AbstractSerum creatinine is widely used to adjust the dosing of drugs eliminated by the kidney in patients with renal dysfunction, as it is a readily accessible indicator of kidney function. However, there are many limitations for drug dosage adjustment based on serum creatinine levels, one of which is the limited understanding of creatinine's tubular transport. Thus, we aimed to complement and advance the renal tubular transport of creatinine by activity-based protein profiling (ABPP) and transporter-overexpression technology. Renal tubular transporters were not identified via ABPP due to the low-affinity interaction between transporters and creatinine. The uptake of isotopically labeled d3-creatinine was significantly increased in OCT2-overexpressing cell lines (p<0.01), and the Km and Vmax of d3-creatinine uptake mediated by OCT2 was 3.1 mM and 408 pmol/mg protein/min, respectively. In the OCT2-overexpressing cell lines, the IC50 of creatinine for d3-creatinine uptake was 10.3 mM, and that of the OCT2 inhibitor cimetidine for d3-creatinine uptake was 99.04 μM. Different dosages of creatinine did not affect the renal excretion of d3-creatinine in mice (p>0.05), while cimetidine significantly reduced the renal excretion of d3-creatinine (p<0.01) without affecting the glomerular filtration rate. Molecular docking in silico showed that the OCT2 amino acid GLN242 could form a hydrogen bond of 2.5 Å with creatinine, and there may be a π-π interaction between TYR362 and creatinine. A site mutation experiment demonstrated that TYR362 and GLN242 were important sites for the OCT2-creatinine interaction. These results demonstrate that OCT2 mediates the renal tubular secretion of creatinine with low affinity and is a minor contributor to creatinine secretion.
Molecular Genetics & Genomic Medicine · 2021 · 10 citations · open access
Treatment efficacy of high‐dose creatine supplementation in a child with creatine transporter (<i>SLC6A8</i>) deficiency
AbstractBACKGROUND: Creatine transporter deficiency is an inborn error of metabolism caused by a deficiency in the creatine transporter protein encoded by the SLC6A8 gene. Previous treatment with creatine supplementation, either alone or in combination with creatine precursors (arginine or glycine), has been attempted; the efficacy of therapy, however, remains controversial. METHODS AND RESULTS: To analyze the treatment efficacy of high-dose creatine supplementation on creatine transporter deficiency, we reported a child diagnosed with creatine transporter deficiency, who was treated with a conventional dose of creatine (400 mg/kg/d) for 1 month, then twice the dose (800 mg/kg/d) for 2 months, and finally 3 times the dose (1200 mg/kg/d) for 3 months. The patient tolerated the treatment well and showed improvements in muscle mass and strength when the creatine dose was gradually increased to 1200 mg/kg/d. However, when assessed by proton magnetic resonance spectroscopy (H-MRS), the brain creatine concentration did not increase, and there was no improvement in speech and neurodevelopmental symptoms. CONCLUSION: We conclude that high-dose creatine supplementation (1200 mg/kg/d) alone improved muscular symptoms, but did not improve cognitive symptoms and brain creatine concentration assessed using H-MRS. Therefore, new treatment strategies are required for the management of creatine transporter deficiency.
Urine creatine metabolite panel as a screening test in neurodevelopmental disorders
AbstractAbstract Background Cerebral creatine deficiency disorders (CCDD) are inherited metabolic disorders of creatine synthesis and transport. Urine creatine metabolite panel is helpful to identify these disorders. Methods We reviewed electronic patient charts for all patients that underwent urine creatine metabolite panel testing in the metabolic laboratory at our institution. Results There were 498 tests conducted on 413 patients. Clinical, molecular genetics and neuroimaging features were available in 318 patients. Two new patients were diagnosed with creatine transporter deficiency: one female and one male, both had markedly elevated urine creatine. Urine creatine metabolite panel was also used as a monitoring test in our metabolic laboratory. Diagnostic yield of urine creatine metabolite panel was 0.67% (2/297). There were six known patients with creatine transporter deficiency. The prevalence of creatine transporter deficiency was 2.64% in our study in patients with neurodevelopmental disorders who underwent screening or monitoring of CCDS at our institution. Conclusion Even though the diagnostic yield of urine creatine metabolite panel is low, it can successfully detect CCDD patients, despite many neurodevelopmental disorders are not a result of CCDD. To the best of our knowledge, this study is the first Canadian study to report diagnostic yield of urine creatine metabolite panel for CCDD from a single center.
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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