RARE DISEASE
X-linked creatine transporter deficiency
X-linked creatine transporter deficiency
X-linked creatine transporter deficiency
Synonyms: Creatine transporter deficiency, SLC6A8 deficiency
Synonyms: Creatine transporter deficiency, SLC6A8 deficiency
Synonyms: Creatine transporter deficiency, SLC6A8 deficiency
Drug discovery
3
drugs
With orphan designations
Overview
X-linked creatine transporter deficiency (CTD), caused by SLC6A8 mutations, is a cerebral creatine deficiency syndrome characterized by intellectual disability, expressive speech delay, autism spectrum behaviors, seizures, and hypotonia. Diagnosis relies on elevated urinary creatine/creatinine ratios, reduced brain creatine on magnetic resonance spectroscopy, and genetic confirmation [1][5][10].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
90 drug discovery papers about X-linked creatine transporter deficiency, with 1 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
90 drug discovery papers about X-linked creatine transporter deficiency, with 1 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-05-19 | Identification of blood biomarkers associated with brain dysfunction in creatine transporter deficiency
Creatine transporter deficiency (CTD) is a rare X-linked disorder resulting from pathogenic variants in the SLC6A8 gene. These variants cause cognitive disability through by disrupting energy metabolism as well as other mechanism within the central nervous system. In order to identify potential plasmatic biomarkers in relation with the CNS phenotype of male CTD patients, a shotgun proteomic analysis of plasma samples from male CTD patients with confirmed SLC6A8 pathogenic variants was performed with a high-resolution tandem mass spectrometer. Proteins from the samples were proteolyzed in technical duplicate. The resulting peptides were characterized by tandem mass spectrometry with an Exploris 480 instrument (Thermo). Files .raw.quant were obtained with DIA-NN. The dataset comprises the list of 24 raw files (12 samples analyzed in technical duplicates), the 24 raw quant files, and the DIA-NN outputs (list of protein groups and their abundances, list of precursors and their intensities). This dataset is associated with the scientific manuscript entitled "Proteomic analysis reveals blood biomarkers associated with brain dysfunction in creatine transporter deficiency" authored by Clémence Disdier, Rania Harati, Aurore Curie, Anne-Cécile Guyot, Jean Armengaud, Nathalie Dufay, David Cheillan, Farha Gheurbi, Marion Buchy, Rifat Hamoudi, and Aloise Mabondzo, submitted to publication.
2026-04-01 | Creatine Transporter Deficiency
Abstract XLID caused by cerebral creatine deficiency with decreased muscle mass, hypotonia, expressive language impairment, seizures, and aberrant behavior. Mutations in the solute transporter SLC6A8 are the cause and may represent one of the most common causes of XLID (1–3%).
2024-02-29 | Breaking the rules of SLC6 transporters: Export of the human creatine transporter-1 from the endoplasmic reticulum is supported by its N-terminus.
Mutations in the human creatine transporter 1 (CRT1/SLC6A8) cause the creatine transporter deficiency syndrome, which is characterized by intellectual disability, epilepsy, autism, and developmental delay. The vast majority of mutations cause protein misfolding and hence reduce cell surface expression. Hence, it is important to understand the molecular machinery supporting folding and export of CRT1 from the endoplasmic reticulum (ER). All other SLC6 members thus far investigated rely on a C-terminal motif for binding the COPII-component SEC24 to drive their ER export; their N-termini are dispensable. Here, we show that, in contrast, in CRT1 the C-terminal ER-export motif is cryptic and it is the N-terminus, which supports ER export. This conclusion is based on the following observations: (i) siRNA-induced depletion of individual SEC24 isoforms revealed that CRT1 relied on SEC24C for ER export. However, mutations of the C-terminal canonical ER-export motif of CRT1 did not impair its cell surface delivery. (ii) Nevertheless, the C-terminal motif of CRT1 was operational in a chimeric protein comprising the serotonin transporter (SERT/SLC6A4) and the C-terminus of CRT1. (iii) Tagging of the N-terminus-but not the C-terminus-with yellow fluorescent protein (YFP) resulted in ER retention. (iv) Serial truncations of the N-terminus showed that removal of ≥51 residues of CRT1 impaired surface delivery, because the truncated CRT1 were confined to the ER. (v) Mutation of P51 to alanine also reduced cell surface delivery of CRT1 and relieved its dependence on SEC24C. Thus, the ER-export motif in the N-terminus of CRT1 overrides the canonical C-terminal motif.
2024-01-04 | Probing binding and occlusion of substrate in the human creatine transporter-1 by computation and mutagenesis.
In chordates, energy buffering is achieved in part through phosphocreatine, which requires cellular uptake of creatine by the membrane-embedded creatine transporter (CRT1/SLC6A8). Mutations in human slc6a8 lead to creatine transporter deficiency syndrome, for which there is only limited treatment. Here, we used a combined homology modeling, molecular dynamics, and experimental approach to generate a structural model of CRT1. Our observations support the following conclusions: contrary to previous proposals, C144, a key residue in the substrate binding site, is not present in a charged state. Similarly, the side chain D458 must be present in a protonated form to maintain the structural integrity of CRT1. Finally, we identified that the interaction chain Y148-creatine-Na+ is essential to the process of occlusion, which occurs via a "hold-and-pull" mechanism. The model should be useful to study the impact of disease-associated point mutations on the folding of CRT1 and identify approaches which correct folding-deficient mutants.
2021-12-23 | Improving Brain Creatine Uptake by Klotho Protein Stimulation: Can Diet Hit the Big Time?
OPINION article Front. Nutr., 23 December 2021Sec. Nutrition, Psychology and Brain Health https://doi.org/10.3389/fnut.2021.795599
small molecules
2026-02-20 | Genetic Determinants of Creatine Bioavailability and Responsiveness: Emphasis on Common Low-Impact Variants
Background: Creatine is a central regulator of cellular energy homeostasis and one of the most extensively studied dietary supplements in human nutrition. Although creatine supplementation consistently increases tissue creatine availability and supports performance and health across diverse populations, substantial interindividual variability in responsiveness persists. Approximately one-quarter of individuals demonstrate minimal increases in tissue creatine or functional benefit following supplementation. While non-genetic factors such as baseline creatine status, diet, age, sex, and training load contribute to this heterogeneity, the role of common genetic variation remains insufficiently explored. Importantly, creatine bioavailability and functional responsiveness are related but distinct outcomes, and both may be modified by genetic background. Objective: This paper aims to reframe creatine responsiveness as a quantitative, polygenic trait shaped by common low-impact genetic variants rather than a binary responder-non-responder phenomenon driven by rare pathogenic mutations. The review synthesizes evidence on genetic variation affecting creatine transport, endogenous synthesis, and downstream energy metabolism, with an emphasis on population-relevant mechanisms. Methods: A narrative, mechanism-oriented review was conducted integrating data from human genetics databases, biochemical pathways, and physiological studies. The analysis focused on (i) common low-impact variants in genes directly regulating creatine transport (SLC6A8) and biosynthesis (GATM, GAMT), and (ii) modifier genes involved in mitochondrial function, phosphagen buffering, and muscle or neural energetic phenotype. Variant classification frameworks from expert curation initiatives were used to distinguish pathogenic from low-impact population variants. Results: Low-impact variants in the creatine transporter gene SLC6A8 are highly prevalent and likely contribute to a continuum of creatine transport efficiency, with sex-dependent effects due to X-linked inheritance. Similarly, common polymorphisms in creatine biosynthetic enzymes (GATM and GAMT) may subtly alter synthetic efficiency or methyl-group demand, increasing dietary creatine dependence while not causing overt deficiency. Beyond creatine-specific pathways, genetic variation in mitochondrial regulators, electron transport chain components, creatine kinase isoforms, and muscle fiber-type determinants can act as effect modifiers, amplifying or dampening the functional benefits of creatine despite comparable tissue uptake. Collectively, small additive effects across transport, synthesis, and utilization pathways may prevent supplementation from exceeding the threshold required for measurable benefit in certain individuals. Conclusions: Creatine non-responsiveness in the general population is more plausibly explained by the cumulative influence of common low-impact genetic variants than by rare monogenic defects. Viewing creatine responsiveness as a graded, polygenic trait provides a coherent framework to interpret heterogeneous findings in supplementation trials. Incorporating genetic context into study design, through stratified analyses or pathway-based approaches, may improve sensitivity to detect true effects and support the development of precision-guided creatine supplementation strategies in both clinical and public health settings.
2026-01-28 | New Insights into Drug Development via the Nose-to-Brain Pathway: Exemplification Through Dodecyl Creatine Ester for Neuronal Disorders.
Brain disorders remain a major global health challenge, highlighting the urgent need for innovative therapeutic strategies and efficient drug-delivery approaches. Among alternative routes, intranasal administration has garnered significant interest over recent decades, not only for its systemic delivery but also for its unique ability to bypass the bloodstream and the blood-brain barrier via the Nose-to-Brain (NtB) pathway. While numerous reviews have explored the opportunities and challenges of this route, industrial considerations-critical for successful clinical implementation and commercial development-remain insufficiently addressed. This review provides a comprehensive and critical assessment of the NtB pathway from a drug development and chemistry, manufacturing, and controls perspective, addressing key constraints in pre-clinical-clinical extrapolation, formulation design, device selection, dose feasibility, chronic safety, and regulatory requirements. We also discuss recent advances in neuronal targeting mechanisms, also with a focus on the role of trigeminal nerves. Dodecyl creatine ester (DCE), a highly unstable in plasma creatine prodrug developed by Ceres Brain Therapeutics, is presented as an illustrative case study. Delivered as a nasal spray, DCE enables direct neuronal delivery, exemplifying the potential of the NtB pathway for disorders characterized by neuronal energy deficiency, including creatine transporter deficiency and mitochondrial dysfunction. Overall, the NtB pathway-or, more precisely, the "Nose-to-Neurons" pathway-offers distinct advantages for unstable molecules and metabolic supplementation, particularly in neuron-centric diseases. Its successful implementation will depend on rational molecule design, optimized nasal formulations, appropriate devices, and early integration of industrial constraints to ensure feasibility, scalability, and safety for long-term treatment.
2025-09-02 | Structural insights into the substrate uptake and inhibition of the human creatine transporter (hCRT).
Creatine plays a vital role in cellular energy production and adenosine triphosphate (ATP) homeostasis and has also been identified as a neurotransmitter in the mammalian brain. Creatine is transported into cells by the human creatine transporter (hCRT) (SLC6A8), an Na+/Cl--dependent symporter encoded on the X chromosome. Mutations in hCRT cause cerebral creatine deficiency syndrome 1, a neurological disorder marked by intellectual disability, speech delay, and seizures. Beyond its role in the brain and muscle, hCRT is highly expressed in metabolically active tumors. Many cancer cells, including colorectal cancer and glioblastoma, upregulate hCRT to sustain intracellular creatine levels and buffer ATP under energy stress. Pharmacological blockade of hCRT by RGX202 has been shown to impair tumor growth by disrupting energy homeostasis. Here, we report the high-resolution cryo-Electron Microscopy (cryo-EM) structures of human hCRT in three states: apo, creatine-bound, and RGX202-bound. hCRT adopts a canonical LeuT-fold with 12 transmembrane helices and two pseudosymmetric inverted repeats. Creatine is coordinated in the central substrate-binding site through interactions with transmembrane helices TM1, TM3, TM6, and TM8, while the inhibitor RGX202 occupies the same binding pocket, engaging in overlapping contacts that competitively block creatine access. Our structural and mechanistic findings clarify substrate recognition and inhibitory binding of hCRT, providing a molecular rationale for targeting hCRT in both inherited metabolic diseases and cancer therapy.
2025-06-05 | Ineffectiveness of creatine, glycine, and arginine supplementation in a female with creatine transporter deficiency: A case report
Background Creatine transporter deficiency (CTD), caused by pathogenic variants of the SLC6A8 gene, is a significant cause of X-linked neurodevelopmental disorders. Heterozygous female patients with CTD exhibit residual creatine transporter activity. Therefore, supplementation therapy with creatine, arginine, and glycine is hypothesized to elevate cerebral creatine levels and improve clinical symptoms. Case presentation We describe the case of a 12-year-old Japanese girl diagnosed with CTD using genetic analysis and magnetic resonance spectroscopy (MRS). The patient presented with intellectual disabilities, behavioral disturbances, and drug-resistant epilepsy. Supplementation therapy with creatine (400 mg/kg/day), glycine (200 mg/kg/day), and arginine (200 mg/kg/day) led to an increase in cerebral creatine levels as measured by MRS; however, no clinical improvement was observed in her seizures and behavioral symptoms. Discussion Previously reported cases revealed variability in responses to supplementation therapy among female patients with CTD. Although the factors underlying the differences in therapeutic efficacy remain unclear, higher doses of arginine may be correlated with improved outcomes. Standardized quantitative evaluations using MRS could facilitate more accurate predictions of the efficacy of supplementation therapy. Conclusion This case highlights the complexities involved in managing female patients with CTD and underscores the need for standardized treatment and evaluation protocols. International collaboration is crucial for developing optimized therapeutic strategies for this rare condition.
2025-05-05 | Transport and inhibition mechanisms of human creatine transporter
Creatine, a guanidine-based molecule, acts as a rapid phosphate energy buffer in its phosphorylated form by donating a phosphate group to ADP, thereby regenerating ATP 1 . This process is crucial for maintaining ATP levels and energy metabolism in tissues with high and variable energy requirements, such as the brain and muscles 2 . Additionally, creatine functions as a compatible osmolyte in the brain and a neuromodulator or neurotransmitter by interacting with N -methyl- d -aspartate receptors and GABA A receptors 3 , 4 , 5 . Creatine is obtained by the diet or synthesized by endogenous enzymes, and specifically transported into the cell using the creatine transporter (CRT) 6 , a sodium- and chloride-dependent transporter, belonging to the solute carrier 6 (SLC6) family. Impaired function of CRT leads to intracellular creatine deficiency 7 , resulting in X-linked creatine transporter deficiency (CTD), a disorder characterized by intellectual disability, speech and language delay, behavioral abnormalities, and seizures. Over 80 CRT pathogenic variants have been identified, but no effective treatment is currently available for this condition. Determining the atomic structure of CRT would greatly aid in developing therapeutic strategies targeting these pathogenic variants.
gene therapies
2025-05-09 | Gene delivery of AGAT and GAMT boosts creatine levels in creatine transporter deficiency patient fibroblasts.
Creatine is a critical metabolite used to buffer cellular energy demands in highly energetic tissues such as the brain and muscle. Genetic defects in endogenous creatine synthesis or transport across cellular membranes lead to a common set of phenotypes referred to as Cerebral Creatine Deficiency Syndrome (CCDS). The most common form of CCDS is Creatine Transporter 1 (CT1) Deficiency (CTD). It accounts for ~ 70% of cases and results from loss-of-function mutations in the X-linked gene SLC6A8. Affected individuals suffer from intellectual disability, autistic-like behaviors, and epilepsy. There are currently no effective therapies for this disorder, but gene therapy has emerged as a potential approach. The two enzymes which comprise the endogenous creatine synthetic pathway (AGAT and GAMT) are selectively expressed by specific cell types throughout the body. However, after synthesized, creatine uptake relies on the protein product of SLC6A8, CT1, to transport creatine into target cell types. We hypothesized that gene delivery of GATM (encoding AGAT) and GAMT into end-user cell types would bypass the need for CT1, allowing for intracellular synthesis of creatine. We tested this strategy in two human cell types: HEK293T cells and primary fibroblasts. Co-delivery of GATM and GAMT increased internal creatine concentrations by 7.6-fold in HEK293T cells and 12.3-fold in healthy control fibroblasts. We then employed this approach to primary fibroblasts from patients with CTD. This resulted in an up to 11.6-fold increase in intracellular creatine concentrations, far exceeding the intracellular concentration of creatine in healthy control fibroblasts. Importantly, overexpression of AGAT and GAMT resulted in proper targeting of these enzymes to their natural cellular compartment and did not impair the growth of patient fibroblasts. These findings establish gene therapy with GATM and GAMT as a potential strategy for patients with CTD.
proteins
2026-05-19 | Identification of blood biomarkers associated with brain dysfunction in creatine transporter deficiency
Creatine transporter deficiency (CTD) is a rare X-linked disorder resulting from pathogenic variants in the SLC6A8 gene. These variants cause cognitive disability through by disrupting energy metabolism as well as other mechanism within the central nervous system. In order to identify potential plasmatic biomarkers in relation with the CNS phenotype of male CTD patients, a shotgun proteomic analysis of plasma samples from male CTD patients with confirmed SLC6A8 pathogenic variants was performed with a high-resolution tandem mass spectrometer. Proteins from the samples were proteolyzed in technical duplicate. The resulting peptides were characterized by tandem mass spectrometry with an Exploris 480 instrument (Thermo). Files .raw.quant were obtained with DIA-NN. The dataset comprises the list of 24 raw files (12 samples analyzed in technical duplicates), the 24 raw quant files, and the DIA-NN outputs (list of protein groups and their abundances, list of precursors and their intensities). This dataset is associated with the scientific manuscript entitled "Proteomic analysis reveals blood biomarkers associated with brain dysfunction in creatine transporter deficiency" authored by Clémence Disdier, Rania Harati, Aurore Curie, Anne-Cécile Guyot, Jean Armengaud, Nathalie Dufay, David Cheillan, Farha Gheurbi, Marion Buchy, Rifat Hamoudi, and Aloise Mabondzo, submitted to publication.
2026-04-01 | Creatine Transporter Deficiency
Abstract XLID caused by cerebral creatine deficiency with decreased muscle mass, hypotonia, expressive language impairment, seizures, and aberrant behavior. Mutations in the solute transporter SLC6A8 are the cause and may represent one of the most common causes of XLID (1–3%).
2024-02-29 | Breaking the rules of SLC6 transporters: Export of the human creatine transporter-1 from the endoplasmic reticulum is supported by its N-terminus.
Mutations in the human creatine transporter 1 (CRT1/SLC6A8) cause the creatine transporter deficiency syndrome, which is characterized by intellectual disability, epilepsy, autism, and developmental delay. The vast majority of mutations cause protein misfolding and hence reduce cell surface expression. Hence, it is important to understand the molecular machinery supporting folding and export of CRT1 from the endoplasmic reticulum (ER). All other SLC6 members thus far investigated rely on a C-terminal motif for binding the COPII-component SEC24 to drive their ER export; their N-termini are dispensable. Here, we show that, in contrast, in CRT1 the C-terminal ER-export motif is cryptic and it is the N-terminus, which supports ER export. This conclusion is based on the following observations: (i) siRNA-induced depletion of individual SEC24 isoforms revealed that CRT1 relied on SEC24C for ER export. However, mutations of the C-terminal canonical ER-export motif of CRT1 did not impair its cell surface delivery. (ii) Nevertheless, the C-terminal motif of CRT1 was operational in a chimeric protein comprising the serotonin transporter (SERT/SLC6A4) and the C-terminus of CRT1. (iii) Tagging of the N-terminus-but not the C-terminus-with yellow fluorescent protein (YFP) resulted in ER retention. (iv) Serial truncations of the N-terminus showed that removal of ≥51 residues of CRT1 impaired surface delivery, because the truncated CRT1 were confined to the ER. (v) Mutation of P51 to alanine also reduced cell surface delivery of CRT1 and relieved its dependence on SEC24C. Thus, the ER-export motif in the N-terminus of CRT1 overrides the canonical C-terminal motif.
2024-01-04 | Probing binding and occlusion of substrate in the human creatine transporter-1 by computation and mutagenesis.
In chordates, energy buffering is achieved in part through phosphocreatine, which requires cellular uptake of creatine by the membrane-embedded creatine transporter (CRT1/SLC6A8). Mutations in human slc6a8 lead to creatine transporter deficiency syndrome, for which there is only limited treatment. Here, we used a combined homology modeling, molecular dynamics, and experimental approach to generate a structural model of CRT1. Our observations support the following conclusions: contrary to previous proposals, C144, a key residue in the substrate binding site, is not present in a charged state. Similarly, the side chain D458 must be present in a protonated form to maintain the structural integrity of CRT1. Finally, we identified that the interaction chain Y148-creatine-Na+ is essential to the process of occlusion, which occurs via a "hold-and-pull" mechanism. The model should be useful to study the impact of disease-associated point mutations on the folding of CRT1 and identify approaches which correct folding-deficient mutants.
2021-12-23 | Improving Brain Creatine Uptake by Klotho Protein Stimulation: Can Diet Hit the Big Time?
OPINION article Front. Nutr., 23 December 2021Sec. Nutrition, Psychology and Brain Health https://doi.org/10.3389/fnut.2021.795599
small molecules
2026-02-20 | Genetic Determinants of Creatine Bioavailability and Responsiveness: Emphasis on Common Low-Impact Variants
Background: Creatine is a central regulator of cellular energy homeostasis and one of the most extensively studied dietary supplements in human nutrition. Although creatine supplementation consistently increases tissue creatine availability and supports performance and health across diverse populations, substantial interindividual variability in responsiveness persists. Approximately one-quarter of individuals demonstrate minimal increases in tissue creatine or functional benefit following supplementation. While non-genetic factors such as baseline creatine status, diet, age, sex, and training load contribute to this heterogeneity, the role of common genetic variation remains insufficiently explored. Importantly, creatine bioavailability and functional responsiveness are related but distinct outcomes, and both may be modified by genetic background. Objective: This paper aims to reframe creatine responsiveness as a quantitative, polygenic trait shaped by common low-impact genetic variants rather than a binary responder-non-responder phenomenon driven by rare pathogenic mutations. The review synthesizes evidence on genetic variation affecting creatine transport, endogenous synthesis, and downstream energy metabolism, with an emphasis on population-relevant mechanisms. Methods: A narrative, mechanism-oriented review was conducted integrating data from human genetics databases, biochemical pathways, and physiological studies. The analysis focused on (i) common low-impact variants in genes directly regulating creatine transport (SLC6A8) and biosynthesis (GATM, GAMT), and (ii) modifier genes involved in mitochondrial function, phosphagen buffering, and muscle or neural energetic phenotype. Variant classification frameworks from expert curation initiatives were used to distinguish pathogenic from low-impact population variants. Results: Low-impact variants in the creatine transporter gene SLC6A8 are highly prevalent and likely contribute to a continuum of creatine transport efficiency, with sex-dependent effects due to X-linked inheritance. Similarly, common polymorphisms in creatine biosynthetic enzymes (GATM and GAMT) may subtly alter synthetic efficiency or methyl-group demand, increasing dietary creatine dependence while not causing overt deficiency. Beyond creatine-specific pathways, genetic variation in mitochondrial regulators, electron transport chain components, creatine kinase isoforms, and muscle fiber-type determinants can act as effect modifiers, amplifying or dampening the functional benefits of creatine despite comparable tissue uptake. Collectively, small additive effects across transport, synthesis, and utilization pathways may prevent supplementation from exceeding the threshold required for measurable benefit in certain individuals. Conclusions: Creatine non-responsiveness in the general population is more plausibly explained by the cumulative influence of common low-impact genetic variants than by rare monogenic defects. Viewing creatine responsiveness as a graded, polygenic trait provides a coherent framework to interpret heterogeneous findings in supplementation trials. Incorporating genetic context into study design, through stratified analyses or pathway-based approaches, may improve sensitivity to detect true effects and support the development of precision-guided creatine supplementation strategies in both clinical and public health settings.
2026-01-28 | New Insights into Drug Development via the Nose-to-Brain Pathway: Exemplification Through Dodecyl Creatine Ester for Neuronal Disorders.
Brain disorders remain a major global health challenge, highlighting the urgent need for innovative therapeutic strategies and efficient drug-delivery approaches. Among alternative routes, intranasal administration has garnered significant interest over recent decades, not only for its systemic delivery but also for its unique ability to bypass the bloodstream and the blood-brain barrier via the Nose-to-Brain (NtB) pathway. While numerous reviews have explored the opportunities and challenges of this route, industrial considerations-critical for successful clinical implementation and commercial development-remain insufficiently addressed. This review provides a comprehensive and critical assessment of the NtB pathway from a drug development and chemistry, manufacturing, and controls perspective, addressing key constraints in pre-clinical-clinical extrapolation, formulation design, device selection, dose feasibility, chronic safety, and regulatory requirements. We also discuss recent advances in neuronal targeting mechanisms, also with a focus on the role of trigeminal nerves. Dodecyl creatine ester (DCE), a highly unstable in plasma creatine prodrug developed by Ceres Brain Therapeutics, is presented as an illustrative case study. Delivered as a nasal spray, DCE enables direct neuronal delivery, exemplifying the potential of the NtB pathway for disorders characterized by neuronal energy deficiency, including creatine transporter deficiency and mitochondrial dysfunction. Overall, the NtB pathway-or, more precisely, the "Nose-to-Neurons" pathway-offers distinct advantages for unstable molecules and metabolic supplementation, particularly in neuron-centric diseases. Its successful implementation will depend on rational molecule design, optimized nasal formulations, appropriate devices, and early integration of industrial constraints to ensure feasibility, scalability, and safety for long-term treatment.
2025-09-02 | Structural insights into the substrate uptake and inhibition of the human creatine transporter (hCRT).
Creatine plays a vital role in cellular energy production and adenosine triphosphate (ATP) homeostasis and has also been identified as a neurotransmitter in the mammalian brain. Creatine is transported into cells by the human creatine transporter (hCRT) (SLC6A8), an Na+/Cl--dependent symporter encoded on the X chromosome. Mutations in hCRT cause cerebral creatine deficiency syndrome 1, a neurological disorder marked by intellectual disability, speech delay, and seizures. Beyond its role in the brain and muscle, hCRT is highly expressed in metabolically active tumors. Many cancer cells, including colorectal cancer and glioblastoma, upregulate hCRT to sustain intracellular creatine levels and buffer ATP under energy stress. Pharmacological blockade of hCRT by RGX202 has been shown to impair tumor growth by disrupting energy homeostasis. Here, we report the high-resolution cryo-Electron Microscopy (cryo-EM) structures of human hCRT in three states: apo, creatine-bound, and RGX202-bound. hCRT adopts a canonical LeuT-fold with 12 transmembrane helices and two pseudosymmetric inverted repeats. Creatine is coordinated in the central substrate-binding site through interactions with transmembrane helices TM1, TM3, TM6, and TM8, while the inhibitor RGX202 occupies the same binding pocket, engaging in overlapping contacts that competitively block creatine access. Our structural and mechanistic findings clarify substrate recognition and inhibitory binding of hCRT, providing a molecular rationale for targeting hCRT in both inherited metabolic diseases and cancer therapy.
2025-06-05 | Ineffectiveness of creatine, glycine, and arginine supplementation in a female with creatine transporter deficiency: A case report
Background Creatine transporter deficiency (CTD), caused by pathogenic variants of the SLC6A8 gene, is a significant cause of X-linked neurodevelopmental disorders. Heterozygous female patients with CTD exhibit residual creatine transporter activity. Therefore, supplementation therapy with creatine, arginine, and glycine is hypothesized to elevate cerebral creatine levels and improve clinical symptoms. Case presentation We describe the case of a 12-year-old Japanese girl diagnosed with CTD using genetic analysis and magnetic resonance spectroscopy (MRS). The patient presented with intellectual disabilities, behavioral disturbances, and drug-resistant epilepsy. Supplementation therapy with creatine (400 mg/kg/day), glycine (200 mg/kg/day), and arginine (200 mg/kg/day) led to an increase in cerebral creatine levels as measured by MRS; however, no clinical improvement was observed in her seizures and behavioral symptoms. Discussion Previously reported cases revealed variability in responses to supplementation therapy among female patients with CTD. Although the factors underlying the differences in therapeutic efficacy remain unclear, higher doses of arginine may be correlated with improved outcomes. Standardized quantitative evaluations using MRS could facilitate more accurate predictions of the efficacy of supplementation therapy. Conclusion This case highlights the complexities involved in managing female patients with CTD and underscores the need for standardized treatment and evaluation protocols. International collaboration is crucial for developing optimized therapeutic strategies for this rare condition.
2025-05-05 | Transport and inhibition mechanisms of human creatine transporter
Creatine, a guanidine-based molecule, acts as a rapid phosphate energy buffer in its phosphorylated form by donating a phosphate group to ADP, thereby regenerating ATP 1 . This process is crucial for maintaining ATP levels and energy metabolism in tissues with high and variable energy requirements, such as the brain and muscles 2 . Additionally, creatine functions as a compatible osmolyte in the brain and a neuromodulator or neurotransmitter by interacting with N -methyl- d -aspartate receptors and GABA A receptors 3 , 4 , 5 . Creatine is obtained by the diet or synthesized by endogenous enzymes, and specifically transported into the cell using the creatine transporter (CRT) 6 , a sodium- and chloride-dependent transporter, belonging to the solute carrier 6 (SLC6) family. Impaired function of CRT leads to intracellular creatine deficiency 7 , resulting in X-linked creatine transporter deficiency (CTD), a disorder characterized by intellectual disability, speech and language delay, behavioral abnormalities, and seizures. Over 80 CRT pathogenic variants have been identified, but no effective treatment is currently available for this condition. Determining the atomic structure of CRT would greatly aid in developing therapeutic strategies targeting these pathogenic variants.
gene therapies
2025-05-09 | Gene delivery of AGAT and GAMT boosts creatine levels in creatine transporter deficiency patient fibroblasts.
Creatine is a critical metabolite used to buffer cellular energy demands in highly energetic tissues such as the brain and muscle. Genetic defects in endogenous creatine synthesis or transport across cellular membranes lead to a common set of phenotypes referred to as Cerebral Creatine Deficiency Syndrome (CCDS). The most common form of CCDS is Creatine Transporter 1 (CT1) Deficiency (CTD). It accounts for ~ 70% of cases and results from loss-of-function mutations in the X-linked gene SLC6A8. Affected individuals suffer from intellectual disability, autistic-like behaviors, and epilepsy. There are currently no effective therapies for this disorder, but gene therapy has emerged as a potential approach. The two enzymes which comprise the endogenous creatine synthetic pathway (AGAT and GAMT) are selectively expressed by specific cell types throughout the body. However, after synthesized, creatine uptake relies on the protein product of SLC6A8, CT1, to transport creatine into target cell types. We hypothesized that gene delivery of GATM (encoding AGAT) and GAMT into end-user cell types would bypass the need for CT1, allowing for intracellular synthesis of creatine. We tested this strategy in two human cell types: HEK293T cells and primary fibroblasts. Co-delivery of GATM and GAMT increased internal creatine concentrations by 7.6-fold in HEK293T cells and 12.3-fold in healthy control fibroblasts. We then employed this approach to primary fibroblasts from patients with CTD. This resulted in an up to 11.6-fold increase in intracellular creatine concentrations, far exceeding the intracellular concentration of creatine in healthy control fibroblasts. Importantly, overexpression of AGAT and GAMT resulted in proper targeting of these enzymes to their natural cellular compartment and did not impair the growth of patient fibroblasts. These findings establish gene therapy with GATM and GAMT as a potential strategy for patients with CTD.
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Drug Discovery Landscape
3 orphan drug designations for X-linked creatine transporter deficiency.
3 orphan drug designations for X-linked creatine transporter deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
adeno-associated vector-based gene therapy expressing codon-optimized human SLC6A8 | gene therapies | FDA | 2025-11-25 | — | Ronald Reagan UCLA Medical Center |
Dodecyl Creatine Ester | small molecules | FDA | 2021-03-09 | — | CERES BRAIN Therapeutics |
cyclocreatine | small molecules | FDA | 2012-06-18 | — | Lumos Pharma |
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