RARE DISEASE
Fragile X syndrome
Fragile X syndrome
Fragile X syndrome
Synonyms: FRAXA syndrome, FXS, FraX syndrome, Martin-Bell syndrome
Synonyms: FRAXA syndrome, FXS, FraX syndrome, Martin-Bell syndrome
Synonyms: FRAXA syndrome, FXS, FraX syndrome, Martin-Bell syndrome
Drug discovery
53
drugs
With orphan designations
Overview
Fragile X syndrome (FXS) is a genetic disorder caused by a CGG trinucleotide repeat expansion (>200 repeats) in the FMR1 gene on the X chromosome, leading to reduced production of fragile X mental retardation protein (FMRP). This results in intellectual disability, developmental delays, autism spectrum features (33% of cases) [1][6], anxiety, ADHD, and characteristic physical traits (long face, large ears, macroorchidism) [1][6][16]. Males are typically more severely affected due to X-linked inheritance [12][17].
Therapies
Multidisciplinary care: Speech-language, occupational, and physical therapies [3][16][18]
Pharmacotherapy: SSRIs (sertraline), stimulants (methylphenidate), and antipsychotics (aripiprazole) for anxiety, ADHD, and aggression [8][18]
Early intervention: Behavioral strategies and environmental modifications to enhance function [3][6][16]
Categories: rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases, rare neurological diseases, rare ophthalmic disorders
Research Papers
1,561 drug discovery papers about Fragile X syndrome, with 6 first-in-class and 28 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,561 drug discovery papers about Fragile X syndrome, with 6 first-in-class and 28 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-21 | A cell type-specific switch in GluN2D NMDA receptors drives cortical circuit hyperexcitability and sensory-driven cortical synchronization deficits in a Fragile X Syndrome model.
Altered sensory processing and sensitivity are prevalent in Fragile X Syndrome (FXS) and may be mediated by dysfunction of cortical circuits. Evidence from individuals with FXS and/or the FXS mouse model, Fmr1 KO, indicates hyperexcitability of sensory cortical circuits, deficits in sensory-driven circuit synchrony and sensory-induced seizures. GluN2D-containing NMDA receptors (NMDARs) are enriched in cortical inhibitory neurons. We hypothesized that selective activation of GluN2D may correct cortical circuit hyperexcitability, seizures, and synchrony deficits in Fmr1 KO mice. To test this hypothesis, we used pharmacology and cell type-specific genetic manipulation of GluN2D combined with multi-unit and single cell electrophysiology in cortical slices and multielectrode EEG in vivo to examine the functional contribution of GluN2D to cortical circuit dysfunction in the Fmr1 KO mouse. In contrast to our hypothesis, pharmacological inhibition of GluN2D-containing NMDARs corrects cortical circuit hyperexcitability, reduces sensory-driven seizures and improves EEG synchrony in Fmr1 KO mice. We demonstrate a switch in the cell type-specific functional expression of GluN2D-containing NMDARs in Fmr1 KO, from inhibitory to excitatory cortical neurons, which drives circuit hyperexcitability. In support of this conclusion, the mRNA for GluN2D (Grin2d) is upregulated in Fmr1 KO excitatory neurons and genetic reduction of Grin2d in excitatory neurons corrects measures of circuit hyperexcitability in Fmr1 KO mice. Our results reveal an unexpected cell type-specific switch in GluN2D-containing NMDARs in a model of a major genetic cause of intellectual disability and autism and suggest a novel therapeutic strategy to aid sensory processing deficits in FXS.
2026-09-19 | Translational dysregulation as a mechanistic driver of cognitive, behavioral, and affective phenotypes in FXS and TSC.
Neurodevelopmental disorders (NDDs) are characterized by a spectrum of cognitive, behavioral, and affective morbidities, reflecting underlying disruptions in neural circuit development. Emerging evidence implicates translational dysregulation of synaptic proteins as a central mechanistic driver of these disordered phenotypes. Translational dysregulation entails atypical mechanisms of impaired initiation, elongation, and mRNA targeting, causing imbalanced protein synthesis. In NDDs specifically, translation of synaptic proteins is perturbed across developing neurons. Tuberous Sclerosis Complex (TSC) and Fragile X Syndrome (FXS) are notable monogenic NDDs, in which mutations in regulatory genes (Tsc1/Tsc2 in TSC, Fmr1 in FXS) disrupt signaling pathways that converge on mTORC1, PERK, and ERK/MAPK proteins, and result in excessive or insufficient translation of key synaptic proteins. These translational imbalances eventually compromise synapse formation, dendritic spine maturation, and neuronal network connectivity, contributing to deficits in learning, memory, social behavior, and emotional regulation. This review highlights the molecular mechanisms by which aberrant protein synthesis contributes to the cognitive and behavioral manifestations of TSC and FXS. Importantly, we also highlight cell-type-specific mechanisms, illustrating how translational dysregulation differentially impacts distinct neuronal and glial populations to shape behavioral and cognitive outcomes. Understanding the links between translational control and neurodevelopmental outcomes provides critical insights into the pathophysiology of these disorders and informs the development of targeted therapeutic interventions aimed at restoring synaptic protein homeostasis.
2026-09-15 | HK2 drives synaptic dysfunction in fragile X syndrome via epigenetic regulation of H3K18 lactylation.
Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by loss of fragile X messenger ribonucleoprotein (FMRP) expression and characterized by synaptic dysfunction and cognitive impairment. However, the metabolic and epigenetic mechanisms underlying these abnormalities remain poorly understood. To address this gap, this study investigated the role of hexokinase 2 (HK2) in FXS pathogenesis and explored downstream metabolic and epigenetic mechanisms associated with synaptic dysfunction and cognitive impairment. Using an Fmr1 -/Y mouse model, we evaluated HK2 expression and its cell-type specificity in hippocampal neurons. RNA immunoprecipitation (RIP) analysis was performed to examine the association between FMRP and Hk2 mRNA. Genetic knockdown of HK2 was used to assess its effects on neurite outgrowth, synapse density, synaptic transmission, and hippocampal long-term potentiation (LTP). Finally, pharmacological experiments using the HDAC3 inhibitor RGFP966 were performed to examine whether modulation of H3K18la levels contributes to HK2-associated phenotypes. HK2 expression was markedly elevated in hippocampal neurons of Fmr1 -/Y mice. RIP analysis revealed an association between FMRP and Hk2 mRNA, suggesting that HK2 may represent an FMRP-associated transcript. Genetic suppression of HK2 promoted neurite outgrowth, increased synapse density, and improved synaptic transmission and hippocampal long-term potentiation (LTP) in Fmr1 -/Y mice. Mechanistically, HK2 knockdown selectively reduced H3K18la levels without affecting H3K18 acetylation, supporting a role for HK2 in regulating histone lactylation. Consistent with these findings, pharmacological inhibition of HDAC3 with RGFP966 increased H3K18la levels and attenuated the beneficial effects of HK2 suppression on neuronal morphology, synaptic plasticity, and cognitive function. Behavioral analyses demonstrated that modulation of the HK2-H3K18la axis improved spatial learning and memory in Fmr1 -/Y mice. Taken together, these findings support a role for the HK2-H3K18la axis in synaptic dysfunction in FXS. Targeting this metabolic-epigenetic axis may provide a potential avenue for future therapeutic exploration in FXS and related neurodevelopment disorders.
2026-09-06 | ERK-dependent hyperexcitability of BLA neurons projecting to dCA3 underlies social dysfunction in a male mouse model of fragile X syndrome.
Social dysfunction is a core symptom of autism spectrum disorder (ASD), including fragile X syndrome (FXS), but its underlying neural circuits and molecular mechanisms remain poorly understood. Previous studies have implicated the amygdala and hippocampus in social behaviour, yet the specific pathways and signalling events linking genetic deficits to behavioural dysfunction have not been fully delineated. Using activity-dependent c-Fos mapping, fibre photometry, closed-loop optogenetics, pharmacological inhibition, and shRNA-mediated knockdown, we investigated the role of the BLA-dCA3 projection and ERK signalling in male Fmr1 KO mice, complemented by re-analysis of human ASD snRNA-seq data and whole-cell patch-clamp recordings. We found that BLA-dCA3 projecting neurons are aberrantly hyperactivated in Fmr1 KO mice during interactions with both novel and familiar mice, and that closed-loop activation of this pathway in WT mice during familiar interaction impairs social discrimination, whereas its inhibition in KO mice rescues the deficit. Additionally, ERK signalling is upregulated in the BLA of both patients with ASD and Fmr1 KO mice; knocking down FMR1 in the adult BLA recapitulates both the social deficit and ERK hyperactivation, while pharmacological ERK inhibition rescues social behaviour and normalises neuronal hyperexcitability. These findings pinpoint the BLA-dCA3 circuit and BLA-specific ERK signalling as critical mediators of social discrimination deficits in FXS. Our study establishes a causal link from FMRP loss to circuit dysfunction and ERK pathway dysregulation, and suggests that targeting this pathway may offer a promising strategy for treating social dysfunction in ASD and FXS. This work was supported by grants from the National Science and Technology Major Project (2025ZD0214701), the National Natural Science Foundation of China (32171014, 31970940, and 32500889), Nanhu Brain-Computer Interface Institute (010904018), and the Zhejiang Provincial Natural Science Foundation of China (LMS25C090004).
2026-09-03 | Loss of FMRP leads to translationally relevant functional connectivity differences in a rat model of Fragile X Syndrome
ABSTRACT Fragile X syndrome (FXS), a leading monogenic cause of intellectual disability and autism- related features, results from loss of fragile X messenger ribonucleoprotein (FMRP). Although early synaptic and cellular abnormalities associated with the loss of FMRP are well described, it remains unclear how these changes shape the maturation of large-scale functional networks, or whether early pharmacological intervention can normalize circuit development. Our previous work demonstrated that cognitive deficits in Fmr1 -/y rats emerge during development and can be prevented by brief early-life lovastatin treatment. Here, we asked whether large-scale functional connectivity (FC) shows a similarly dynamic developmental trajectory and whether early intervention alters its emergence. Using longitudinal resting-state functional magnetic resonance imaging (rsfMRI), we found that Fmr1 -/y rats displayed an age-dependent FC phenotype, with increased connectivity within the retrosplenial cortex (RSC) at 4 weeks but reduced connectivity within the RSC and distributed brain networks by adulthood compared with wild-type controls. This suggests FC abnormalities emerge over development rather than representing a stable deficit. In contrast to its effects on cognitive measures, brief early-life lovastatin treatment did not prevent the emergence of connectivity abnormalities. Reduced RSC FC was also observed in a small cohort of individuals with FXS (n = 5 per group), supporting further investigation of functional connectivity measures alongside behavioural and molecular endpoints in translational studies of FXS. ONE SENTENCE SUMMARY An age-dependent brain connectivity phenotype in a rat model of FXS is not rescued by lovastatin and aligns with human RSC hypoconnectivity
oligonucleotides
2026-09-29 | Dysregulation of FMR1 Splicing in Human Fragile X Syndrome
Fragile X Syndrome (FXS) is a neuro-developmental disorder caused by a CGG expansion in FMR1, leading to transcriptional silencing and loss of the encoded protein FMRP. Surprisingly, ~70% of FXS individuals express FMR1, but the RNA is mis-spliced to isoform FMR1-217, composed of exon 1 spliced to a pseudo-exon in intron 1 and cannot produce FMRP. Splice-switching ASOs rescue proper FMR1 splicing and restore FMRP. FMR1-217 mis-splicing increases with CGG repeat length and is negatively correlated with patient IQ. FMR1-217 is associated with ribosome footprints, indicating it is translated into a polypeptide that may impair cognition. R-loops form at the FMR1 locus and extend into the pseudo-exon, but splice-switching ASOs reduce FMR1-217 and elevate FMRP independently of R-loop formation. DRB-based transcription analysis identified impaired Pol II elongation at the 5 prime region of FMR1 in FXS cells, indicated by accumulation of hypophosphorylated Pol II at the transcription start site. Consistent with this, camptothecin-induced Pol II stalling increased FMR1-217 pseudo-exon inclusion. The splicing factors PTBP1 and PTBP2 regulate FMR1-217 splicing in a differentiation stage-dependent manner. Together, these findings indicate that FMR1-217 mis-splicing in FXS is associated with CGG repeat expansion, R-loop formation, impaired co-transcriptional Pol II elongation and context-dependent regulation by PTBP1/PTBP2.
2026-06-16 | The role of FMR1 mRNA structure on the efficiency of non-canonical translation of toxic polyglycine protein.
Repeat-associated non-AUG (RAN) translation of mutant FMR1 messenger RNA (mRNA) containing CGG repeat expansions results in the production of a toxic polyglycine protein (FMRpolyG), which contributes to fragile X premutation-associated conditions (FXPAC), including fragile X-associated tremor/ataxia syndrome (FXTAS). The 5' untranslated region of FMR1 mRNA folds into a thermodynamically stable secondary structure at the region of excessively expanded CGG repeats and constitutes a template for RAN translation initiated from near-cognate start codons located upstream of the CGGs. Cis-regulatory elements, including sequence context and stable secondary structures within mRNA, can affect translation initiation and elongation. Here, we show that different nucleotide sequence contexts close to the near-cognate start codon affect FMRpolyG synthesis. Moreover, the distance between the near-cognate start codon and downstream stable RNA structure considerably affects the efficiency of RAN translation initiation, which is positively correlated with the number of CGG repeats. In contrast, translation elongation is impaired as CGG repeats expand. We show that native FMRpolyG containing a short polyglycine tract is synthesized efficiently but rapidly degraded by the proteasome. Our results provide insight into the structural dependencies that regulate the translation of CGGs and can be used in other repeat expansion disorders. We also show that the RNA structure is a potential therapeutic target in FXPAC.
2026-02-04 | FMR1 RNA interaction with DNMT1 blocks DNA methylation at the FMR1 locus.
In the FMR1 gene, expansion of the CGG triplet beyond 200 repeats triggers DNA methylation, resulting in the Fragile X Syndrome (FXS). There exist rare individuals who carry a CGG expansion >200 that remains unmethylated, rescuing them from expressing the FXS phenotype. We tested the hypothesis that active FMR1 transcription regulates DNA methylation of the locus through the binding of its mRNA to DNMT1 enzyme. Our results show that DNMT1 binds FMR1-mRNA in transcriptionally active cells preventing them from being methylated, whereas it binds to the FMR1 locus in FXS cells, resulting in gene silencing. DNMT1 binds to the transcript or to the locus after reactivating or blocking FMR1 transcription using specific drugs, respectively. As proof of concept, aptamers capable of binding and inhibiting DNMT1 were shown to reactivate the silenced FMR1 gene. We propose that DNMT1 represents a specific molecular target to reactivate the FMR1 gene expression.
2025-12-11 | IGF2BPs directly regulate the noncanonical translation of toxic proteins from mutant FMR1 mRNA containing expanded CGG repeats.
Mutant mRNA of the fragile X messenger ribonucleoprotein 1 gene (FMR1) containing expanded CGG repeats in its 5'UTR is a primary cause of fragile X premutation associated conditions. It serves as a template for the biosynthesis of the major open reading frame encoding canonical protein and the downstream open reading frame containing expanded CGG repeats encoding toxic FMRpolyG protein that comprise a long polyglycine stretch, produced via repeat-associated non-AUG initiated translation. Here, we show that insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) binds directly to the 5'UTR of FMR1 RNA, and the sequence in the vicinity of near-cognate start codons of non-AUG translation is pivotal for IGF2BP3 binding. Upon IGF2BP3's knockdown, FMRpolyG biosynthesis and cell toxicity evoked by FMRpolyG, significantly decreased in cells expressing mutant FMR1 with expanded CGG repeats. Disruption of IGF2BP ortholog in novel fragile X premutation associated conditions C. elegans model rescues the disease phenotype induced by expression of a human FMR1 RNA fragment containing expanded CGG repeats. Our results suggest that IGF2BP3 positively regulates the noncanonical translation of expanded CGG repeats and may be a promising target for clinical applications.
2025-11-17 | RNA-based therapies for neurodevelopmental disorders: innovative tools for molecular correction.
Modulation of RNA and protein expression to restore or normalize neuronal function has emerged as a powerful therapeutic strategy for neurodevelopmental disorders (NDDs) tailoring individual genetic mutations causing intellectual disability (ID), or autism spectrum disorder (ASD), or developmental epileptic encephalopathy (DEE). In recent years, diverse classes of RNA-based molecules have been developed with therapeutic potential, including antisense oligonucleotides (ASOs), oligonucleotides targeting natural antisense transcripts (antagoNATs), Short Interspersed Nuclear Element UP-regulating RNAs (SINEUPs), interfering RNAs (RNAi), Exon-Specific engineering U1 small nuclear RNAs (ExSpeU1s), and small-activating RNA (saRNA) This review highlights the promising advances of these RNA-based therapeutics in addressing syndromic ID, such as Fragile X syndrome, MECP2 duplication syndrome, FOXG1-gene related Rett syndrome and Angelman syndrome, which are characterized by well-defined genetic mutations with limited treatment options. Moreover, ASD-related condition linked to mutations in CHD8 is under investigation, extending the therapeutic landscape to complex behavioral and cognitive disorders. In the same way, several DEEs caused by mutations in CDKL5, DNM1, KCNT1, SCN1A, SCN2A, SCN8A, and UBA5 genes, which present severe pharmaco-resistant epilepsy, are increasingly becoming targets for RNA molecules that aim to restore neuronal excitability and network function. Together, these findings underscore the expanding therapeutic landscape enabled by RNA technologies, offering unprecedented specificity and flexibility for gene-targeted interventions in NDDs. As the field of RNA medicine continues to evolve across genomics and neuroscience, we aim to provide a resource for researchers and clinicians on promising innovative tools for molecular correction.
proteins
2026-05-01 | Cerebral Cortex Morphometry and Relaxometry in Male Children With Fragile X Syndrome and Autism.
An estimated 30%-50% of male individuals with fragile X syndrome (FXS) meet criteria for autism spectrum disorder (ASD), indicating phenotypic overlap but potentially distinct neurobiology. Here, we aimed to characterize shared and divergent cortical features between FXS and ASD. High-resolution, motion-corrected quantitative MRI was used to compare cortical morphometry and relaxometry in 61 male participants (9-18 years) with FXS or ASD. To increase power, ASD participants were pooled from multiple MPnRAGE studies and harmonized across protocols using ComBat. Cortical thickness and R1 (longitudinal relaxation rate; proxy for myelination) were computed across the cerebral cortex. Relative to ASD, FXS exhibited greater cortical thickness predominantly in early sensory cortices implicated in low-level visual and auditory processing spanning occipital, parietal, and temporal regions. No significant group differences in R1 were found. Thicker cortex in FXS within primary and early associative sensory areas suggests divergent early sensory processing mechanisms between FXS and ASD. Characterizing different neuroanatomical features between the two disorders provides a grounding to develop more disorder-specific interventions despite similar behavioral difficulties. Future work should test developmental trajectories, include females and comorbidities, and link imaging markers to individual sensory/clinical profiles to inform and improve personalized therapies and interventions.
2026-04-29 | Lasting effects of early-life oxytocin treatment on LTP and episodic memory in a mouse model of Fragile X syndrome.
Deficits in episodic memory are a debilitating feature of Fragile X syndrome (FXS) and other congenital autism spectrum disorders (ASDs). There is evidence that oxytocin (OXT) treatments can improve sociability in persons with ASD and related animal models, encouraging the idea that benefits might extend to cognitive function. We tested this possibility in male FXS model, Fmr1-knockout (KO) mice. Intranasal treatments with OXT or saline were given daily during the second or fifth postnatal week, and effects on social behavior, spatial and episodic memory, and hippocampal synaptic plasticity were assessed in adulthood. Saline-treated Fmr1-KOs exhibited profound deficits in social recognition, object location memory, what-when-where components of episodic memory and long-term potentiation (LTP) in both the CA3-CA1 and lateral perforant path (LPP) systems; NMDAR-mediated components of LPP responses were also impaired. OXT treatments during the second week postnatal normalized all of these functions in Fmr1-KOs assessed in adulthood; this included restoration of initial stages of CA3-CA1 LTP and granule cell NMDAR-mediated currents. In hippocampal slices from naïve adult male Fmr1-KO mice, bath-applied OXT treatment restored LTP in CA1 but not the LPP, indicating pathway-specific effects. Intranasal OXT treatments during the 5th week postnatal did not have enduring effects in either genotype. The present evidence that early OXT treatment corrects a broad range of cognitive and synaptic plasticity deficits in Fmr1-KO mice identifies a clinically plausible strategy for normalizing hippocampal function in ASD and FXS, and highlights the presence of a critical developmental window for effective intervention.
2025-12-16 | Toward peptide-based protein replacement in fragile X syndrome: Evaluating the N-tat strategy
Fragile X syndrome (FXS), a leading inherited cause of intellectual disability and autism, arises from loss of the RNA-binding protein FMRP and consequent dysregulation of synaptic mRNA translation. No clinically approved therapies exist to restore FMRP function. A recent study showed that a Tat-conjugated FMRP fragment spanning residues 1–297 (FMRP N-tat) can transiently reduce hyperexcitability in an FXS mouse model, supporting peptide replacement as a feasible therapeutic strategy. Extending this concept, Leguay et al. demonstrated in FXS patient iPSC-derived neurons that N-tat reconstitutes interactions with endogenous protein partners correcting dysregulated translation and mitochondrial defects. However, despite recapitulating several functions of full-length FMRP, the in vivo effects of N-tat remain short-lived, highlighting challenges in stability and the potential need for additional functional domains. Herein, this commentary outlines both the promise of N-tat–based protein replacement and the remaining gaps that must be addressed to achieve clinically durable restoration of FMRP function.
2025-06-07 | Interactome of FMRP-N-tat therapeutic unveils key interactions for cellular function in Fragile X neurons.
Therapeutic protein replacement has demonstrated preclinical and clinical efficacy in neurological disorders but has not been used clinically for Fragile X syndrome (FXS), a genetic neurodevelopmental disorder caused by loss of Fragile X messenger ribonucleoprotein (FMRP). FXS results from a triplet repeat expansion of more than 200 CGG repeats in the 5'-UTR of the FMR1 gene leading to epigenetic silencing of FMRP. Currently, no clinically approved disease-modifying treatments for FXS exist. Recently, a tat-conjugated FMRP fragment encompassing residues 1 to 297 (FMRP N-tat) was shown to restore aspects of neuronal function in a mouse model of FXS. Promising in vivo data hinted to the therapeutic potential of FMRP N-tat. Herein, affinity purification mass spectrometry was used to identify the FMRP N-tat interactome in tsA-201 FMR1 knockout cells and FXS patient iPSC-derived neurons. The FMRP N-tat interactome included RNA binding proteins and constituents of the ribosome, which aligned closely with the known functions of FMRP. Further, the FMRP N-tat associated proteins included FXR2, STAU1, TRIM28, C1QBP, VDAC2, and several ribosomal proteins to regulate mRNA stability, cellular stress responses, mitochondrial function, and translation. The results highlight the potential of FMRP N-tat to orchestrate assembly of factors to correct lost function in FMRP deficient cells.
2025-04-07 | Soy-based purified ingredient diet affects mouse gut permeability and the microbiome in fragile X mice.
Gastrointestinal problems including vomiting, reflux, flatulence, diarrhea, constipation and colic are common comorbidities in fragile X syndrome. There is accumulating evidence suggesting that leaky gut syndrome causes neurological phenotypes. Although fragile X messenger ribonucleoprotein is ubiquitously expressed, there is a dearth of knowledge regarding its role outside of the brain including effects on gut dysfunction in fragile X. The aim of this study was to generate novel data on gastrointestinal barrier function and the gut microbiome in response to Fmr1 genotype, sex and diet in mice. Fmr1KO male mice and littermate controls in an FVB background were maintained on two purified ingredient diets (AIN-93G with casein protein versus soy protein isolate) versus two standard chows (Teklad 2019 with wheat, corn and yeast protein versus Purina 5015 with wheat, soy, corn, yeast and whey protein sources). Gut permeability was quantified by FITC-dextran levels in blood plasma. The cecal microbiome was identified by 16S rRNA sequencing. In addition, gut permeability was tested in Fmr1KO mice in the C57BL/6 J background maintained on casein- and soy protein isolate-based AIN-93G versus Teklad 2019. Knockout of the Fmr1 gene in FVB mice did not affect gut permeability. Soy protein isolate-based AIN-93G increased gut permeability. Beta-diversity of the cecal microbiome was significantly altered as a function of the four test diets. Akkermansia_muciniphila was increased in Fmr1KO mice fed AIN-93G while unnamed species within the genus Anaerovorax and family Ruminococcaceae were increased and the order Clostridales decreased in Fmr1KO mice fed AIN-93G/soy. Fmr1KO mice in the C57BL/6 J background exhibited increased gut permeability in response to soy protein. These findings regarding the effects of diet on gut permeability and the microbiome have important implications for experimental design. Single-source diets are ubiquitously used to maintain laboratory animals for medical research and feed details are frequently not reported in publications. Diet/phenotype interactions could have a large impact on inter-laboratory replicability in premedical research. For infants with fragile X, early-life diet could impact the severity of disease outcomes.
gene therapies
2026-08-26 | Statistical power in UK genetic syndrome research; evidence from studies of Down syndrome, Fragile X syndrome and Williams syndrome as model syndrome groups.
Research on genetic syndromes is vital to our understanding of how development unfolds, but the rarity of genetic syndromes can mean that studies are carried out with small sample sizes. Small sample sizes can reduce the statistical power of a study to produce reliable and replicable results. Here, we review all UK journal articles on three target genetic syndromes published from 2013 to 2022. There were 368 eligible articles. The median sample size of genetic syndrome groups was N = 30, and only 6.5% of articles reported a power analysis. Power analysis was performed on the 123 articles classed as 'Cognitive' research, as a test case. This demonstrated an average power of only 54% for a medium effect size and an alpha of 0.05. This is well below the recommended threshold of 80% power. The low power of UK genetic syndrome research has consequences for the replicability of the field due to the risk of Type II errors and reduced precision in effect size estimates, as well as implications for the communities that this research seeks to serve. We provide suggestions for researchers, journal editors and funders for improving the replicability of the field of genetic syndrome research.
2026-07-11 | FMR1 gene therapy restores translationally relevant phenotypes in a mouse model for fragile X syndrome.
Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability. It is caused by a trinucleotide expansion in the 5' UTR of the Fragile X messenger ribonucleoprotein 1 (FMR1) gene leading to loss of expression of Fragile X messenger ribonucleoprotein (FMRP). There is currently no cure for FXS. We developed an FMR1 gene therapy based on an adeno-associated viral vector designed with strong translational potential for future clinical testing. The viral vector was tested in Fmr1 knockout mice using two translationally relevant delivery routes and ages corresponding to in utero, toddler, and adolescent ages in humans. Functional studies showed that the FMR1 gene therapy improved select translational FXS phenotypes spanning three critical domains: sensory hyperexcitability, adaptation to change, and altered brain activity. Expression after intracerebroventricular injection was most prominent in the forebrain, whereas intravenous delivery predominantly led to expression across midbrain and brainstem, suggesting that a dual route may be needed to achieve full brain coverage. Biodistribution analyses further suggested that FMRP expression must be titrated carefully for optimal rescue. In summary, we show that FMR1 gene therapy using delivery routes and vehicles approved for clinical use improves core phenotypes in a mouse model for FXS.
2026-07-02 | Neonatal expression of human FMRP isoform corrects cortical deficits and improves behavior in a mouse model of fragile X syndrome.
Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by CGG trinucleotide repeat expansion in the fragile X messenger ribonucleoprotein 1 (FMR1) gene and the resulting loss of fragile X messenger ribonucleoprotein (FMRP). Gene therapy using recombinant adeno-associated virus (AAV) to restore FMRP expression, particularly in the brain, is a promising therapeutic strategy targeting the underlying cause of FXS. We examined the impact of AAV serotype 9 (AAV9)-mediated expression of a brain-abundant human FMRP isoform (isoform 7) driven by a fragment of the human FMR1 promoter on circuit and behavioral dysfunctions in the male Fmr1 knockout (KO) mouse, FXS model. Following intracerebroventricular (i.c.v.) injection of AAV9-NG276 into neonatal KO mice at a low (1e11 vg/animal) or high (3e11 vg/animal) dose, we assessed cortical phenotypes using electroencephalography (EEG) recordings and behavioral testing. High-dose AAV9-NG276 normalized baseline gamma power, improved sound-evoked responses, and reduced background neural activity. Analysis of behavioral deficits in adult KO mice showed that high-dose neonatal AAV9-NG276 delivery normalized exploratory behaviors, social preference, and probabilistic reversal learning. Thus, early AAV-mediated delivery of human FMR1 isoform 7 ameliorates cortical dysfunction and behavioral deficits in a murine FXS model and suggests that widespread cortical biodistribution is required for therapeutic benefit.
2026-06-11 | Recognizing repeat expansion disorders in clinical practice.
Repeat expansion disorders are caused by unstable DNA sequences that exceed pathogenic thresholds, disrupting normal gene function. These conditions often affect the nervous system, but may involve multiple organs, with presentations ranging from subtle cognitive or motor changes to overt neuromuscular or neurodevelopmental syndromes. Early symptoms can mimic common conditions, making clinical suspicion, family history, and awareness of intergenerational patterns essential. Molecular features, including repeat size, sequence, location and stability, determine disease severity and variability. Nurse practitioners are well positioned to recognize early signs, make early referrals to genetics, and support families with education, anticipatory guidance, and coordination of follow-up care. Case examples include Huntington disease, fragile X syndrome, and myotonic dystrophy and illustrate clinical heterogeneity, premutation effects, and genetic anticipation. Early recognition and referral remain crucial, particularly as emerging gene-targeted therapies may offer potential disease-modifying options.
2026-04-23 | Suppression of astrocyte BMP signaling improves molecular signatures and functional deficits in a fragile X syndrome mouse model.
Fragile X syndrome (FXS) is a monogenic neurodevelopmental disorder with molecular, neuroanatomical, and behavioral changes. In FXS, astrocytes express dysregulated gene and protein networks, therefore identifying upstream pathways mediating astrocyte changes may provide a point of intervention. We focus on the bone morphogenetic protein (BMP) pathway, which is upregulated in FXS astrocytes. We generated a conditional KO (cKO) of Smad4 in astrocytes to suppress BMP signaling, finding that this lessens audiogenic seizure severity in male FXS mice. We performed in vivo transcriptomic and proteomic profiling of cortical astrocytes, finding upregulation of metabolic pathways, and downregulation of secretory machinery and secreted and membrane proteins in FXS astrocytes, with these alterations mitigated when BMP signaling is suppressed. Functionally, astrocyte Smad4 cKO restores deficits in inhibitory synapses in the FXS auditory cortex. Our findings show that astrocytes contribute to some FXS mouse molecular and functional phenotypes, and targeting astrocyte BMP signaling improves some FXS symptoms.
other
2025-01-17 | GABAergic Progenitor Cell Graft Rescues Cognitive Deficits in Fragile X Syndrome Mice.
Fragile X syndrome (FXS) is an inherited neurodevelopmental disorder characterized by a range of clinical manifestations with no effective treatment strategy to date. Here, transplantation of GABAergic precursor cells from the medial ganglionic eminence (MGE) is demonstrated to significantly improve cognitive performance in Fmr1 knockout (KO) mice. Within the hippocampus of Fmr1-KO mice, MGE-derived cells from wild-type donor mice survive, migrate, differentiate into functionally mature interneurons, and form inhibitory synaptic connections with host pyramidal neurons. MGE cell transplantation restores Ras-PKB signaling in pyramidal neurons, enhances AMPA receptor trafficking, rescues synaptic plasticity, and corrects abnormal hippocampal neural oscillations. These findings highlight the potential of GABAergic precursor cell transplantation as a promising therapeutic strategy for FXS.
2022-12-05 | Fragile X Syndrome Patient-Derived Neurons Developing in the Mouse Brain Show FMR1-Dependent Phenotypes.
Fragile X syndrome (FXS) is characterized by physical abnormalities, anxiety, intellectual disability, hyperactivity, autistic behaviors, and seizures. Abnormal neuronal development in FXS is poorly understood. Data on patients with FXS remain scarce, and FXS animal models have failed to yield successful therapies. In vitro models do not fully recapitulate the morphology and function of human neurons. To mimic human neuron development in vivo, we coinjected neural precursor cells derived from FXS patient-derived induced pluripotent stem cells and neural precursor cells derived from corrected isogenic control induced pluripotent stem cells into the brain of neonatal immune-deprived mice. The transplanted cells populated the brain and a proportion differentiated into neurons and glial cells. Immunofluorescence and single and bulk RNA sequencing analyses showed accelerated maturation of FXS neurons after an initial delay. Additionally, we found increased percentages of Arc- and Egr-1-positive FXS neurons and wider dendritic protrusions of mature FXS striatal medium spiny neurons. This transplantation approach provides new insights into the alterations of neuronal development in FXS by facilitating physiological development of cells in a 3-dimensional context.
2022-08-23 | A genetic labeling system to study dendritic spine development in zebrafish models of neurodevelopmental disorders.
Dendritic spines are the principal site of excitatory synapse formation in the human brain. Several neurodevelopmental disorders cause spines to develop abnormally, resulting in altered spine number and morphology. Although spine development has been thoroughly characterized in the mammalian brain, spines are not unique to mammals. We have developed a genetic system in zebrafish to enable high-resolution in vivo imaging of spine dynamics during larval development. Although spiny neurons are rare in the larval zebrafish, pyramidal neurons (PyrNs) of the zebrafish tectum form an apical dendrite containing a dense array of dendritic spines. To characterize dendritic spine development, we performed mosaic genetic labeling of individual PyrNs labeled by an id2b:gal4 transgene. Our findings identify a developmental period during which PyrN dendrite growth is concurrent with spine formation. Throughout this period, motile, transient filopodia gradually transform into stable spines containing postsynaptic specializations. The utility of this system to study neurodevelopmental disorders was validated by examining spine development in fmr1 mutant zebrafish, a model of fragile X syndrome. PyrNs in fmr1 mutants exhibited pronounced defects in dendrite growth and spine stabilization. Taken together, these findings establish a genetic labeling system to study dendritic spine development in larval zebrafish. In the future, this system could be combined with high-throughput screening approaches to identify genes and drug targets that regulate spine formation.
2020-12-04 | The effect of fecal microbiota transplantation on autistic-like behaviors in Fmr1 KO mice.
The importance of alterations in bidirectional communication between gut and brain has become obvious in neuropsychiatric disorders. Gastrointestinal (GI) disturbances are very common in autism spectrum disorders (ASD), and the GI microbiota profiles in children with ASD are significantly different from those in the general population. Fragile X syndrome (FXS) is an inheritable developmental disability in humans, and patients with FXS exhibit autistic behaviors such as mental retardation and impaired social communication or interaction. We hypothesized that an increase in specific gut microbiota by fecal microbiota transplantation (FMT) would mitigate autistic-like behaviors. To test this hypothesis, we measured the effects of FMT from normal mice to Fmr1 KO mice on autistic-like behaviors using several behavioral tests. Because the amounts of A. muciniphila in Fmr1 KO mice was very low, we assessed A. muciniphila population, tested the expression of MUC2, and analyzed goblet cells in the gut after the FMT. We found that FMT ameliorated autistic-like behaviors, especially memory deficits and social withdrawal, and we observed that the levels of A. muciniphila were normalized to wild-type levels. In addition, FMT attenuated the increased levels of TNFα and Iba1 in the brains of Fmr1 KO mice. These results suggest that FMT could be a useful tool for the treatments of cognitive deficits and social withdrawal symptoms observed in FXS or ASD because it increases the population of A. muciniphila and decreases TNFα and Iba1 levels.
2020-11-09 | Advances in Human Stem Cells and Genome Editing to Understand and Develop Treatment for Fragile X Syndrome.
Fragile X syndrome (FXS), the most common genetic form of autism spectrum disorder, is caused by deficiency of the fragile X mental retardation protein (FMRP). Despite extensive research using animal models, understanding how FMRP regulates human brain development and function remains a major challenge. Human pluripotent stem cells (hPSCs) offer powerful platforms for studying mechanisms of human diseases and for evaluating potential treatments. Genome editing, particularly the CRISPR/Cas9-based method, is highly effective for generating models to study genetic human diseases. Here we summarize how hPSCs and genome editing provide much-needed models for studying the genetic underpinnings, cellular mechanisms, and neuropathology that are unique to human FXS. The use of hPSCs and genome editing also provides an essential platform for therapeutic development in FXS.
small molecules
2026-09-21 | A cell type-specific switch in GluN2D NMDA receptors drives cortical circuit hyperexcitability and sensory-driven cortical synchronization deficits in a Fragile X Syndrome model.
Altered sensory processing and sensitivity are prevalent in Fragile X Syndrome (FXS) and may be mediated by dysfunction of cortical circuits. Evidence from individuals with FXS and/or the FXS mouse model, Fmr1 KO, indicates hyperexcitability of sensory cortical circuits, deficits in sensory-driven circuit synchrony and sensory-induced seizures. GluN2D-containing NMDA receptors (NMDARs) are enriched in cortical inhibitory neurons. We hypothesized that selective activation of GluN2D may correct cortical circuit hyperexcitability, seizures, and synchrony deficits in Fmr1 KO mice. To test this hypothesis, we used pharmacology and cell type-specific genetic manipulation of GluN2D combined with multi-unit and single cell electrophysiology in cortical slices and multielectrode EEG in vivo to examine the functional contribution of GluN2D to cortical circuit dysfunction in the Fmr1 KO mouse. In contrast to our hypothesis, pharmacological inhibition of GluN2D-containing NMDARs corrects cortical circuit hyperexcitability, reduces sensory-driven seizures and improves EEG synchrony in Fmr1 KO mice. We demonstrate a switch in the cell type-specific functional expression of GluN2D-containing NMDARs in Fmr1 KO, from inhibitory to excitatory cortical neurons, which drives circuit hyperexcitability. In support of this conclusion, the mRNA for GluN2D (Grin2d) is upregulated in Fmr1 KO excitatory neurons and genetic reduction of Grin2d in excitatory neurons corrects measures of circuit hyperexcitability in Fmr1 KO mice. Our results reveal an unexpected cell type-specific switch in GluN2D-containing NMDARs in a model of a major genetic cause of intellectual disability and autism and suggest a novel therapeutic strategy to aid sensory processing deficits in FXS.
2026-09-19 | Translational dysregulation as a mechanistic driver of cognitive, behavioral, and affective phenotypes in FXS and TSC.
Neurodevelopmental disorders (NDDs) are characterized by a spectrum of cognitive, behavioral, and affective morbidities, reflecting underlying disruptions in neural circuit development. Emerging evidence implicates translational dysregulation of synaptic proteins as a central mechanistic driver of these disordered phenotypes. Translational dysregulation entails atypical mechanisms of impaired initiation, elongation, and mRNA targeting, causing imbalanced protein synthesis. In NDDs specifically, translation of synaptic proteins is perturbed across developing neurons. Tuberous Sclerosis Complex (TSC) and Fragile X Syndrome (FXS) are notable monogenic NDDs, in which mutations in regulatory genes (Tsc1/Tsc2 in TSC, Fmr1 in FXS) disrupt signaling pathways that converge on mTORC1, PERK, and ERK/MAPK proteins, and result in excessive or insufficient translation of key synaptic proteins. These translational imbalances eventually compromise synapse formation, dendritic spine maturation, and neuronal network connectivity, contributing to deficits in learning, memory, social behavior, and emotional regulation. This review highlights the molecular mechanisms by which aberrant protein synthesis contributes to the cognitive and behavioral manifestations of TSC and FXS. Importantly, we also highlight cell-type-specific mechanisms, illustrating how translational dysregulation differentially impacts distinct neuronal and glial populations to shape behavioral and cognitive outcomes. Understanding the links between translational control and neurodevelopmental outcomes provides critical insights into the pathophysiology of these disorders and informs the development of targeted therapeutic interventions aimed at restoring synaptic protein homeostasis.
2026-09-15 | HK2 drives synaptic dysfunction in fragile X syndrome via epigenetic regulation of H3K18 lactylation.
Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by loss of fragile X messenger ribonucleoprotein (FMRP) expression and characterized by synaptic dysfunction and cognitive impairment. However, the metabolic and epigenetic mechanisms underlying these abnormalities remain poorly understood. To address this gap, this study investigated the role of hexokinase 2 (HK2) in FXS pathogenesis and explored downstream metabolic and epigenetic mechanisms associated with synaptic dysfunction and cognitive impairment. Using an Fmr1 -/Y mouse model, we evaluated HK2 expression and its cell-type specificity in hippocampal neurons. RNA immunoprecipitation (RIP) analysis was performed to examine the association between FMRP and Hk2 mRNA. Genetic knockdown of HK2 was used to assess its effects on neurite outgrowth, synapse density, synaptic transmission, and hippocampal long-term potentiation (LTP). Finally, pharmacological experiments using the HDAC3 inhibitor RGFP966 were performed to examine whether modulation of H3K18la levels contributes to HK2-associated phenotypes. HK2 expression was markedly elevated in hippocampal neurons of Fmr1 -/Y mice. RIP analysis revealed an association between FMRP and Hk2 mRNA, suggesting that HK2 may represent an FMRP-associated transcript. Genetic suppression of HK2 promoted neurite outgrowth, increased synapse density, and improved synaptic transmission and hippocampal long-term potentiation (LTP) in Fmr1 -/Y mice. Mechanistically, HK2 knockdown selectively reduced H3K18la levels without affecting H3K18 acetylation, supporting a role for HK2 in regulating histone lactylation. Consistent with these findings, pharmacological inhibition of HDAC3 with RGFP966 increased H3K18la levels and attenuated the beneficial effects of HK2 suppression on neuronal morphology, synaptic plasticity, and cognitive function. Behavioral analyses demonstrated that modulation of the HK2-H3K18la axis improved spatial learning and memory in Fmr1 -/Y mice. Taken together, these findings support a role for the HK2-H3K18la axis in synaptic dysfunction in FXS. Targeting this metabolic-epigenetic axis may provide a potential avenue for future therapeutic exploration in FXS and related neurodevelopment disorders.
2026-09-06 | ERK-dependent hyperexcitability of BLA neurons projecting to dCA3 underlies social dysfunction in a male mouse model of fragile X syndrome.
Social dysfunction is a core symptom of autism spectrum disorder (ASD), including fragile X syndrome (FXS), but its underlying neural circuits and molecular mechanisms remain poorly understood. Previous studies have implicated the amygdala and hippocampus in social behaviour, yet the specific pathways and signalling events linking genetic deficits to behavioural dysfunction have not been fully delineated. Using activity-dependent c-Fos mapping, fibre photometry, closed-loop optogenetics, pharmacological inhibition, and shRNA-mediated knockdown, we investigated the role of the BLA-dCA3 projection and ERK signalling in male Fmr1 KO mice, complemented by re-analysis of human ASD snRNA-seq data and whole-cell patch-clamp recordings. We found that BLA-dCA3 projecting neurons are aberrantly hyperactivated in Fmr1 KO mice during interactions with both novel and familiar mice, and that closed-loop activation of this pathway in WT mice during familiar interaction impairs social discrimination, whereas its inhibition in KO mice rescues the deficit. Additionally, ERK signalling is upregulated in the BLA of both patients with ASD and Fmr1 KO mice; knocking down FMR1 in the adult BLA recapitulates both the social deficit and ERK hyperactivation, while pharmacological ERK inhibition rescues social behaviour and normalises neuronal hyperexcitability. These findings pinpoint the BLA-dCA3 circuit and BLA-specific ERK signalling as critical mediators of social discrimination deficits in FXS. Our study establishes a causal link from FMRP loss to circuit dysfunction and ERK pathway dysregulation, and suggests that targeting this pathway may offer a promising strategy for treating social dysfunction in ASD and FXS. This work was supported by grants from the National Science and Technology Major Project (2025ZD0214701), the National Natural Science Foundation of China (32171014, 31970940, and 32500889), Nanhu Brain-Computer Interface Institute (010904018), and the Zhejiang Provincial Natural Science Foundation of China (LMS25C090004).
2026-09-03 | Loss of FMRP leads to translationally relevant functional connectivity differences in a rat model of Fragile X Syndrome
ABSTRACT Fragile X syndrome (FXS), a leading monogenic cause of intellectual disability and autism- related features, results from loss of fragile X messenger ribonucleoprotein (FMRP). Although early synaptic and cellular abnormalities associated with the loss of FMRP are well described, it remains unclear how these changes shape the maturation of large-scale functional networks, or whether early pharmacological intervention can normalize circuit development. Our previous work demonstrated that cognitive deficits in Fmr1 -/y rats emerge during development and can be prevented by brief early-life lovastatin treatment. Here, we asked whether large-scale functional connectivity (FC) shows a similarly dynamic developmental trajectory and whether early intervention alters its emergence. Using longitudinal resting-state functional magnetic resonance imaging (rsfMRI), we found that Fmr1 -/y rats displayed an age-dependent FC phenotype, with increased connectivity within the retrosplenial cortex (RSC) at 4 weeks but reduced connectivity within the RSC and distributed brain networks by adulthood compared with wild-type controls. This suggests FC abnormalities emerge over development rather than representing a stable deficit. In contrast to its effects on cognitive measures, brief early-life lovastatin treatment did not prevent the emergence of connectivity abnormalities. Reduced RSC FC was also observed in a small cohort of individuals with FXS (n = 5 per group), supporting further investigation of functional connectivity measures alongside behavioural and molecular endpoints in translational studies of FXS. ONE SENTENCE SUMMARY An age-dependent brain connectivity phenotype in a rat model of FXS is not rescued by lovastatin and aligns with human RSC hypoconnectivity
oligonucleotides
2026-09-29 | Dysregulation of FMR1 Splicing in Human Fragile X Syndrome
Fragile X Syndrome (FXS) is a neuro-developmental disorder caused by a CGG expansion in FMR1, leading to transcriptional silencing and loss of the encoded protein FMRP. Surprisingly, ~70% of FXS individuals express FMR1, but the RNA is mis-spliced to isoform FMR1-217, composed of exon 1 spliced to a pseudo-exon in intron 1 and cannot produce FMRP. Splice-switching ASOs rescue proper FMR1 splicing and restore FMRP. FMR1-217 mis-splicing increases with CGG repeat length and is negatively correlated with patient IQ. FMR1-217 is associated with ribosome footprints, indicating it is translated into a polypeptide that may impair cognition. R-loops form at the FMR1 locus and extend into the pseudo-exon, but splice-switching ASOs reduce FMR1-217 and elevate FMRP independently of R-loop formation. DRB-based transcription analysis identified impaired Pol II elongation at the 5 prime region of FMR1 in FXS cells, indicated by accumulation of hypophosphorylated Pol II at the transcription start site. Consistent with this, camptothecin-induced Pol II stalling increased FMR1-217 pseudo-exon inclusion. The splicing factors PTBP1 and PTBP2 regulate FMR1-217 splicing in a differentiation stage-dependent manner. Together, these findings indicate that FMR1-217 mis-splicing in FXS is associated with CGG repeat expansion, R-loop formation, impaired co-transcriptional Pol II elongation and context-dependent regulation by PTBP1/PTBP2.
2026-06-16 | The role of FMR1 mRNA structure on the efficiency of non-canonical translation of toxic polyglycine protein.
Repeat-associated non-AUG (RAN) translation of mutant FMR1 messenger RNA (mRNA) containing CGG repeat expansions results in the production of a toxic polyglycine protein (FMRpolyG), which contributes to fragile X premutation-associated conditions (FXPAC), including fragile X-associated tremor/ataxia syndrome (FXTAS). The 5' untranslated region of FMR1 mRNA folds into a thermodynamically stable secondary structure at the region of excessively expanded CGG repeats and constitutes a template for RAN translation initiated from near-cognate start codons located upstream of the CGGs. Cis-regulatory elements, including sequence context and stable secondary structures within mRNA, can affect translation initiation and elongation. Here, we show that different nucleotide sequence contexts close to the near-cognate start codon affect FMRpolyG synthesis. Moreover, the distance between the near-cognate start codon and downstream stable RNA structure considerably affects the efficiency of RAN translation initiation, which is positively correlated with the number of CGG repeats. In contrast, translation elongation is impaired as CGG repeats expand. We show that native FMRpolyG containing a short polyglycine tract is synthesized efficiently but rapidly degraded by the proteasome. Our results provide insight into the structural dependencies that regulate the translation of CGGs and can be used in other repeat expansion disorders. We also show that the RNA structure is a potential therapeutic target in FXPAC.
2026-02-04 | FMR1 RNA interaction with DNMT1 blocks DNA methylation at the FMR1 locus.
In the FMR1 gene, expansion of the CGG triplet beyond 200 repeats triggers DNA methylation, resulting in the Fragile X Syndrome (FXS). There exist rare individuals who carry a CGG expansion >200 that remains unmethylated, rescuing them from expressing the FXS phenotype. We tested the hypothesis that active FMR1 transcription regulates DNA methylation of the locus through the binding of its mRNA to DNMT1 enzyme. Our results show that DNMT1 binds FMR1-mRNA in transcriptionally active cells preventing them from being methylated, whereas it binds to the FMR1 locus in FXS cells, resulting in gene silencing. DNMT1 binds to the transcript or to the locus after reactivating or blocking FMR1 transcription using specific drugs, respectively. As proof of concept, aptamers capable of binding and inhibiting DNMT1 were shown to reactivate the silenced FMR1 gene. We propose that DNMT1 represents a specific molecular target to reactivate the FMR1 gene expression.
2025-12-11 | IGF2BPs directly regulate the noncanonical translation of toxic proteins from mutant FMR1 mRNA containing expanded CGG repeats.
Mutant mRNA of the fragile X messenger ribonucleoprotein 1 gene (FMR1) containing expanded CGG repeats in its 5'UTR is a primary cause of fragile X premutation associated conditions. It serves as a template for the biosynthesis of the major open reading frame encoding canonical protein and the downstream open reading frame containing expanded CGG repeats encoding toxic FMRpolyG protein that comprise a long polyglycine stretch, produced via repeat-associated non-AUG initiated translation. Here, we show that insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) binds directly to the 5'UTR of FMR1 RNA, and the sequence in the vicinity of near-cognate start codons of non-AUG translation is pivotal for IGF2BP3 binding. Upon IGF2BP3's knockdown, FMRpolyG biosynthesis and cell toxicity evoked by FMRpolyG, significantly decreased in cells expressing mutant FMR1 with expanded CGG repeats. Disruption of IGF2BP ortholog in novel fragile X premutation associated conditions C. elegans model rescues the disease phenotype induced by expression of a human FMR1 RNA fragment containing expanded CGG repeats. Our results suggest that IGF2BP3 positively regulates the noncanonical translation of expanded CGG repeats and may be a promising target for clinical applications.
2025-11-17 | RNA-based therapies for neurodevelopmental disorders: innovative tools for molecular correction.
Modulation of RNA and protein expression to restore or normalize neuronal function has emerged as a powerful therapeutic strategy for neurodevelopmental disorders (NDDs) tailoring individual genetic mutations causing intellectual disability (ID), or autism spectrum disorder (ASD), or developmental epileptic encephalopathy (DEE). In recent years, diverse classes of RNA-based molecules have been developed with therapeutic potential, including antisense oligonucleotides (ASOs), oligonucleotides targeting natural antisense transcripts (antagoNATs), Short Interspersed Nuclear Element UP-regulating RNAs (SINEUPs), interfering RNAs (RNAi), Exon-Specific engineering U1 small nuclear RNAs (ExSpeU1s), and small-activating RNA (saRNA) This review highlights the promising advances of these RNA-based therapeutics in addressing syndromic ID, such as Fragile X syndrome, MECP2 duplication syndrome, FOXG1-gene related Rett syndrome and Angelman syndrome, which are characterized by well-defined genetic mutations with limited treatment options. Moreover, ASD-related condition linked to mutations in CHD8 is under investigation, extending the therapeutic landscape to complex behavioral and cognitive disorders. In the same way, several DEEs caused by mutations in CDKL5, DNM1, KCNT1, SCN1A, SCN2A, SCN8A, and UBA5 genes, which present severe pharmaco-resistant epilepsy, are increasingly becoming targets for RNA molecules that aim to restore neuronal excitability and network function. Together, these findings underscore the expanding therapeutic landscape enabled by RNA technologies, offering unprecedented specificity and flexibility for gene-targeted interventions in NDDs. As the field of RNA medicine continues to evolve across genomics and neuroscience, we aim to provide a resource for researchers and clinicians on promising innovative tools for molecular correction.
proteins
2026-05-01 | Cerebral Cortex Morphometry and Relaxometry in Male Children With Fragile X Syndrome and Autism.
An estimated 30%-50% of male individuals with fragile X syndrome (FXS) meet criteria for autism spectrum disorder (ASD), indicating phenotypic overlap but potentially distinct neurobiology. Here, we aimed to characterize shared and divergent cortical features between FXS and ASD. High-resolution, motion-corrected quantitative MRI was used to compare cortical morphometry and relaxometry in 61 male participants (9-18 years) with FXS or ASD. To increase power, ASD participants were pooled from multiple MPnRAGE studies and harmonized across protocols using ComBat. Cortical thickness and R1 (longitudinal relaxation rate; proxy for myelination) were computed across the cerebral cortex. Relative to ASD, FXS exhibited greater cortical thickness predominantly in early sensory cortices implicated in low-level visual and auditory processing spanning occipital, parietal, and temporal regions. No significant group differences in R1 were found. Thicker cortex in FXS within primary and early associative sensory areas suggests divergent early sensory processing mechanisms between FXS and ASD. Characterizing different neuroanatomical features between the two disorders provides a grounding to develop more disorder-specific interventions despite similar behavioral difficulties. Future work should test developmental trajectories, include females and comorbidities, and link imaging markers to individual sensory/clinical profiles to inform and improve personalized therapies and interventions.
2026-04-29 | Lasting effects of early-life oxytocin treatment on LTP and episodic memory in a mouse model of Fragile X syndrome.
Deficits in episodic memory are a debilitating feature of Fragile X syndrome (FXS) and other congenital autism spectrum disorders (ASDs). There is evidence that oxytocin (OXT) treatments can improve sociability in persons with ASD and related animal models, encouraging the idea that benefits might extend to cognitive function. We tested this possibility in male FXS model, Fmr1-knockout (KO) mice. Intranasal treatments with OXT or saline were given daily during the second or fifth postnatal week, and effects on social behavior, spatial and episodic memory, and hippocampal synaptic plasticity were assessed in adulthood. Saline-treated Fmr1-KOs exhibited profound deficits in social recognition, object location memory, what-when-where components of episodic memory and long-term potentiation (LTP) in both the CA3-CA1 and lateral perforant path (LPP) systems; NMDAR-mediated components of LPP responses were also impaired. OXT treatments during the second week postnatal normalized all of these functions in Fmr1-KOs assessed in adulthood; this included restoration of initial stages of CA3-CA1 LTP and granule cell NMDAR-mediated currents. In hippocampal slices from naïve adult male Fmr1-KO mice, bath-applied OXT treatment restored LTP in CA1 but not the LPP, indicating pathway-specific effects. Intranasal OXT treatments during the 5th week postnatal did not have enduring effects in either genotype. The present evidence that early OXT treatment corrects a broad range of cognitive and synaptic plasticity deficits in Fmr1-KO mice identifies a clinically plausible strategy for normalizing hippocampal function in ASD and FXS, and highlights the presence of a critical developmental window for effective intervention.
2025-12-16 | Toward peptide-based protein replacement in fragile X syndrome: Evaluating the N-tat strategy
Fragile X syndrome (FXS), a leading inherited cause of intellectual disability and autism, arises from loss of the RNA-binding protein FMRP and consequent dysregulation of synaptic mRNA translation. No clinically approved therapies exist to restore FMRP function. A recent study showed that a Tat-conjugated FMRP fragment spanning residues 1–297 (FMRP N-tat) can transiently reduce hyperexcitability in an FXS mouse model, supporting peptide replacement as a feasible therapeutic strategy. Extending this concept, Leguay et al. demonstrated in FXS patient iPSC-derived neurons that N-tat reconstitutes interactions with endogenous protein partners correcting dysregulated translation and mitochondrial defects. However, despite recapitulating several functions of full-length FMRP, the in vivo effects of N-tat remain short-lived, highlighting challenges in stability and the potential need for additional functional domains. Herein, this commentary outlines both the promise of N-tat–based protein replacement and the remaining gaps that must be addressed to achieve clinically durable restoration of FMRP function.
2025-06-07 | Interactome of FMRP-N-tat therapeutic unveils key interactions for cellular function in Fragile X neurons.
Therapeutic protein replacement has demonstrated preclinical and clinical efficacy in neurological disorders but has not been used clinically for Fragile X syndrome (FXS), a genetic neurodevelopmental disorder caused by loss of Fragile X messenger ribonucleoprotein (FMRP). FXS results from a triplet repeat expansion of more than 200 CGG repeats in the 5'-UTR of the FMR1 gene leading to epigenetic silencing of FMRP. Currently, no clinically approved disease-modifying treatments for FXS exist. Recently, a tat-conjugated FMRP fragment encompassing residues 1 to 297 (FMRP N-tat) was shown to restore aspects of neuronal function in a mouse model of FXS. Promising in vivo data hinted to the therapeutic potential of FMRP N-tat. Herein, affinity purification mass spectrometry was used to identify the FMRP N-tat interactome in tsA-201 FMR1 knockout cells and FXS patient iPSC-derived neurons. The FMRP N-tat interactome included RNA binding proteins and constituents of the ribosome, which aligned closely with the known functions of FMRP. Further, the FMRP N-tat associated proteins included FXR2, STAU1, TRIM28, C1QBP, VDAC2, and several ribosomal proteins to regulate mRNA stability, cellular stress responses, mitochondrial function, and translation. The results highlight the potential of FMRP N-tat to orchestrate assembly of factors to correct lost function in FMRP deficient cells.
2025-04-07 | Soy-based purified ingredient diet affects mouse gut permeability and the microbiome in fragile X mice.
Gastrointestinal problems including vomiting, reflux, flatulence, diarrhea, constipation and colic are common comorbidities in fragile X syndrome. There is accumulating evidence suggesting that leaky gut syndrome causes neurological phenotypes. Although fragile X messenger ribonucleoprotein is ubiquitously expressed, there is a dearth of knowledge regarding its role outside of the brain including effects on gut dysfunction in fragile X. The aim of this study was to generate novel data on gastrointestinal barrier function and the gut microbiome in response to Fmr1 genotype, sex and diet in mice. Fmr1KO male mice and littermate controls in an FVB background were maintained on two purified ingredient diets (AIN-93G with casein protein versus soy protein isolate) versus two standard chows (Teklad 2019 with wheat, corn and yeast protein versus Purina 5015 with wheat, soy, corn, yeast and whey protein sources). Gut permeability was quantified by FITC-dextran levels in blood plasma. The cecal microbiome was identified by 16S rRNA sequencing. In addition, gut permeability was tested in Fmr1KO mice in the C57BL/6 J background maintained on casein- and soy protein isolate-based AIN-93G versus Teklad 2019. Knockout of the Fmr1 gene in FVB mice did not affect gut permeability. Soy protein isolate-based AIN-93G increased gut permeability. Beta-diversity of the cecal microbiome was significantly altered as a function of the four test diets. Akkermansia_muciniphila was increased in Fmr1KO mice fed AIN-93G while unnamed species within the genus Anaerovorax and family Ruminococcaceae were increased and the order Clostridales decreased in Fmr1KO mice fed AIN-93G/soy. Fmr1KO mice in the C57BL/6 J background exhibited increased gut permeability in response to soy protein. These findings regarding the effects of diet on gut permeability and the microbiome have important implications for experimental design. Single-source diets are ubiquitously used to maintain laboratory animals for medical research and feed details are frequently not reported in publications. Diet/phenotype interactions could have a large impact on inter-laboratory replicability in premedical research. For infants with fragile X, early-life diet could impact the severity of disease outcomes.
gene therapies
2026-08-26 | Statistical power in UK genetic syndrome research; evidence from studies of Down syndrome, Fragile X syndrome and Williams syndrome as model syndrome groups.
Research on genetic syndromes is vital to our understanding of how development unfolds, but the rarity of genetic syndromes can mean that studies are carried out with small sample sizes. Small sample sizes can reduce the statistical power of a study to produce reliable and replicable results. Here, we review all UK journal articles on three target genetic syndromes published from 2013 to 2022. There were 368 eligible articles. The median sample size of genetic syndrome groups was N = 30, and only 6.5% of articles reported a power analysis. Power analysis was performed on the 123 articles classed as 'Cognitive' research, as a test case. This demonstrated an average power of only 54% for a medium effect size and an alpha of 0.05. This is well below the recommended threshold of 80% power. The low power of UK genetic syndrome research has consequences for the replicability of the field due to the risk of Type II errors and reduced precision in effect size estimates, as well as implications for the communities that this research seeks to serve. We provide suggestions for researchers, journal editors and funders for improving the replicability of the field of genetic syndrome research.
2026-07-11 | FMR1 gene therapy restores translationally relevant phenotypes in a mouse model for fragile X syndrome.
Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability. It is caused by a trinucleotide expansion in the 5' UTR of the Fragile X messenger ribonucleoprotein 1 (FMR1) gene leading to loss of expression of Fragile X messenger ribonucleoprotein (FMRP). There is currently no cure for FXS. We developed an FMR1 gene therapy based on an adeno-associated viral vector designed with strong translational potential for future clinical testing. The viral vector was tested in Fmr1 knockout mice using two translationally relevant delivery routes and ages corresponding to in utero, toddler, and adolescent ages in humans. Functional studies showed that the FMR1 gene therapy improved select translational FXS phenotypes spanning three critical domains: sensory hyperexcitability, adaptation to change, and altered brain activity. Expression after intracerebroventricular injection was most prominent in the forebrain, whereas intravenous delivery predominantly led to expression across midbrain and brainstem, suggesting that a dual route may be needed to achieve full brain coverage. Biodistribution analyses further suggested that FMRP expression must be titrated carefully for optimal rescue. In summary, we show that FMR1 gene therapy using delivery routes and vehicles approved for clinical use improves core phenotypes in a mouse model for FXS.
2026-07-02 | Neonatal expression of human FMRP isoform corrects cortical deficits and improves behavior in a mouse model of fragile X syndrome.
Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by CGG trinucleotide repeat expansion in the fragile X messenger ribonucleoprotein 1 (FMR1) gene and the resulting loss of fragile X messenger ribonucleoprotein (FMRP). Gene therapy using recombinant adeno-associated virus (AAV) to restore FMRP expression, particularly in the brain, is a promising therapeutic strategy targeting the underlying cause of FXS. We examined the impact of AAV serotype 9 (AAV9)-mediated expression of a brain-abundant human FMRP isoform (isoform 7) driven by a fragment of the human FMR1 promoter on circuit and behavioral dysfunctions in the male Fmr1 knockout (KO) mouse, FXS model. Following intracerebroventricular (i.c.v.) injection of AAV9-NG276 into neonatal KO mice at a low (1e11 vg/animal) or high (3e11 vg/animal) dose, we assessed cortical phenotypes using electroencephalography (EEG) recordings and behavioral testing. High-dose AAV9-NG276 normalized baseline gamma power, improved sound-evoked responses, and reduced background neural activity. Analysis of behavioral deficits in adult KO mice showed that high-dose neonatal AAV9-NG276 delivery normalized exploratory behaviors, social preference, and probabilistic reversal learning. Thus, early AAV-mediated delivery of human FMR1 isoform 7 ameliorates cortical dysfunction and behavioral deficits in a murine FXS model and suggests that widespread cortical biodistribution is required for therapeutic benefit.
2026-06-11 | Recognizing repeat expansion disorders in clinical practice.
Repeat expansion disorders are caused by unstable DNA sequences that exceed pathogenic thresholds, disrupting normal gene function. These conditions often affect the nervous system, but may involve multiple organs, with presentations ranging from subtle cognitive or motor changes to overt neuromuscular or neurodevelopmental syndromes. Early symptoms can mimic common conditions, making clinical suspicion, family history, and awareness of intergenerational patterns essential. Molecular features, including repeat size, sequence, location and stability, determine disease severity and variability. Nurse practitioners are well positioned to recognize early signs, make early referrals to genetics, and support families with education, anticipatory guidance, and coordination of follow-up care. Case examples include Huntington disease, fragile X syndrome, and myotonic dystrophy and illustrate clinical heterogeneity, premutation effects, and genetic anticipation. Early recognition and referral remain crucial, particularly as emerging gene-targeted therapies may offer potential disease-modifying options.
2026-04-23 | Suppression of astrocyte BMP signaling improves molecular signatures and functional deficits in a fragile X syndrome mouse model.
Fragile X syndrome (FXS) is a monogenic neurodevelopmental disorder with molecular, neuroanatomical, and behavioral changes. In FXS, astrocytes express dysregulated gene and protein networks, therefore identifying upstream pathways mediating astrocyte changes may provide a point of intervention. We focus on the bone morphogenetic protein (BMP) pathway, which is upregulated in FXS astrocytes. We generated a conditional KO (cKO) of Smad4 in astrocytes to suppress BMP signaling, finding that this lessens audiogenic seizure severity in male FXS mice. We performed in vivo transcriptomic and proteomic profiling of cortical astrocytes, finding upregulation of metabolic pathways, and downregulation of secretory machinery and secreted and membrane proteins in FXS astrocytes, with these alterations mitigated when BMP signaling is suppressed. Functionally, astrocyte Smad4 cKO restores deficits in inhibitory synapses in the FXS auditory cortex. Our findings show that astrocytes contribute to some FXS mouse molecular and functional phenotypes, and targeting astrocyte BMP signaling improves some FXS symptoms.
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2025-01-17 | GABAergic Progenitor Cell Graft Rescues Cognitive Deficits in Fragile X Syndrome Mice.
Fragile X syndrome (FXS) is an inherited neurodevelopmental disorder characterized by a range of clinical manifestations with no effective treatment strategy to date. Here, transplantation of GABAergic precursor cells from the medial ganglionic eminence (MGE) is demonstrated to significantly improve cognitive performance in Fmr1 knockout (KO) mice. Within the hippocampus of Fmr1-KO mice, MGE-derived cells from wild-type donor mice survive, migrate, differentiate into functionally mature interneurons, and form inhibitory synaptic connections with host pyramidal neurons. MGE cell transplantation restores Ras-PKB signaling in pyramidal neurons, enhances AMPA receptor trafficking, rescues synaptic plasticity, and corrects abnormal hippocampal neural oscillations. These findings highlight the potential of GABAergic precursor cell transplantation as a promising therapeutic strategy for FXS.
2022-12-05 | Fragile X Syndrome Patient-Derived Neurons Developing in the Mouse Brain Show FMR1-Dependent Phenotypes.
Fragile X syndrome (FXS) is characterized by physical abnormalities, anxiety, intellectual disability, hyperactivity, autistic behaviors, and seizures. Abnormal neuronal development in FXS is poorly understood. Data on patients with FXS remain scarce, and FXS animal models have failed to yield successful therapies. In vitro models do not fully recapitulate the morphology and function of human neurons. To mimic human neuron development in vivo, we coinjected neural precursor cells derived from FXS patient-derived induced pluripotent stem cells and neural precursor cells derived from corrected isogenic control induced pluripotent stem cells into the brain of neonatal immune-deprived mice. The transplanted cells populated the brain and a proportion differentiated into neurons and glial cells. Immunofluorescence and single and bulk RNA sequencing analyses showed accelerated maturation of FXS neurons after an initial delay. Additionally, we found increased percentages of Arc- and Egr-1-positive FXS neurons and wider dendritic protrusions of mature FXS striatal medium spiny neurons. This transplantation approach provides new insights into the alterations of neuronal development in FXS by facilitating physiological development of cells in a 3-dimensional context.
2022-08-23 | A genetic labeling system to study dendritic spine development in zebrafish models of neurodevelopmental disorders.
Dendritic spines are the principal site of excitatory synapse formation in the human brain. Several neurodevelopmental disorders cause spines to develop abnormally, resulting in altered spine number and morphology. Although spine development has been thoroughly characterized in the mammalian brain, spines are not unique to mammals. We have developed a genetic system in zebrafish to enable high-resolution in vivo imaging of spine dynamics during larval development. Although spiny neurons are rare in the larval zebrafish, pyramidal neurons (PyrNs) of the zebrafish tectum form an apical dendrite containing a dense array of dendritic spines. To characterize dendritic spine development, we performed mosaic genetic labeling of individual PyrNs labeled by an id2b:gal4 transgene. Our findings identify a developmental period during which PyrN dendrite growth is concurrent with spine formation. Throughout this period, motile, transient filopodia gradually transform into stable spines containing postsynaptic specializations. The utility of this system to study neurodevelopmental disorders was validated by examining spine development in fmr1 mutant zebrafish, a model of fragile X syndrome. PyrNs in fmr1 mutants exhibited pronounced defects in dendrite growth and spine stabilization. Taken together, these findings establish a genetic labeling system to study dendritic spine development in larval zebrafish. In the future, this system could be combined with high-throughput screening approaches to identify genes and drug targets that regulate spine formation.
2020-12-04 | The effect of fecal microbiota transplantation on autistic-like behaviors in Fmr1 KO mice.
The importance of alterations in bidirectional communication between gut and brain has become obvious in neuropsychiatric disorders. Gastrointestinal (GI) disturbances are very common in autism spectrum disorders (ASD), and the GI microbiota profiles in children with ASD are significantly different from those in the general population. Fragile X syndrome (FXS) is an inheritable developmental disability in humans, and patients with FXS exhibit autistic behaviors such as mental retardation and impaired social communication or interaction. We hypothesized that an increase in specific gut microbiota by fecal microbiota transplantation (FMT) would mitigate autistic-like behaviors. To test this hypothesis, we measured the effects of FMT from normal mice to Fmr1 KO mice on autistic-like behaviors using several behavioral tests. Because the amounts of A. muciniphila in Fmr1 KO mice was very low, we assessed A. muciniphila population, tested the expression of MUC2, and analyzed goblet cells in the gut after the FMT. We found that FMT ameliorated autistic-like behaviors, especially memory deficits and social withdrawal, and we observed that the levels of A. muciniphila were normalized to wild-type levels. In addition, FMT attenuated the increased levels of TNFα and Iba1 in the brains of Fmr1 KO mice. These results suggest that FMT could be a useful tool for the treatments of cognitive deficits and social withdrawal symptoms observed in FXS or ASD because it increases the population of A. muciniphila and decreases TNFα and Iba1 levels.
2020-11-09 | Advances in Human Stem Cells and Genome Editing to Understand and Develop Treatment for Fragile X Syndrome.
Fragile X syndrome (FXS), the most common genetic form of autism spectrum disorder, is caused by deficiency of the fragile X mental retardation protein (FMRP). Despite extensive research using animal models, understanding how FMRP regulates human brain development and function remains a major challenge. Human pluripotent stem cells (hPSCs) offer powerful platforms for studying mechanisms of human diseases and for evaluating potential treatments. Genome editing, particularly the CRISPR/Cas9-based method, is highly effective for generating models to study genetic human diseases. Here we summarize how hPSCs and genome editing provide much-needed models for studying the genetic underpinnings, cellular mechanisms, and neuropathology that are unique to human FXS. The use of hPSCs and genome editing also provides an essential platform for therapeutic development in FXS.
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Drug Discovery Landscape
53 orphan drug designations for Fragile X syndrome.
53 orphan drug designations for Fragile X syndrome.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
alkanoylamine derivative selective modulator of a Class A G protein coupled receptor | small molecules | FDA | GEXVal Inc. | |
(R)-3-(5-Dimethylcarbamoyl-pent-1-enyl)-N-(2-hydroxy-1methylethyl)benzamide | small molecules | EMA | — | Somerville Development Partners B.V. |
3-Chloro-4-fluorophenyl-[4-fluoro-4-[[(5-methylpyrimidin-2-ylmethyl) amino]methyl]piperidin-1-yl]methanone | small molecules | FDA | Neurolixis, Inc. | |
small molecule modulator of large conductance, calcium-activated potassium (BK, KCa1.1) channels | small molecules | FDA | — | Servier Pharmaceuticals LLC |
3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methylpyrimidin-2-ylmethyl)amino)methyl)piperidin-1yl)methanone | small molecules | EMA | — | Neurolixis |
(R) 3-(5-Dimethylcarbamoyl-pent-1-enyl)-N-(2-hydroxy-1- methylethyl) benzamide | small molecules | FDA | Spinogenix, Inc. | |
Zatolmilast | small molecules | EMA | Shionogi B.V. | |
5,5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2,4-dione | small molecules | EMA | — | Quality Regulatory Clinical Ireland Limited |
blarcamesine | small molecules | FDA | — | Anavex Life Sciences Corp. |
Lisuride Maleate | small molecules | FDA | — | NeuroVenti Inc. |
replication-incompetent adeno-associated virus serotype 9 vector encoding the human fragile x mental retardation 1 gene | gene therapies | FDA | — | Cincinnati Children's Hospital |
Ibudilast | small molecules | FDA | — | Healx Limited |
4-(3-cyano-6-ethoxyquinolin-2-yl)-N- (2-fluorophenyl)-1,4-diazepane-1-carbothiomide | small molecules | FDA | — | Neuronascent, Inc. |
Ibudilast | small molecules | EMA | — | Healx Technology Limited |
Codergocrine mesilate, oxitriptan | small molecules | EMA | Purposeful I.K.E. | |
Cannabidiol | small molecules | EMA | QbD Flanders | |
Psilocybin | small molecules | FDA | Nova Mentis Life Science Corp. | |
Psilocybine | small molecules | EMA | Comac Medical Ltd. | |
2-[4-[3-(methylamino)-1-phenylpropoxy]phenyl]ethanol hydrochloride | small molecules | EMA | Connecta Therapeutics S.L. | |
Sulindac | small molecules | FDA | Healx Limited | |
Sulindac | small molecules | EMA | Healx Technology Limited | |
Balipodect | small molecules | FDA | — | Takeda Development Center Americas, Inc. |
Balipodect | small molecules | EMA | — | Takeda Pharma A/S |
alpha tocopherol and ascorbic acid | small molecules | FDA | GenCo Pharmaceuticals LLC | |
zatolmilast | small molecules | FDA | Tetra Discovery Partners, Inc. | |
Cannabidivarin | small molecules | EMA | — | Jazz Pharmaceuticals Ireland Limited |
Gaboxadol | small molecules | FDA | Healx Limited | |
5,5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2,4-dione | small molecules | FDA | — | Autifony Therapeutics Limited |
Cannabidivarin | small molecules | FDA | — | Jazz Pharmaceuticals Research UK Limited |
N-[(1R)-1-phenylethyl]-6-{1H-pyrazolo[3,4-d]pyrimidin-4-yl}quinazolin-2-amine [SOL 784] | small molecules | EMA | — | Propharma Group The Netherlands B.V. |
Alpha-tocopherol and ascorbic acid | small molecules | EMA | Advanced Medical Projects | |
ganaxolone | small molecules | FDA | Marinus Pharmaceuticals | |
Pyridoxine and L-pyroglutamic acid | small molecules | EMA | — | FGK Representative Service Ltd |
cannabidiol | small molecules | FDA | Harmony Biosciences Management, Inc. | |
(3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one | small molecules | FDA | — | Centre National de la Recherche Scientifique (CNRS) |
Glycyl-L-2-methylprolyl-L-glutamic acid | small molecules | EMA | Voisin Consulting Life Sciences | |
bryostatin 1 | small molecules | FDA | — | Synaptogenix, Inc. |
Tideglusib | small molecules | EMA | — | AMO Pharma Limited |
(3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one | small molecules | EMA | — | Centre National de la Recherche Scientifique (CNRS) |
Acamprosate calcium | small molecules | EMA | Veristat Spain S.L. | |
metadoxine | small molecules | FDA | Alcobra, Inc. | |
Trofinetide | small molecules | FDA | ACADIA Pharmaceuticals Inc. | |
acamprosate | small molecules | FDA | Confluence Pharmaceuticals, LLC | |
Mavoglurant [AFQ056] | small molecules | EMA | Novartis Europharm Limited | |
acetyl-l-carnitine | small molecules | FDA | — | Leadiant Biosciences, Inc. |
basimglurant | small molecules | FDA | Hoffmann-La Roche, Inc. | |
(-)-(3aR,4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester | small molecules | FDA | Stalicla SA | |
R-baclofen | small molecules | EMA | Lakeside Regulatory Consulting Services Ltd | |
R-4-amino-3-(4-chlorophenyl)butanoic acid | small molecules | FDA | Clinical Research Associates, LLC | |
3-fluoro-5-[5-(2-menthyl-thiazol-4-ylethylnyl)-pyridin-2-yl]-benzonitrile dihydrochloride | small molecules | FDA | Seaside Therapeutics | |
Valproate | small molecules | FDA | — | Neuropharm Ltd, |
Fenobam hydrochloride | small molecules | FDA | — | Neuropharm, Ltd. |
guanfacine | small molecules | FDA | — | Watson Laboratories, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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