RARE DISEASE
Proximal Xq28 duplication syndrome
Proximal Xq28 duplication syndrome
Proximal Xq28 duplication syndrome
Synonyms: MECP2 duplication syndrome, X-linked intellectual disability syndrome, Lubs type
Synonyms: MECP2 duplication syndrome, X-linked intellectual disability syndrome, Lubs type
Synonyms: MECP2 duplication syndrome, X-linked intellectual disability syndrome, Lubs type
Drug discovery
4
drugs
With orphan designations
Overview
Proximal Xq28 duplication syndrome is an X-linked disorder caused by duplications in the Xq28 region encompassing MECP2, leading to severe neurodevelopmental impairments. Males typically present with infantile hypotonia, global developmental delay, intellectual disability, progressive spasticity, seizures, recurrent infections, and gastrointestinal dysfunction. Females exhibit variable phenotypes due to skewed X-inactivation. Respiratory infections and neurological deterioration contribute to reduced life expectancy, with approximately 30% mortality before age 25 [1][7][16]. Diagnosis relies on chromosomal microarray or targeted duplication analysis [1][6].
Burden
High morbidity: Progressive spasticity (60% of males), intellectual disability (moderate-severe), and lifelong dependency [1][7].
Mortality: 27-39% die before age 25 from respiratory complications [1][17].
Significant caregiver burden due to complex needs, including mobility aids and specialized education [6][8].
Therapies
Symptomatic management: Antiepileptics for seizures, antibiotics for infections, and GI interventions (e.g., reflux management, feeding support) [3][6][8].
Multidisciplinary care: Early physical/occupational therapy, respiratory support, and scoliosis monitoring [1][6][17].
No disease-modifying therapies; genetic counseling recommended for family planning [1][8].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases
Research Papers
99 drug discovery papers about Proximal Xq28 duplication syndrome, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
99 drug discovery papers about Proximal Xq28 duplication syndrome, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-01-07 | MECP2 Duplication Uncouples Mitochondrial and Purine Metabolism During neuronal maturation.
Mitochondria and nucleotide metabolism are critical for cellular and developmental homeostasis, yet their potential interdependence and role in neurodevelopmental disease remain unclear. In MECP2 Duplication Syndrome (MDS), we identify a conserved correlation between mitochondrial function and purine metabolism that is disrupted across human, organoid, and mouse models. Multiomics integration reveals Complex III as the focal point of mitochondrial collapse, leading to redox stress, DNA damage, and hyperactivation of the de novo purine biosynthesis via purinosome assembly. The breakdown of mitochondria-purinosome coupling compromises genome stability, impairs radial glia proliferation, and delays neuronal maturation. By linking a defined genetic dosage imbalance to metabolic network failure, our study positions the mitochondria-purinosome coordination as a fundamental control axis for neurodevelopment and a therapeutic entry point across metabolic and neurodevelopmental disorders.
2025-12-18 | Mesodermal-specific MECP2 expression in Drosophila induces visceral and skeletal muscle defects rescued by butyrate supplementation
Abstract Background Patients affected by Rett syndrome (RTT) and MECP2 duplication syndrome (MDS) experience disabling muscle weakness and gastrointestinal dysmotility of unclear origin. Whether these defects arise cell-autonomously, rather than secondarily to neural dysfunction, and which developmental windows are most vulnerable to MeCP2 disfunction remains unresolved. MeCP2 is a dosage-sensitive transcriptional regulator, whose functions are tightly linked to chromatin states. Because short-chain fatty acids (SCFAs) are known to inhibit histone deacetylases (HDACs), a tractable in vivo model is needed to test the effect of HDAC modulation on muscle defects. Methods We misexpressed human MECP2 in the Drosophila melanogaster mesoderm that gives rise to skeletal and visceral muscles. We analyzed quantitatively their morphology and function. To assess the effects of SCFA supplementation, we also supplemented diets with sodium butyrate (NaB), Lalbaay®, a NaB-containing supplement, acetate (AcOH), and valproate (VPA). Findings MECP2 misexpression caused pre-eclosion lethality, thinning of larval skeletal fibers with nuclear mispositioning and altered mitochondria. Functionally, it reduced locomotion, decreased food transit and gut peristalsis. Phenotypes were strongest when expression began during development. NaB and VPA supplementation rescue most of these phenotypes, consistent with their histone-deacetylase (HDAC) activity. Defects were not observed upon comparable misexpression of an RTT-associated MeCP2 loss-of-function variant, indicating that they might be relevant to pathogenesis of MECP2-related disorders. Interpretation Our genetic in vivo analysis models peripheral effects of MeCP2 dysregulation and their amelioration, supporting the possibility of HDAC-targeted strategies for MECP2-related muscle and gastrointestinal dysfunction.
2025-11-24 | Reciprocal regulation of the H3 histamine receptor in Rett syndrome and MECP2 Duplication syndrome: implications for therapeutic development.
Rett syndrome (RTT) and MECP2 Duplication syndrome (MDS) are disorders caused by reciprocal decreases and increases in the expression of the transcriptional regulator, Methyl CpG Binding Protein 2 (MeCP2). We previously performed an mRNA expression profiling study of the temporal cortex region from patients diagnosed with RTT and corresponding age, postmortem interval, and sex-matched controls. These studies identified a significant reduction in the expression of the histamine H3 receptor (HRH3). In the current manuscript, we expanded this H3 receptor profiling to additional RTT patient brain samples representing distinct MECP2 mutations and confirmed significantly reduced levels of H3 receptor expression in the majority of patients compared to controls. Using mouse models of RTT and MDS, we observed antiparallel changes in H3 receptor expression across various brain areas, with Hrh3 expression being reduced in RTT model animals and increased in a mouse model of MDS. We then evaluated both a small molecule agonist of the H3 receptor, (R)-α-methylhistamine (RAMH), and the H3 receptor inverse agonist, pitolisant (Wakix®), in RTT and MDS models, respectively, to determine impacts on phenotypes in these disease models. Our results show that RAMH significantly impacted an anxiety phenotype in mice modeling RTT (Mecp Null/+ ), but pitolisant had no effect on the behaviors examined here in MDS animals (MECP2 Tg1 ).
2024-12-19 | Structural variant allelic heterogeneity in MECP2 duplication syndrome provides insight into clinical severity and variability of disease expression.
MECP2 Duplication Syndrome, also known as X-linked intellectual developmental disorder Lubs type (MRXSL; MIM: 300260), is a neurodevelopmental disorder caused by copy number gains spanning MECP2. Despite varying genomic rearrangement structures, including duplications and triplications, and a wide range of duplication sizes, no clear correlation exists between DNA rearrangement and clinical features. We had previously demonstrated that up to 38% of MRXSL families are characterized by complex genomic rearrangements (CGRs) of intermediate complexity (2 ≤ copy number variant breakpoints < 5), yet the impact of these genomic structures on regulation of gene expression and phenotypic manifestations have not been investigated. To study the role of the genomic rearrangement structures on an individual's clinical phenotypic variability, we employed a comprehensive genomics, transcriptomics, and deep phenotyping analysis approach on 137 individuals affected by MRXSL. Genomic structural information was correlated with transcriptomic and quantitative phenotypic analysis using Human Phenotype Ontology (HPO) semantic similarity scores. Duplication sizes in the cohort ranging from 64.6 kb to 16.5 Mb were classified into four categories comprising of tandem duplications (48%), terminal duplications (22%), inverted triplications (20%), and other CGRs (10%). Most of the terminal duplication structures consist of translocations (65%) followed by recombinant chromosomes (23%). Notably, 65% of de novo events occurred in the Terminal duplication group in contrast with 17% observed in Tandem duplications. RNA-seq data from lymphoblastoid cell lines indicated that the MECP2 transcript quantity in MECP2 triplications is statistically different from all duplications, but not between other classes of genomic structures. We also observed a significant (p < 0.05) correlation (Pearson R = 0.6, Spearman p = 0.63) between the log-transformed MECP2 RNA levels and MECP2 protein levels, demonstrating that genomic aberrations spanning MECP2 lead to altered MECP2 RNA and MECP2 protein levels. Genotype-phenotype analyses indicated a gradual worsening of phenotypic features, including overall survival, developmental levels, microcephaly, epilepsy, and genitourinary/eye abnormalities in the following order: Tandem duplications, Other complex duplications, Terminal duplications/Translocations, and Triplications encompassing MECP2. In aggregate, this combined analysis uncovers an interplay between MECP2 dosage, genomic rearrangement structure and phenotypic traits. Whereas the level of MECP2 is a key determinant of the phenotype, the DNA rearrangement structure can contribute to clinical severity and disease expression variability. Employing this type of analytical approach will advance our understanding of the impact of genomic rearrangements on genomic disorders and may help guide more targeted therapeutic approaches.
2024-10-08 | USP15 inhibits hypoxia-induced IL-6 signaling by deubiquitinating and stabilizing MeCP2.
Methyl-CpG binding protein 2 (MeCP2) is an important X-linked DNA methylation reader and a key heterochromatin organizer. The expression level of MeCP2 is crucial, as indicated by the observation that loss-of-function mutations of MECP2 cause Rett syndrome, whereas an extra copy spanning the MECP2 locus results in MECP2 duplication syndrome, both being progressive neurodevelopmental disorders. Our previous study demonstrated that MeCP2 protein expression is rapidly induced by renal ischemia-reperfusion injury (IRI) and protects the kidney from IRI through transcriptionally repressing the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 signaling pathway. However, the mechanisms underlying the upregulation of MeCP2 have remained elusive. Here, by using two hypoxia cell models, hypoxia and reoxygenation and cobalt chloride stimulation, we confirmed that the removal of lysine 48-linked ubiquitination from MeCP2 prevented its proteasome-dependent degradation under hypoxic conditions. Through unbiased screening based on a deubiquitinating enzymes library, we identified ubiquitin-specific protease 15 (USP15) as a stabilizer of MeCP2. Further studies revealed that USP15 could attenuate hypoxia-induced MeCP2 degradation by cleaving lysine 48-linked ubiquitin chains from MeCP2, primarily targeting its C-terminal domain. Consistently, USP15 inhibited hypoxia-induced signal transducer and activator of transcription 3 activation, resulting in reduced transcription of IL-6 downstream genes. In summary, our study reveals an important role for USP15 in the maintenance of MeCP2 stability and the regulation of IL-6 signaling.
gene therapies
2026-01-15 | Functional skills in MECP2 duplication syndrome: developmental dynamics and regression.
MECP2 duplication syndrome (MDS) is an ultrarare, X-linked neurodevelopmental disorder that is poorly understood in terms of its natural history and phenotypic variability. There is limited information on how individuals with MDS acquire, retain or lose fundamental functional skills (gross motor, purposeful hand function and communication) - that of which this study aimed to better characterise in the largest case series to date.For 160 individuals with MDS (median age 9.06 y, range: 0.57-51.63 y; 84% male), we report that phenotypic penetrance in females can, in some, result in a similar functional skill deficits to males. However, a higher proportion of females acquired gross motor and fine motor skills compared to males. Use of words was the most common parent-reported skill regression (34/90 [38%]) followed by fine motor/hand function (26/90 [29%]), independent walking (25/90 [28%]) and feeding (25/90 [28%]). Additionally, lower proportions of functional ability were present in those with seizures compared to those without. A general trend was also observed for decreasing functional skills with increasing age. Additionally, those with a larger duplication length (1 + Mb) were less likely to be able to acquire independent walking compared with those with less than a 1 + Mb duplication (p < 0.001).This is the first study to comprehensively map the developmental trajectory of functional skills in MDS and provides a seminal baseline for better characterising the natural history of this disorder. Further investigations are required to understand the importance of interventional therapy on the retainment of functional skills.
2024-12-13 | An RNA editing strategy rescues gene duplication in a mouse model of MECP2 duplication syndrome and nonhuman primates.
Duplication of methyl-CpG-binding protein 2 (MECP2) gene causes MECP2 duplication syndrome (MDS). To normalize the duplicated MECP2 in MDS, we developed a high-fidelity Cas13Y (hfCas13Y) system capable of targeting the MECP2 (hfCas13Y-gMECP2) messenger RNA for degradation and reducing protein levels in the brain of humanized MECP2 transgenic mice. Moreover, the intracerebroventricular adeno-associated virus (AAV) delivery of hfCas13Y-gMECP2 in newborn or adult MDS mice restored dysregulated gene expression and improved behavior deficits. Notably, treatment with AAV9-hfCas13Y-gMECP2 extended the median survival of MECP2 transgenic mice from 156.5 to 226 d. Furthermore, studies with monkeys showed a single injection of AAV9-hfCas13Y-gMECP2 was sufficient to drive robust expression of hfCas13Y in widespread brain regions, with MECP2 knockdown efficiency reaching 52.19 ± 0.03% and significantly decreased expression of biomarker gene GDF11. Our results demonstrate that the RNA-targeting hfCas13Y-gMECP2 system is an effective intervention for MDS, providing a potential strategy for treating other dosage-sensitive diseases.
2024-11-12 | Multi-gene duplication removal in an engineered human cellular MECP2 duplication syndrome model with an IRAK1-MECP2 duplication.
Recent progress in genome editing technologies has catalyzed the generation of sophisticated cell models; however, the precise modeling of copy-number variation (CNV) diseases remains a significant challenge despite their substantial prevalence in the human population. To overcome this barrier, we have explored the utility of HAP1 cells for the accurate modeling of disease genomes with large structural variants. As an example, this study details the strategy to generate a novel cell line that serves as a model for the neurological disorder methyl CpG binding protein 2 (MECP2) duplication syndrome (MDS), featuring the critical duplication of both the MECP2 and IRAK1 genes. This model faithfully recapitulates MDS genomic rearrangement, allowing for the mechanistic study of gene overexpression and the development of therapeutic interventions. Employing a single-guide RNA (gRNA) CRISPR-Cas9 strategy, we successfully excised the duplicated genomic segment, notably halving both MECP2 and IRAK1 expression levels. The evidence establishes our model as a crucial tool for research into MDS. Furthermore, the outlined workflow is readily adaptable to model other CNV disorders and subsequently test genomic and pharmacological interventions.
2024-02-29 | Overcoming genetic and cellular complexity to study the pathophysiology of X-linked intellectual disabilities
Abstract X-linked genetic causes of intellectual disability (ID) account for a substantial proportion of cases and remain poorly understood, in part due to the heterogeneous expression of X-linked genes in females. This is because most genes on the X chromosome are subject to random X chromosome inactivation (XCI) during early embryonic development, which results in a mosaic pattern of gene expression for a given X-linked mutant allele. This mosaic expression produces substantial complexity, especially when attempting to study the already complicated neural circuits that underly behavior, thus impeding the understanding of disease-related pathophysiology and the development of therapeutics. Here, we review a few selected X-linked forms of ID that predominantly affect heterozygous females and the current obstacles for developing effective therapies for such disorders. We also propose a genetic strategy to overcome the complexity presented by mosaicism in heterozygous females and highlight specific tools for studying synaptic and circuit mechanisms, many of which could be shared across multiple forms of intellectual disability.
2022-10-06 | MeCP2 regulates Gdf11, a dosage-sensitive gene critical for neurological function
ABSTRACT Loss- and gain-of-function of MeCP2 causes Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively. MeCP2 binds methyl-cytosines to finely tune gene expression in the brain, though identifying genes robustly regulated by MeCP2 has been difficult. By integrating multiple transcriptomics datasets, we identified that MeCP2 finely regulates Growth differentiation factor 11 ( Gdf11). Gdf11 is down-regulated in RTT mouse models and is inversely up-regulated in MDS mouse models. Strikingly, genetically normalizing Gdf11 dosage levels improved several behavioral deficits in a mouse model of MDS. Next, we discovered that losing one copy of Gdf11 alone was sufficient to cause multiple neurobehavioral deficits in mice, most notably hyperactivity and decreased learning and memory. This decrease in learning and memory was not due to changes in proliferation or numbers of progenitor cells in the hippocampus. Lastly, loss of one copy of Gdf11 decreased longevity and survival in mice, corroborating its putative role in aging. Our data demonstrate that Gdf11 dosage is important for brain function.
oligonucleotides
2026-07-22 | Single-dose administration of therapeutic divalent siRNA targeting MECP2 prevents lethality in an MECP2 duplication mouse model.
MECP2 duplication syndrome (MDS) is a rare X-linked neurodevelopmental disorder caused by duplications of the dosage-sensitive methyl-CpG-binding protein 2 (MECP2) gene. Developing therapies for MDS is challenging due to the variability in MECP2 expression among patients and the risk of inducing Rett syndrome through excessive pharmacological intervention. Reducing dosage to optimize silencing often compromises durability and necessitates increased dosing frequency. We present here a series of fully chemically modified small interfering RNAs (siRNAs) designed for isoform-selective and total Mecp2 silencing. Among these, we identify six lead siRNA candidates across two chemical scaffolds, achieving targeted total Mecp2 expression reductions ranging from 25% to 75%, sustained for at least four months following a single administration. The efficacy and safety of human ortholog silencing are evaluated using a mouse model with ~8-fold human Mecp2 transgene expression. In this severe duplication model, a single dose of the total isoform-silencing siRNA rescues early mortality and select behavioral impairments. Overall, this study introduces preclinical candidates for the treatment of MDS. Furthermore, it establishes a target selection strategy applicable to other dosage-sensitive gene imbalances.
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.
2025-05-19 | MECP2 duplication syndrome: Recent advances in pathophysiology and therapeutic perspectives.
MECP2 duplication syndrome (MDS) is an X-linked neurodevelopmental disorder caused by duplication or extra copies of MECP2 gene. It primarily affects males and is characterized by intellectual disability, hypotonia, epilepsy, recurrent infections, and autistic features. Methyl-CpG binding protein 2 (MeCP2) encoded by MECP2 is a crucial epigenetic regulator of brain function. Expression levels are strictly regulated during brain development and maturation, and altered levels lead to severe neurodevelopmental disorders; excessive levels are associated with MDS, while insufficient levels cause Rett syndrome. This review provides a comprehensive overview of the recent advances in the pathophysiology and therapeutic perspectives of MDS, focusing on its pathophysiology, clinical features, disease models, and therapeutic strategies. Advances in studies using animal and patient-derived induced pluripotent stem cells (iPSCs)-derived neuronal models have provided insights into the molecular and cellular abnormalities associated with MDS and have facilitated therapeutic development. Among the emerging treatments, antisense oligonucleotide (ASO) therapy has gained significant attention as a promising approach for selectively suppressing MeCP2 overexpression. Preclinical studies using MDS mouse models and iPSCs-derived neurons have demonstrated that ASO treatment can partially restore neuronal abnormalities and clinical trials are currently underway.
2025-04-08 | Single-dose administration of therapeutic divalent siRNA targeting MECP2 prevents lethality for one year in an MECP2 duplication mouse model.
MECP2 duplication syndrome (MDS) is a rare X-linked neurodevelopmental disorder caused by duplications of the dosage-sensitive methyl-CpG-binding protein 2 (MECP2) gene. Developing effective therapies for MDS is particularly challenging due to the variability in MECP2 expression among patients and the potential risk of inducing Rett syndrome through excessive pharmacological intervention. Reducing dosage to optimize silencing levels often compromises durability and necessitates increased dosing frequency. We present here a series of fully chemically modified small interfering RNAs (siRNAs) designed for both isoform-selective and total MECP2 silencing. Among these, we identify six lead siRNA candidates across two distinct chemical scaffolds, achieving targeted total MECP2 expression reductions ranging from 25% to 75%, sustained for at least four months following a single administration. The efficacy and safety of human ortholog silencing were evaluated using two mouse models with distinct levels of human MECP2 transgene expression. In the severe duplication model, a single dose of the total isoform-silencing siRNA fully rescued early mortality and behavioral impairments. Additionally, we show that the isoform-selective targeting strategy may be safer in mild cases of MDS where exaggerated pharmacology may lead to Rett Syndrome. Overall, this study introduces a series of preclinical candidates with the capacity to address the varying levels of MECP2 duplication encountered in clinical settings. Furthermore, it establishes a target selection strategy that may be applied to other dosage-sensitive gene imbalances.
2024-09-15 | Modeling antisense oligonucleotide therapy in MECP2 duplication syndrome human iPSC-derived neurons reveals gene expression programs responsive to MeCP2 levels.
Genomic copy-number variations (CNVs) that can cause neurodevelopmental disorders often encompass many genes, which complicates our understanding of how individual genes within a CNV contribute to pathology. MECP2 duplication syndrome (MDS or MRXSL in OMIM; OMIM#300260) is one such CNV disorder caused by duplications spanning methyl CpG-binding protein 2 (MECP2) and other genes on Xq28. Using an antisense oligonucleotide (ASO) to normalize MECP2 dosage is sufficient to rescue abnormal neurological phenotypes in mouse models overexpressing MECP2 alone, implicating the importance of increased MECP2 dosage within CNVs of Xq28. However, because MDS CNVs span MECP2 and additional genes, we generated human neurons from multiple MDS patient-derived induced pluripotent cells (iPSCs) to evaluate the benefit of using an ASO against MECP2 in a MDS human neuronal context. Importantly, we identified a signature of genes that is partially and qualitatively modulated upon ASO treatment, pinpointed genes sensitive to MeCP2 function, and altered in a model of Rett syndrome, a neurological disorder caused by loss of MeCP2 function. Furthermore, the signature contained genes that are aberrantly altered in unaffected control human neurons upon MeCP2 depletion, revealing gene expression programs qualitatively sensitive to MeCP2 levels in human neurons. Lastly, ASO treatment led to a partial rescue of abnormal neuronal morphology in MDS neurons. All together, these data demonstrate that ASOs targeting MECP2 benefit human MDS neurons. Moreover, our study establishes a paradigm by which to evaluate the contribution of individual genes within a CNV to pathogenesis and to assess their potential as a therapeutic target.
proteins
2025-02-13 | A novel approach to metabolic profiling in case models of MECP2-related disorders.
Genetic abnormalities of the MECP2 gene cause several conditions grouped under the umbrella term of MECP2-related disorders and characterized by a variety of phenotypes. We applied a functional approach to identify metabolic profiles in two patients with Rett syndrome (RTT) and one patient with MECP2 duplication syndrome (MRXSL). Such an approach is based on the Phenotype Mammalian Microarray (PM-M) technology, which is designed to assess the cellular production of energy in the presence of different compounds generating distinct metabolic environments. The findings in the three case models were compared versus 50 controls. Although the small number of samples prevented most results from reaching significant p-values when adjusted with the Benjamini-Hochberg correction, some interesting trends emerged. Some compounds indicated metabolic trends shared by the two conditions, like increased energy production in the presence of energy sources such as pectin, adenosine, and pyruvic acid, or decreased metabolic response to certain hormones. Other compounds showed opposite trends for the two disorders, like interleukin-1 beta (IL-1 beta), which caused decreased energy production in the RTT group but increased energy production in the patient with MRXSL. The response to IL-1 beta also offers valuable insights into the pathogenic mechanism and potential therapeutic approaches. The metabolic profiling of MECP2-related disorders bears a remarkable translational potential since it may be helpful to investigate the molecular abnormalities underlying the phenotypical variety in this spectrum of conditions, develop biomarkers for the identification of ideal candidates for treatments like the recently approved trofenatide, and identify potential targets for the development of novel therapeutic approaches.
small molecules
2026-01-07 | MECP2 Duplication Uncouples Mitochondrial and Purine Metabolism During neuronal maturation.
Mitochondria and nucleotide metabolism are critical for cellular and developmental homeostasis, yet their potential interdependence and role in neurodevelopmental disease remain unclear. In MECP2 Duplication Syndrome (MDS), we identify a conserved correlation between mitochondrial function and purine metabolism that is disrupted across human, organoid, and mouse models. Multiomics integration reveals Complex III as the focal point of mitochondrial collapse, leading to redox stress, DNA damage, and hyperactivation of the de novo purine biosynthesis via purinosome assembly. The breakdown of mitochondria-purinosome coupling compromises genome stability, impairs radial glia proliferation, and delays neuronal maturation. By linking a defined genetic dosage imbalance to metabolic network failure, our study positions the mitochondria-purinosome coordination as a fundamental control axis for neurodevelopment and a therapeutic entry point across metabolic and neurodevelopmental disorders.
2025-12-18 | Mesodermal-specific MECP2 expression in Drosophila induces visceral and skeletal muscle defects rescued by butyrate supplementation
Abstract Background Patients affected by Rett syndrome (RTT) and MECP2 duplication syndrome (MDS) experience disabling muscle weakness and gastrointestinal dysmotility of unclear origin. Whether these defects arise cell-autonomously, rather than secondarily to neural dysfunction, and which developmental windows are most vulnerable to MeCP2 disfunction remains unresolved. MeCP2 is a dosage-sensitive transcriptional regulator, whose functions are tightly linked to chromatin states. Because short-chain fatty acids (SCFAs) are known to inhibit histone deacetylases (HDACs), a tractable in vivo model is needed to test the effect of HDAC modulation on muscle defects. Methods We misexpressed human MECP2 in the Drosophila melanogaster mesoderm that gives rise to skeletal and visceral muscles. We analyzed quantitatively their morphology and function. To assess the effects of SCFA supplementation, we also supplemented diets with sodium butyrate (NaB), Lalbaay®, a NaB-containing supplement, acetate (AcOH), and valproate (VPA). Findings MECP2 misexpression caused pre-eclosion lethality, thinning of larval skeletal fibers with nuclear mispositioning and altered mitochondria. Functionally, it reduced locomotion, decreased food transit and gut peristalsis. Phenotypes were strongest when expression began during development. NaB and VPA supplementation rescue most of these phenotypes, consistent with their histone-deacetylase (HDAC) activity. Defects were not observed upon comparable misexpression of an RTT-associated MeCP2 loss-of-function variant, indicating that they might be relevant to pathogenesis of MECP2-related disorders. Interpretation Our genetic in vivo analysis models peripheral effects of MeCP2 dysregulation and their amelioration, supporting the possibility of HDAC-targeted strategies for MECP2-related muscle and gastrointestinal dysfunction.
2025-11-24 | Reciprocal regulation of the H3 histamine receptor in Rett syndrome and MECP2 Duplication syndrome: implications for therapeutic development.
Rett syndrome (RTT) and MECP2 Duplication syndrome (MDS) are disorders caused by reciprocal decreases and increases in the expression of the transcriptional regulator, Methyl CpG Binding Protein 2 (MeCP2). We previously performed an mRNA expression profiling study of the temporal cortex region from patients diagnosed with RTT and corresponding age, postmortem interval, and sex-matched controls. These studies identified a significant reduction in the expression of the histamine H3 receptor (HRH3). In the current manuscript, we expanded this H3 receptor profiling to additional RTT patient brain samples representing distinct MECP2 mutations and confirmed significantly reduced levels of H3 receptor expression in the majority of patients compared to controls. Using mouse models of RTT and MDS, we observed antiparallel changes in H3 receptor expression across various brain areas, with Hrh3 expression being reduced in RTT model animals and increased in a mouse model of MDS. We then evaluated both a small molecule agonist of the H3 receptor, (R)-α-methylhistamine (RAMH), and the H3 receptor inverse agonist, pitolisant (Wakix®), in RTT and MDS models, respectively, to determine impacts on phenotypes in these disease models. Our results show that RAMH significantly impacted an anxiety phenotype in mice modeling RTT (Mecp Null/+ ), but pitolisant had no effect on the behaviors examined here in MDS animals (MECP2 Tg1 ).
2024-12-19 | Structural variant allelic heterogeneity in MECP2 duplication syndrome provides insight into clinical severity and variability of disease expression.
MECP2 Duplication Syndrome, also known as X-linked intellectual developmental disorder Lubs type (MRXSL; MIM: 300260), is a neurodevelopmental disorder caused by copy number gains spanning MECP2. Despite varying genomic rearrangement structures, including duplications and triplications, and a wide range of duplication sizes, no clear correlation exists between DNA rearrangement and clinical features. We had previously demonstrated that up to 38% of MRXSL families are characterized by complex genomic rearrangements (CGRs) of intermediate complexity (2 ≤ copy number variant breakpoints < 5), yet the impact of these genomic structures on regulation of gene expression and phenotypic manifestations have not been investigated. To study the role of the genomic rearrangement structures on an individual's clinical phenotypic variability, we employed a comprehensive genomics, transcriptomics, and deep phenotyping analysis approach on 137 individuals affected by MRXSL. Genomic structural information was correlated with transcriptomic and quantitative phenotypic analysis using Human Phenotype Ontology (HPO) semantic similarity scores. Duplication sizes in the cohort ranging from 64.6 kb to 16.5 Mb were classified into four categories comprising of tandem duplications (48%), terminal duplications (22%), inverted triplications (20%), and other CGRs (10%). Most of the terminal duplication structures consist of translocations (65%) followed by recombinant chromosomes (23%). Notably, 65% of de novo events occurred in the Terminal duplication group in contrast with 17% observed in Tandem duplications. RNA-seq data from lymphoblastoid cell lines indicated that the MECP2 transcript quantity in MECP2 triplications is statistically different from all duplications, but not between other classes of genomic structures. We also observed a significant (p < 0.05) correlation (Pearson R = 0.6, Spearman p = 0.63) between the log-transformed MECP2 RNA levels and MECP2 protein levels, demonstrating that genomic aberrations spanning MECP2 lead to altered MECP2 RNA and MECP2 protein levels. Genotype-phenotype analyses indicated a gradual worsening of phenotypic features, including overall survival, developmental levels, microcephaly, epilepsy, and genitourinary/eye abnormalities in the following order: Tandem duplications, Other complex duplications, Terminal duplications/Translocations, and Triplications encompassing MECP2. In aggregate, this combined analysis uncovers an interplay between MECP2 dosage, genomic rearrangement structure and phenotypic traits. Whereas the level of MECP2 is a key determinant of the phenotype, the DNA rearrangement structure can contribute to clinical severity and disease expression variability. Employing this type of analytical approach will advance our understanding of the impact of genomic rearrangements on genomic disorders and may help guide more targeted therapeutic approaches.
2024-10-08 | USP15 inhibits hypoxia-induced IL-6 signaling by deubiquitinating and stabilizing MeCP2.
Methyl-CpG binding protein 2 (MeCP2) is an important X-linked DNA methylation reader and a key heterochromatin organizer. The expression level of MeCP2 is crucial, as indicated by the observation that loss-of-function mutations of MECP2 cause Rett syndrome, whereas an extra copy spanning the MECP2 locus results in MECP2 duplication syndrome, both being progressive neurodevelopmental disorders. Our previous study demonstrated that MeCP2 protein expression is rapidly induced by renal ischemia-reperfusion injury (IRI) and protects the kidney from IRI through transcriptionally repressing the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 signaling pathway. However, the mechanisms underlying the upregulation of MeCP2 have remained elusive. Here, by using two hypoxia cell models, hypoxia and reoxygenation and cobalt chloride stimulation, we confirmed that the removal of lysine 48-linked ubiquitination from MeCP2 prevented its proteasome-dependent degradation under hypoxic conditions. Through unbiased screening based on a deubiquitinating enzymes library, we identified ubiquitin-specific protease 15 (USP15) as a stabilizer of MeCP2. Further studies revealed that USP15 could attenuate hypoxia-induced MeCP2 degradation by cleaving lysine 48-linked ubiquitin chains from MeCP2, primarily targeting its C-terminal domain. Consistently, USP15 inhibited hypoxia-induced signal transducer and activator of transcription 3 activation, resulting in reduced transcription of IL-6 downstream genes. In summary, our study reveals an important role for USP15 in the maintenance of MeCP2 stability and the regulation of IL-6 signaling.
gene therapies
2026-01-15 | Functional skills in MECP2 duplication syndrome: developmental dynamics and regression.
MECP2 duplication syndrome (MDS) is an ultrarare, X-linked neurodevelopmental disorder that is poorly understood in terms of its natural history and phenotypic variability. There is limited information on how individuals with MDS acquire, retain or lose fundamental functional skills (gross motor, purposeful hand function and communication) - that of which this study aimed to better characterise in the largest case series to date.For 160 individuals with MDS (median age 9.06 y, range: 0.57-51.63 y; 84% male), we report that phenotypic penetrance in females can, in some, result in a similar functional skill deficits to males. However, a higher proportion of females acquired gross motor and fine motor skills compared to males. Use of words was the most common parent-reported skill regression (34/90 [38%]) followed by fine motor/hand function (26/90 [29%]), independent walking (25/90 [28%]) and feeding (25/90 [28%]). Additionally, lower proportions of functional ability were present in those with seizures compared to those without. A general trend was also observed for decreasing functional skills with increasing age. Additionally, those with a larger duplication length (1 + Mb) were less likely to be able to acquire independent walking compared with those with less than a 1 + Mb duplication (p < 0.001).This is the first study to comprehensively map the developmental trajectory of functional skills in MDS and provides a seminal baseline for better characterising the natural history of this disorder. Further investigations are required to understand the importance of interventional therapy on the retainment of functional skills.
2024-12-13 | An RNA editing strategy rescues gene duplication in a mouse model of MECP2 duplication syndrome and nonhuman primates.
Duplication of methyl-CpG-binding protein 2 (MECP2) gene causes MECP2 duplication syndrome (MDS). To normalize the duplicated MECP2 in MDS, we developed a high-fidelity Cas13Y (hfCas13Y) system capable of targeting the MECP2 (hfCas13Y-gMECP2) messenger RNA for degradation and reducing protein levels in the brain of humanized MECP2 transgenic mice. Moreover, the intracerebroventricular adeno-associated virus (AAV) delivery of hfCas13Y-gMECP2 in newborn or adult MDS mice restored dysregulated gene expression and improved behavior deficits. Notably, treatment with AAV9-hfCas13Y-gMECP2 extended the median survival of MECP2 transgenic mice from 156.5 to 226 d. Furthermore, studies with monkeys showed a single injection of AAV9-hfCas13Y-gMECP2 was sufficient to drive robust expression of hfCas13Y in widespread brain regions, with MECP2 knockdown efficiency reaching 52.19 ± 0.03% and significantly decreased expression of biomarker gene GDF11. Our results demonstrate that the RNA-targeting hfCas13Y-gMECP2 system is an effective intervention for MDS, providing a potential strategy for treating other dosage-sensitive diseases.
2024-11-12 | Multi-gene duplication removal in an engineered human cellular MECP2 duplication syndrome model with an IRAK1-MECP2 duplication.
Recent progress in genome editing technologies has catalyzed the generation of sophisticated cell models; however, the precise modeling of copy-number variation (CNV) diseases remains a significant challenge despite their substantial prevalence in the human population. To overcome this barrier, we have explored the utility of HAP1 cells for the accurate modeling of disease genomes with large structural variants. As an example, this study details the strategy to generate a novel cell line that serves as a model for the neurological disorder methyl CpG binding protein 2 (MECP2) duplication syndrome (MDS), featuring the critical duplication of both the MECP2 and IRAK1 genes. This model faithfully recapitulates MDS genomic rearrangement, allowing for the mechanistic study of gene overexpression and the development of therapeutic interventions. Employing a single-guide RNA (gRNA) CRISPR-Cas9 strategy, we successfully excised the duplicated genomic segment, notably halving both MECP2 and IRAK1 expression levels. The evidence establishes our model as a crucial tool for research into MDS. Furthermore, the outlined workflow is readily adaptable to model other CNV disorders and subsequently test genomic and pharmacological interventions.
2024-02-29 | Overcoming genetic and cellular complexity to study the pathophysiology of X-linked intellectual disabilities
Abstract X-linked genetic causes of intellectual disability (ID) account for a substantial proportion of cases and remain poorly understood, in part due to the heterogeneous expression of X-linked genes in females. This is because most genes on the X chromosome are subject to random X chromosome inactivation (XCI) during early embryonic development, which results in a mosaic pattern of gene expression for a given X-linked mutant allele. This mosaic expression produces substantial complexity, especially when attempting to study the already complicated neural circuits that underly behavior, thus impeding the understanding of disease-related pathophysiology and the development of therapeutics. Here, we review a few selected X-linked forms of ID that predominantly affect heterozygous females and the current obstacles for developing effective therapies for such disorders. We also propose a genetic strategy to overcome the complexity presented by mosaicism in heterozygous females and highlight specific tools for studying synaptic and circuit mechanisms, many of which could be shared across multiple forms of intellectual disability.
2022-10-06 | MeCP2 regulates Gdf11, a dosage-sensitive gene critical for neurological function
ABSTRACT Loss- and gain-of-function of MeCP2 causes Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively. MeCP2 binds methyl-cytosines to finely tune gene expression in the brain, though identifying genes robustly regulated by MeCP2 has been difficult. By integrating multiple transcriptomics datasets, we identified that MeCP2 finely regulates Growth differentiation factor 11 ( Gdf11). Gdf11 is down-regulated in RTT mouse models and is inversely up-regulated in MDS mouse models. Strikingly, genetically normalizing Gdf11 dosage levels improved several behavioral deficits in a mouse model of MDS. Next, we discovered that losing one copy of Gdf11 alone was sufficient to cause multiple neurobehavioral deficits in mice, most notably hyperactivity and decreased learning and memory. This decrease in learning and memory was not due to changes in proliferation or numbers of progenitor cells in the hippocampus. Lastly, loss of one copy of Gdf11 decreased longevity and survival in mice, corroborating its putative role in aging. Our data demonstrate that Gdf11 dosage is important for brain function.
oligonucleotides
2026-07-22 | Single-dose administration of therapeutic divalent siRNA targeting MECP2 prevents lethality in an MECP2 duplication mouse model.
MECP2 duplication syndrome (MDS) is a rare X-linked neurodevelopmental disorder caused by duplications of the dosage-sensitive methyl-CpG-binding protein 2 (MECP2) gene. Developing therapies for MDS is challenging due to the variability in MECP2 expression among patients and the risk of inducing Rett syndrome through excessive pharmacological intervention. Reducing dosage to optimize silencing often compromises durability and necessitates increased dosing frequency. We present here a series of fully chemically modified small interfering RNAs (siRNAs) designed for isoform-selective and total Mecp2 silencing. Among these, we identify six lead siRNA candidates across two chemical scaffolds, achieving targeted total Mecp2 expression reductions ranging from 25% to 75%, sustained for at least four months following a single administration. The efficacy and safety of human ortholog silencing are evaluated using a mouse model with ~8-fold human Mecp2 transgene expression. In this severe duplication model, a single dose of the total isoform-silencing siRNA rescues early mortality and select behavioral impairments. Overall, this study introduces preclinical candidates for the treatment of MDS. Furthermore, it establishes a target selection strategy applicable to other dosage-sensitive gene imbalances.
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.
2025-05-19 | MECP2 duplication syndrome: Recent advances in pathophysiology and therapeutic perspectives.
MECP2 duplication syndrome (MDS) is an X-linked neurodevelopmental disorder caused by duplication or extra copies of MECP2 gene. It primarily affects males and is characterized by intellectual disability, hypotonia, epilepsy, recurrent infections, and autistic features. Methyl-CpG binding protein 2 (MeCP2) encoded by MECP2 is a crucial epigenetic regulator of brain function. Expression levels are strictly regulated during brain development and maturation, and altered levels lead to severe neurodevelopmental disorders; excessive levels are associated with MDS, while insufficient levels cause Rett syndrome. This review provides a comprehensive overview of the recent advances in the pathophysiology and therapeutic perspectives of MDS, focusing on its pathophysiology, clinical features, disease models, and therapeutic strategies. Advances in studies using animal and patient-derived induced pluripotent stem cells (iPSCs)-derived neuronal models have provided insights into the molecular and cellular abnormalities associated with MDS and have facilitated therapeutic development. Among the emerging treatments, antisense oligonucleotide (ASO) therapy has gained significant attention as a promising approach for selectively suppressing MeCP2 overexpression. Preclinical studies using MDS mouse models and iPSCs-derived neurons have demonstrated that ASO treatment can partially restore neuronal abnormalities and clinical trials are currently underway.
2025-04-08 | Single-dose administration of therapeutic divalent siRNA targeting MECP2 prevents lethality for one year in an MECP2 duplication mouse model.
MECP2 duplication syndrome (MDS) is a rare X-linked neurodevelopmental disorder caused by duplications of the dosage-sensitive methyl-CpG-binding protein 2 (MECP2) gene. Developing effective therapies for MDS is particularly challenging due to the variability in MECP2 expression among patients and the potential risk of inducing Rett syndrome through excessive pharmacological intervention. Reducing dosage to optimize silencing levels often compromises durability and necessitates increased dosing frequency. We present here a series of fully chemically modified small interfering RNAs (siRNAs) designed for both isoform-selective and total MECP2 silencing. Among these, we identify six lead siRNA candidates across two distinct chemical scaffolds, achieving targeted total MECP2 expression reductions ranging from 25% to 75%, sustained for at least four months following a single administration. The efficacy and safety of human ortholog silencing were evaluated using two mouse models with distinct levels of human MECP2 transgene expression. In the severe duplication model, a single dose of the total isoform-silencing siRNA fully rescued early mortality and behavioral impairments. Additionally, we show that the isoform-selective targeting strategy may be safer in mild cases of MDS where exaggerated pharmacology may lead to Rett Syndrome. Overall, this study introduces a series of preclinical candidates with the capacity to address the varying levels of MECP2 duplication encountered in clinical settings. Furthermore, it establishes a target selection strategy that may be applied to other dosage-sensitive gene imbalances.
2024-09-15 | Modeling antisense oligonucleotide therapy in MECP2 duplication syndrome human iPSC-derived neurons reveals gene expression programs responsive to MeCP2 levels.
Genomic copy-number variations (CNVs) that can cause neurodevelopmental disorders often encompass many genes, which complicates our understanding of how individual genes within a CNV contribute to pathology. MECP2 duplication syndrome (MDS or MRXSL in OMIM; OMIM#300260) is one such CNV disorder caused by duplications spanning methyl CpG-binding protein 2 (MECP2) and other genes on Xq28. Using an antisense oligonucleotide (ASO) to normalize MECP2 dosage is sufficient to rescue abnormal neurological phenotypes in mouse models overexpressing MECP2 alone, implicating the importance of increased MECP2 dosage within CNVs of Xq28. However, because MDS CNVs span MECP2 and additional genes, we generated human neurons from multiple MDS patient-derived induced pluripotent cells (iPSCs) to evaluate the benefit of using an ASO against MECP2 in a MDS human neuronal context. Importantly, we identified a signature of genes that is partially and qualitatively modulated upon ASO treatment, pinpointed genes sensitive to MeCP2 function, and altered in a model of Rett syndrome, a neurological disorder caused by loss of MeCP2 function. Furthermore, the signature contained genes that are aberrantly altered in unaffected control human neurons upon MeCP2 depletion, revealing gene expression programs qualitatively sensitive to MeCP2 levels in human neurons. Lastly, ASO treatment led to a partial rescue of abnormal neuronal morphology in MDS neurons. All together, these data demonstrate that ASOs targeting MECP2 benefit human MDS neurons. Moreover, our study establishes a paradigm by which to evaluate the contribution of individual genes within a CNV to pathogenesis and to assess their potential as a therapeutic target.
proteins
2025-02-13 | A novel approach to metabolic profiling in case models of MECP2-related disorders.
Genetic abnormalities of the MECP2 gene cause several conditions grouped under the umbrella term of MECP2-related disorders and characterized by a variety of phenotypes. We applied a functional approach to identify metabolic profiles in two patients with Rett syndrome (RTT) and one patient with MECP2 duplication syndrome (MRXSL). Such an approach is based on the Phenotype Mammalian Microarray (PM-M) technology, which is designed to assess the cellular production of energy in the presence of different compounds generating distinct metabolic environments. The findings in the three case models were compared versus 50 controls. Although the small number of samples prevented most results from reaching significant p-values when adjusted with the Benjamini-Hochberg correction, some interesting trends emerged. Some compounds indicated metabolic trends shared by the two conditions, like increased energy production in the presence of energy sources such as pectin, adenosine, and pyruvic acid, or decreased metabolic response to certain hormones. Other compounds showed opposite trends for the two disorders, like interleukin-1 beta (IL-1 beta), which caused decreased energy production in the RTT group but increased energy production in the patient with MRXSL. The response to IL-1 beta also offers valuable insights into the pathogenic mechanism and potential therapeutic approaches. The metabolic profiling of MECP2-related disorders bears a remarkable translational potential since it may be helpful to investigate the molecular abnormalities underlying the phenotypical variety in this spectrum of conditions, develop biomarkers for the identification of ideal candidates for treatments like the recently approved trofenatide, and identify potential targets for the development of novel therapeutic approaches.
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Drug Discovery Landscape
4 orphan drug designations for Proximal Xq28 duplication syndrome.
4 orphan drug designations for Proximal Xq28 duplication syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
2'-O-(2-Methoxyethyl) modified antisense oligonucleotide against MECP2 pre-mRNA | oligonucleotides | EMA | 2025-11-21 | — | Ionis Ireland Limited |
2-O-(2-methoxyethyl)/DNA modified antisense drug that selectively targets MECP2 pre-mRNA | oligonucleotides | FDA | 2025-01-07 | — | Ionis Pharmaceuticals, Inc. |
Adeno-associated virus serotype 9 containing CRISPR/Cas13Y and guide RNA against the human MECP2 gene | gene therapies | EMA | 2024-05-24 | — | Granzer Regulatory Consulting & Services GmbH |
recombinant adeno-associated virus serotype 9 vector carrying high-fidelity Cas13Y (hfCas13Y), an RNA editor, gene expression cassette, and guide RNAs targeting human MECP2 | gene therapies | FDA | 2023-10-30 | — | Cholgene Therapeutics, Inc. |
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