ArticleHuman molecular genetics2020
Pharmacological read-through of R294X Mecp2 in a novel mouse model of Rett syndrome.
Article in Human molecular genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 28 citations in OpenAlex.
- Release factor 3 degradation enhances aminoglycoside-mediated translational readthrough at MECP2 nonsense mutations.Journal of molecular medicine (Berlin, Germany) · 2026Article
- RiboScreenBiomedicines · 2026Review
- Recent advances in epigenetic therapeutics for Rett syndrome: from mechanisms to clinical trials.Frontiers in behavioral neuroscience · 2026Review
- Exploring the complexity of MECP2 function in Rett syndrome.Nature reviews. Neuroscience · 2025Review
- Potentiation of group III metabotropic glutamate receptors positively affects neurophysiological features in a mouse model of Rett syndrome.The Journal of pharmacology and experimental therapeutics · 2025Article
- Site-blocking antisense oligonucleotides as a mechanism to fine-tune MeCP2 expression.RNA (New York, N.Y.) · 2024Article
- Testing the PEST hypothesis using relevant Rett mutations in MeCP2 E1 and E2 isoforms.Human molecular genetics · 2024Article
- Developing AAV-delivered nonsense suppressor tRNAs for neurological disorders.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Review
- Therapeutic Nonsense Suppression Modalities: From Small Molecules to Nucleic Acid-Based Approaches.Biomedicines · 2024Review
- Systematic and quantitative analysis of stop codon readthrough in Rett syndrome nonsense mutations.Journal of molecular medicine (Berlin, Germany) · 2024Article
- Analysis of the interplay between MeCP2 and histone H1 duringEpigenetics · 2023Article
- Top caregiver concerns in Rett syndrome and related disorders: data from the US natural history study.Journal of neurodevelopmental disorders · 2023Article
- Evaluation of Novel Enhancer Compounds in Gentamicin-Mediated Readthrough of Nonsense Mutations in Rett Syndrome.International journal of molecular sciences · 2023Article
- Advanced genetic therapies for the treatment of Rett syndrome: state of the art and future perspectives.Frontiers in neuroscience · 2023Review
- Exploration of group II metabotropic glutamate receptor modulation in mouse models of Rett syndrome and MECP2 Duplication syndrome.Neuropharmacology · 2022Article
- Article
- Gene therapy for Rett syndrome.Genes, brain, and behavior · 2022Article
- Rett Syndrome andNeuropsychiatric disease and treatment · 2022Review
- Profiling beneficial and potential adverse effects of MeCP2 overexpression in a hypomorphic Rett syndrome mouse model.Genes, brain, and behavior · 2022Article
- Safety and efficacy of genetic MECP2 supplementation in the R294X mouse model of Rett syndrome.Genes, brain, and behavior · 2022Article
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in Methyl-CpG-binding Protein 2 (MECP2). More than 35% of affected individuals have nonsense mutations in MECP2. For these individuals, nonsense suppression has been suggested as a possible therapeutic approach. To assess the viability of this strategy, we created and characterized a mouse model with the common p.R294X mutation introduced into the endogenous Mecp2 locus (Mecp2R294X). Mecp2R294X mice exhibit phenotypic abnormalities similar to those seen in complete null mouse models; however, these occur at a later time point consistent with the reduced phenotypic severity seen in affected individuals containing this specific mutation. The delayed onset of severe phenotypes is likely due to the presence of truncated MeCP2 in Mecp2R294X mice. Supplying the MECP2 transgene in Mecp2R294X mice rescued phenotypic abnormalities including early death and demonstrated that the presence of truncated MeCP2 in these mice does not interfere with wild-type MeCP2. In vitro treatment of a cell line derived from Mecp2R294X mice with the nonsense suppression agent G418 resulted in full-length MeCP2 protein production, demonstrating feasibility of this therapeutic approach. Intraperitoneal administration of G418 in Mecp2R294X mice was sufficient to elicit full-length MeCP2 protein expression in peripheral tissues. Finally, intracranial ventricular injection of G418 in Mecp2R294X mice induced expression of full-length MeCP2 protein in the mouse brain. These experiments demonstrate that translational read-through drugs are able to suppress the Mecp2 p.R294X mutation in vivo and provide a proof of concept for future preclinical studies of nonsense suppression agents in RTT.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.