ArticleHuman molecular genetics2009
Translational readthrough by the aminoglycoside geneticin (G418) modulates SMN stability in vitro and improves motor function in SMA mice in vivo.
Article in Human molecular genetics, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers, 2 of them syntheses that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
62 citing papers in PubMed, 2 syntheses or guidelines pooled it, 121 citations in OpenAlex.
- Drug treatment for spinal muscular atrophy types II and III.The Cochrane database of systematic reviews · 2020Pooled it
- Drug treatment for spinal muscular atrophy type I.The Cochrane database of systematic reviews · 2019Pooled it
- Intravenous gentamicin therapy induces functional type VII collagen in patients with recessive dystrophic epidermolysis bullosa: an open-label clinical trial.The British journal of dermatology · 2024Trial
- Release factor 3 degradation enhances aminoglycoside-mediated translational readthrough at MECP2 nonsense mutations.Journal of molecular medicine (Berlin, Germany) · 2026Article
- Sulfite oxidase deficiency causes persulfidation loss and hydrogen sulfide release.The Journal of clinical investigation · 2025Article
- The effect of coadministration of D156844 and AR42 (REC-2282) on the survival and motor phenotype of mice with spinal muscular atrophy.Scientific reports · 2025Article
- High-fidelity and differential nonsense suppression in live cells and a frontotemporal dementia allele with human transfer RNAs.Nucleic acids research · 2025Article
- Translational error in mice increases with ageing in an organ-dependent manner.Nature communications · 2025Article
- Mechanisms and Delivery of tRNA Therapeutics.Chemical reviews · 2024Review
- Systematic and quantitative analysis of stop codon readthrough in Rett syndrome nonsense mutations.Journal of molecular medicine (Berlin, Germany) · 2024Article
- The synthetic aminoglycoside ELX-02 induces readthrough of G550X-CFTR producing superfunctional protein that can be further enhanced by CFTR modulators.American journal of physiology. Lung cellular and molecular physiology · 2023Article
- Emerging Personalized Opportunities for Enhancing Translational Readthrough in Rare Genetic Diseases and Beyond.International journal of molecular sciences · 2023Review
- Targeted pseudouridylation: An approach for suppressing nonsense mutations in disease genes.Molecular cell · 2023Article
- Functional Restoration ofFrontiers in pharmacology · 2022Article
- Nuclear interaction of Arp2/3 complex and BRAFAmerican journal of cancer research · 2022Article
- Nonsense suppression therapies in human genetic diseases.Cellular and molecular life sciences : CMLS · 2021Review
- Synergy between Readthrough and Nonsense Mediated Decay Inhibition in a Murine Model of Cystic Fibrosis Nonsense Mutations.International journal of molecular sciences · 2020Article
- Molecular Insights into Determinants of Translational Readthrough and Implications for Nonsense Suppression Approaches.International journal of molecular sciences · 2020Review
- Germline CRISPR/Cas9-Mediated Gene Editing Prevents Vision Loss in a Novel Mouse Model of Aniridia.Molecular therapy. Methods & clinical development · 2020Article
- New and Developing Therapies in Spinal Muscular Atrophy: From Genotype to Phenotype to Treatment and Where Do We Stand?International journal of molecular sciences · 2020Review
2 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
Proximal spinal muscular atrophy (SMA) is a neuromuscular disorder for which there is no available therapy. SMA is caused by loss or mutation of the survival motor neuron 1 gene, SMN1, with retention of a nearly identical copy gene, SMN2. In contrast to SMN1, most SMN2 transcripts lack exon 7. This alternatively spliced transcript, Delta7-SMN, encodes a truncated protein that is rapidly degraded. Inhibiting this degradation may be of therapeutic value for the treatment of SMA. Recently aminoglycosides, which decrease translational fidelity to promote readthrough of termination codons, were shown to increase SMN levels in patient cell lines. Amid uncertainty concerning the role of SMN's C-terminus, the potential of translational readthrough as a therapeutic mechanism for SMA is unclear. Here, we used stable cell lines to demonstrate the SMN C-terminus modulates protein stability in a sequence-independent manner that is reproducible by translational readthrough. Geneticin (G418) was then identified as a potent inducer of the Delta7-SMN target sequence in vitro through a novel quantitative assay amenable to high throughput screens. Subsequent treatment of patient cell lines demonstrated that G418 increases SMN levels and is a potential lead compound. Furthermore, treatment of SMA mice with G418 increased both SMN protein and mouse motor function. Chronic administration, however, was associated with toxicity that may have prevented the detection of a survival benefit. Collectively, these results substantiate a sequence independent role of SMN's C-terminus in protein stability and provide the first in vivo evidence supporting translational readthrough as a therapeutic strategy for the treatment of SMA.
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Registered trials
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.