{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T22:46:11Z","timestamp":1784673971715,"version":"3.55.0"},"reference-count":91,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:00:00Z","timestamp":1769731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology","award":["2023D50"],"award-info":[{"award-number":["2023D50"]}]},{"name":"Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology","award":["2023B15"],"award-info":[{"award-number":["2023B15"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nonsense mutations, responsible for ~11% of gene lesions causing human monogenic diseases, introduce premature termination codons (PTCs) that lead to truncated proteins and nonsense-mediated mRNA decay (NMD). In the central nervous system (CNS), these mutations drive severe, progressive neurological conditions such as spinal muscular atrophy, Rett syndrome, and Duchenne muscular dystrophy. Readthrough therapies\u2014strategies to override PTCs and restore full-length protein expression\u2014have evolved from early aminoglycosides to modern precision tools including suppressor tRNAs, RNA editing, and CRISPR-based platforms. Yet clinical translation remains hampered by inefficient CNS delivery, variable efficacy, and the absence of personalized stratification. In this review, we propose a translational framework\u2014the 4 Ds of Readthrough Therapy\u2014to systematically address these barriers. The framework dissects the pipeline into Detection (precision patient identification and biomarker profiling), Delivery (engineered vectors for CNS targeting), Decoding (context-aware molecular correction), and Durability (long-term safety and efficacy). By integrating advances in machine learning, nanocarriers, base editing, and adaptive trial designs, this roadmap provides a structured strategy to bridge the translational gap. We advocate that a synergistic, modality-tailored approach will transform nonsense suppression from palliative care to durable, precision-based cures for once-untreatable neurological disorders.<\/jats:p>","DOI":"10.3390\/ijms27031418","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T17:38:34Z","timestamp":1769794714000},"page":"1418","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Translational Roadmap for Neurological Nonsense Mutation Disorders"],"prefix":"10.3390","volume":"27","author":[{"given":"Jiaqing","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0477-3666","authenticated-orcid":false,"given":"Zhenyun","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanqing","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1016\/j.tibs.2022.06.003","article-title":"The Broader Sense of Nonsense","volume":"47","author":"Karousis","year":"2022","journal-title":"Trends Biochem. 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