🧬 PubMed RNA Editing Daily Digest

The rapid development of DNA- and RNA-editing tools (collectively referred to as gene editing technologies) has caused a paradigm shift in the treatment of human diseases from symptomatic treatment to precision-based medicine. Both DNA-based and RNA-based editing systems, including Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-derived technologies and newly developed RNA editing tools, have pushed technological frontiers in terms of editing precision, hierarchical control, and reversibility; they have accumulated a growing body of preclinical and clinical evidence across diverse diseases ranging from inherited disorders to cancer, infectious diseases, and neurodegenerative diseases (ND). This review systematically summarizes the core principles and representative advances of DNA-based genome editing and RNA-based transcriptome editing technologies, comprehensively compares the two categories of technical strategies in terms of therapeutic potential, durability of effects, and risk profiles, and further explores the key challenges for achieving long-term safe and efficient in vivo applications, covering core bottlenecks such as delivery efficiency, tissue specificity, genotoxicity, and immunogenicity. Safety assessment has broadened to include tracking genotoxicity and genomic structural variations, whereas delivery systems and tissue specificity are determinant factors for in vivo therapeutic applications. Through the employment of both permanent and reversible editing strategies with high cargo-writing capacity and low integration risk, combined with programmable delivery systems, the therapeutic potential of hard-to-transfect tissues and complex diseases is anticipated to be broadened, opening new paths for clinical translation.

Stop codon readthrough is widespread across eukaryotes and often dismissed as translational noise, yet its tissue/stage-specific occurrence suggests adaptive roles in proteome tuning. We asked whether readthrough-related mechanisms can mitigate stage-specific pleiotropic trade-offs without genomic change. In the filamentous ascomycete

The 1717-1G>A is a prevalent splicing mutation causing cystic fibrosis (CF) for which no pharmacological treatments have been approved. This mutation disrupts a canonical 3' AG splice acceptor site in the

The advent of CRISPR systems has transformed genome editing, offering unparalleled efficiency and versatility with wide therapeutic potential. However, conventional CRISPR systems face key limitations, including unpredictable and imprecise outcomes during repair of double stranded breaks and reliance on specific protospacer adjacent motif sequences. In response, prime editing (PE) has emerged as a powerful alternative, enabling precise custom edits using a fusion of Cas9 nickase and an engineered reverse transcriptase (RT) together with a prime editing guide RNA (pegRNA) that encodes the desired repair template. PE enables edits to be installed at or downstream of the target site, expanding the range of targetable sequences. Since its inception, PE has undergone extensive optimisation, including Cas variant selection, RT engineering, and pegRNA improvements. In parallel, advances in delivery, including nanoparticles and split viral systems, have accelerated translation across preclinical disease models. Notably, PE has now entered the clinic, with the first in-human study reporting functional restoration with a promising safety profile to date. Here, we summarise recent mechanistic insights, architectural innovations, and therapeutic applications of PE, and discuss the remaining challenges in efficiency, delivery, and safety that will shape broader clinical impact.

Fuchs endothelial corneal dystrophy (FECD) is a degenerative disease characterized by progressive loss of corneal endothelial cells, yet the role of adenosine-to-inosine (A-to-I) RNA editing mediated by adenosine deaminases acting on RNA (ADARs) remains unelucidated. Our current study aimed to investigate the A-to-I editome in FECD and its underlying epigenetic mechanisms. Cross-cohort editome analysis was performed using corneal endothelial transcriptome datasets from two independent FECD cohorts. RNA editing was identified and compared across groups to assess differential RNA editing and its associated gene functions and pathways, followed by cell experiments and RNA-sequencing (RNA-seq) to evaluate the functional impact of selected RNA editing events. Our results showed a cross-cohort reduction of average A-to-I RNA editing levels and significant upregulation of ADARB1, with 10,416 differential RNA editing events in 1138 genes in FECD compared with controls, including FECD-related genes, such as transcription factor 4. Moreover, differentially edited genes were mainly involved in cell growth and autophagy-related pathways. Notably, FECD exhibited upregulated missense RNA editing, leading to K95R recoding in insulin-like growth factor binding protein 7 (IGFBP7), positively correlated with ADARB1 expression. In vitro overexpression of ADARB1 enhanced IGFBP7 K95R editing, inhibiting cell proliferation, and inducing apoptosis via the p53-p21 axis. Transcriptome analysis further revealed that cells overexpressing recoded K95R IGFBP7 exhibited compromised expression in the mitochondrial electron transport chain. Our findings demonstrate substantial editome dysregulation in FECD, highlighting a role of ADARB1-mediated IGFBP7 recoding in promoting cell apoptosis and dysfunction, and providing insights into the epigenetic mechanisms underlying FECD and potential therapeutic targets.