Molecular Therapy. Nucleic Acids最新文献_第3页

A series of precise and controllable base editors with split-TadA-8e. 一系列精确和可控的碱基编辑器与分裂- tada -8e。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-08-12 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102672

Jinxin Wang, Qingjing He, Yuqiang Zeng, Youming Wu, Mufeng Wang, Wenqing Xu, Zhizhi Wang, Xiaohui Zhang

{"title":"A series of precise and controllable base editors with split-TadA-8e.","authors":"Jinxin Wang, Qingjing He, Yuqiang Zeng, Youming Wu, Mufeng Wang, Wenqing Xu, Zhizhi Wang, Xiaohui Zhang","doi":"10.1016/j.omtn.2025.102672","DOIUrl":"10.1016/j.omtn.2025.102672","url":null,"abstract":"Adenine base editors (ABEs) enable efficient A-to-G base conversions in genomic DNA, serving as powerful tools for basic research and clinical disease treatment. TadA-8e with high processive and compatibility makes ABE8e to be the most widely used adenine base editor and has also facilitated the creation of more elegant base editors based on TadA-8e fusion, such as AYBE and eA&C-BEmax. However, ABE8e has more off-target events including DNA off-target and RNA off-target, which raises safety concerns for precision gene editing. Here, we split the TadA-8e of ABE8e (sABE8e) to enable controlled adenine base editing through rapamycin-induced dimerization between FRB and FKBP12. sABE8e has comparable on-target adenine editing activity to ABE8e while maintaining reduced DNA and RNA off-target effects. Harnessing this site of split TadA-8e, we have also developed controllable AYBE (sAYBE) and eA&C-BEmax (seA&C-BEmax), which both offer similar or slightly low base editing efficiency with decreased off-targets compared to AYBE or eA&C-BEmax. These precise and controllable base editing tools will advance the future application of base editors in basic research and clinical disease treatment.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102672"},"PeriodicalIF":6.1,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12408220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RNA trans-splicing to rescue β-catenin: A novel approach for treating CTNNB1-Haploinsufficiency disorder. RNA反式剪接挽救β-连环蛋白：一种治疗ctnnb1单倍功能不全疾病的新方法。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-08-12 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102680

Matea Maruna, Petra Sušjan-Leite, Maja Meško, Špela Miroševič, Roman Jerala

{"title":"RNA trans-splicing to rescue β-catenin: A novel approach for treating CTNNB1-Haploinsufficiency disorder.","authors":"Matea Maruna, Petra Sušjan-Leite, Maja Meško, Špela Miroševič, Roman Jerala","doi":"10.1016/j.omtn.2025.102680","DOIUrl":"10.1016/j.omtn.2025.102680","url":null,"abstract":"Loss-of-function mutations in the CTNNB1 gene cause β-catenin deficiency, resulting in CTNNB1 syndrome, a rare neurodevelopmental disorder characterized by motor and cognitive impairments. Given the wide variety of mutations across CTNNB1 and its dosage sensitivity, a mutation-independent therapeutic approach that preserves endogenous gene regulation is critically needed. This study introduces spliceosome-mediated RNA trans-splicing as a novel approach to restore β-catenin production. Pre-trans-splicing RNA molecules (PTMs) targeting CTNNB1 introns 2, 5, and 6 were designed and evaluated using a split yellow fluorescent protein reporter system. Rationally designed short antisense RNAs, which mask splicing regulatory elements, significantly enhanced PTM-mediated trans-splicing at both mRNA and protein levels. Additionally, introducing a self-cleaving ribozyme at the PTM's 5' end further improved trans-splicing efficiency, likely due to increased nuclear retention. CMV promoter-driven PTM expression yielded the highest efficiency. Importantly, successful trans-splicing of the endogenous CTNNB1 transcript confirmed the physiological relevance of this strategy. This study is the first to apply and optimize spliceosome-mediated RNA trans-splicing (SMaRT) for CTNNB1 mRNA correction, providing a promising, mutation-agnostic approach for treating CTNNB1 syndrome.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102680"},"PeriodicalIF":6.1,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Transcriptomic analysis reveals lung cancer and subtype-specific alternative splicing biomarkers regulated by RNA-binding proteins. 转录组学分析揭示了由rna结合蛋白调控的肺癌和亚型特异性选择性剪接生物标志物。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-08-12 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102681

Yilei Liu, Chenxi Zhang, Youqi Zheng, Shuo Jin, Jiale Niu, Zhenzhen Liu, Xiaoping Wu, Zhixing Feng, Xiaohua Hu, Huijuan Feng

{"title":"Transcriptomic analysis reveals lung cancer and subtype-specific alternative splicing biomarkers regulated by RNA-binding proteins.","authors":"Yilei Liu, Chenxi Zhang, Youqi Zheng, Shuo Jin, Jiale Niu, Zhenzhen Liu, Xiaoping Wu, Zhixing Feng, Xiaohua Hu, Huijuan Feng","doi":"10.1016/j.omtn.2025.102681","DOIUrl":"10.1016/j.omtn.2025.102681","url":null,"abstract":"Lung cancer is the leading cause of cancer-related death worldwide, and the complex molecular mechanisms underlying its development, particularly the role of alternative splicing (AS) in different subtypes, remain poorly understood. In this study, we performed RNA sequencing of 178 lung cancer patients and conducted a comprehensive analysis of the transcriptomic landscape with a focus on AS. We identified robust lung cancer- and subtype-specific AS biomarkers that were consistently effective in both tissue samples and cancer cell lines. Notably, several of these biomarkers also serve as critical regulators in lung cancer progression. Our regulatory network analysis, with a focus on RNA-binding proteins, revealed QKI and SR proteins as key splicing factors. Specifically, QKI was found to modulate the splicing of PLEKHA1 exon 15, a cancer-specific AS biomarker, while SRSF1 regulated the splicing of MKNK2 exon 14, a subtype-specific AS biomarker. Our study provides valuable insights into key AS events and their regulatory mechanisms in lung cancer, paving the way for potential therapeutic targets.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102681"},"PeriodicalIF":6.1,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12408228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MicroRNAs and synaptic dysfunction in Parkinson's disease. 帕金森病的microrna与突触功能障碍

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-08-12 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102673

Morgan N Ogwo, Bhupender Sharma, Gunjan Goyal, Rajkumar Lakshmanaswamy, Subodh Kumar

{"title":"MicroRNAs and synaptic dysfunction in Parkinson's disease.","authors":"Morgan N Ogwo, Bhupender Sharma, Gunjan Goyal, Rajkumar Lakshmanaswamy, Subodh Kumar","doi":"10.1016/j.omtn.2025.102673","DOIUrl":"10.1016/j.omtn.2025.102673","url":null,"abstract":"Parkinson's disease (PD) is a debilitating neurodegenerative condition. Synaptic dysfunctions are associated with the onset and progressive neurodegeneration exhibited in PD. Healthy, active synapses are a prerequisite for non-pathological neurotransmission. When neurotransmission becomes pathological, such as observed in neurodegenerative conditions like PD, the biomolecules found in and around such synapses need distinctive investigation. MicroRNAs (miRNAs) found in neuronal subcellular compartments, such as dendrites, pre-synaptic boutons, and synaptic vesicles, have been garnering attention in neurogenerative diseases. MiRNAs that modulate synaptic activity and synapse function are called synaptic miRNAs. Several miRNAs have been identified that regulate key synaptic proteins; however, information about synaptic miRNAs is largely unknown in PD. In this review, we focused on the most promising synaptic miRNAs, those that are critical for normal synapse function and play a crucial role in PD pathology. We also discussed the synaptic miRNA's interplay with PD-associated synaptic dysfunction. Investigating further how synaptic miRNAs impacts PD pathogenesis may uncover novel etiological information and potential pathways for treatments and a cure for PD.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102673"},"PeriodicalIF":6.1,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12408229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Aptamer-conjugation targets decoy-ODN-therapeutics to liver fibrosis. 适配体偶联靶向诱饵odn治疗肝纤维化。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-08-12 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102660

Larissa W Picard, Ziwen Jiang

引用次数: 0

Preclinical efficacy of multi-targeting mRNA-based CAR T cell therapy in resection models of glioblastoma. 基于多靶点mrna的CAR - T细胞治疗胶质母细胞瘤切除术模型的临床前疗效。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-08-11 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102676

Oula K Dagher, Martin Pedard, Darel Martinez Bedoya, Shawna K Brookens, Denis Migliorini, Avery D Posey

{"title":"Preclinical efficacy of multi-targeting mRNA-based CAR T cell therapy in resection models of glioblastoma.","authors":"Oula K Dagher, Martin Pedard, Darel Martinez Bedoya, Shawna K Brookens, Denis Migliorini, Avery D Posey","doi":"10.1016/j.omtn.2025.102676","DOIUrl":"10.1016/j.omtn.2025.102676","url":null,"abstract":"Traditional viral-based chimeric antigen receptor (CAR) T cell therapies have vanquished multiple blood malignancies with decade-long remissions yet struggle against solid tumors. Nonviral engineering of CAR T cells via electroporation or lipid nanoparticle (LNP) delivery of CAR-encoding mRNA results in highly efficient yet transient CAR expression, challenging the adequacy of available preclinical models for mRNA-based CAR T cell evaluation. This study presents a unique three-pronged approach that combines mRNA-based CAR T cells, multi-targeting of glioblastoma (GBM)-associated receptors, and maximal surgical resection as a novel and readily translatable platform for preclinical evaluation of mRNA-based CAR T cells against solid tumors. We performed head-to-head in vitro and in vivo analyses of mRNA-based CAR T cells generated using different expansion conditions, mRNA delivery methods, or combination approaches. Besides potent in vitro cytotoxicity, our findings unveil a therapeutic window of anti-tumor efficacy, as well as robust and durable complete remissions in xenograft mouse models of GBM receiving maximal surgical resection and locoregional injections of multivalent CAR T cells (MVCAR). Such efficacies were significantly better in 5-day expanded versus quiescent T cells. Interestingly, MVCAR T cells were superior to pooled CAR T cells (CARPool) expressing the same CAR scFv combinations in an orthotopic resection model of GBM.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102676"},"PeriodicalIF":6.1,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12397939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Alterations in mitochondrial base editors enhance targeted editing efficiency for mouse model generation. 线粒体碱基编辑器的改变提高了小鼠模型生成的靶向编辑效率。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-08-11 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102678

Seongho Hong, Sol Pin Kim, Sanghun Kim, Soo Kyung Kang, Sungmo Jung, Yeji Oh, Seung Hee Choi, Su Bin Lee, Hou Cha, Jieun Kim, Jiyoung Bae, Jiyoon Park, Kyoungmi Kim, Chang Geun Choi, Soo-Ji Park, Do Hyun Kim, Lark Kyun Kim, Je Kyung Seong, Hyunji Lee

{"title":"Alterations in mitochondrial base editors enhance targeted editing efficiency for mouse model generation.","authors":"Seongho Hong, Sol Pin Kim, Sanghun Kim, Soo Kyung Kang, Sungmo Jung, Yeji Oh, Seung Hee Choi, Su Bin Lee, Hou Cha, Jieun Kim, Jiyoung Bae, Jiyoon Park, Kyoungmi Kim, Chang Geun Choi, Soo-Ji Park, Do Hyun Kim, Lark Kyun Kim, Je Kyung Seong, Hyunji Lee","doi":"10.1016/j.omtn.2025.102678","DOIUrl":"10.1016/j.omtn.2025.102678","url":null,"abstract":"Mitochondrial DNA (mtDNA) base editors are powerful tools for investigating mitochondrial diseases. However, their editing efficiency can vary significantly depending on the target site within the mtDNA. In this study, we developed two improved versions of the mitochondrial adenine base editor (Hifi-sTALED and αnHifi-sTALED) by modifying components other than the TadA8e-V28R deaminase variant. These enhancements significantly increased editing efficiency while preserving minimal off-target effects across the transcriptome. Using these optimized editors, we achieved improved mtDNA editing in mouse embryos and successfully generated mt-Rnr1 mutant mice with high heteroplasmic loads. Functional analyses revealed that the mt-Rnr1 mutation impaired mitochondrial function, as indicated by reduced ATP production and decreased oxygen consumption rate (OCR). These findings demonstrate the utility of the enhanced base editors in generating mitochondrial disease models and advancing research in mitochondrial genetics.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102678"},"PeriodicalIF":6.1,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

To modify or not to modify-That is still the question for some mRNA applications. 修饰还是不修饰——这仍然是一些mRNA应用的问题。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-08-11 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102655

Sofía Soler, Katharina Maser, Thomas Zillinger, Eva Bartok

引用次数: 0

Formulation matters: LION nanoparticles improve RNA vaccine immunogenicity by containing systemic inflammation. 配方问题：LION纳米颗粒通过抑制全身性炎症提高RNA疫苗的免疫原性。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-08-11 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102659

Chandru Subramani, Tarani Kanta Barman

引用次数: 0

Human opsin restoration by histone methylation using methyltransferase fusion protein SETD7-dCas9. 甲基转移酶融合蛋白SETD7-dCas9通过组蛋白甲基化修复人视蛋白。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-08-11 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102677

Na Ly Tran, Yoo Eun Kang, Hyeyeon Jeong, Yeojin Kim, Sang Chul Shin, Sang-Heon Kim, Byeongho Park, Seung Ja Oh

{"title":"Human opsin restoration by histone methylation using methyltransferase fusion protein SETD7-dCas9.","authors":"Na Ly Tran, Yoo Eun Kang, Hyeyeon Jeong, Yeojin Kim, Sang Chul Shin, Sang-Heon Kim, Byeongho Park, Seung Ja Oh","doi":"10.1016/j.omtn.2025.102677","DOIUrl":"10.1016/j.omtn.2025.102677","url":null,"abstract":"Epigenetic modulation enables precise gene regulation without altering DNA sequences. While histone acetylation has been widely utilized for gene activation, the therapeutic potential of histone methylation remains underexplored. In this study, we developed a new epigenetic activator by fusing the histone methyltransferase SETD7 to deactivated Cas9 (dCas9). The optimized SETD7-dCas9 fusion protein successfully induced H3K4 mono-methylation and activated transcription at multiple target loci. We further established a prediction model using promoter CpG methylation status to identify genes most responsive to SETD7-dCas9-mediated activation. To evaluate therapeutic relevance, we targeted the medium-wavelength-sensitive opsin gene (OPN1MW), which is crucial for cone photoreceptor function as a strategy for treating retinitis pigmentosa. SETD7-dCas9-mediated activation of OPN1 MW restored light absorption properties comparable with rhodopsin, effectively compensating for rhodopsin deficiency in an in vitro disease model. These findings demonstrate the potential of histone methylation-based gene activation as a mutation-independent therapeutic strategy. The SETD7-dCas9 system represents a promising epigenome editing platform for precision gene regulation in diverse diseases.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102677"},"PeriodicalIF":6.1,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12410342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0