Molecular Therapy. Nucleic Acids最新文献_第9页

Anti-gene oligonucleotides targeting Friedreich's ataxia expanded GAA⋅TTC repeats increase Frataxin expression. 靶向弗里德赖希共济失调的抗基因寡核苷酸扩增GAA⋅TTC重复序列，增加Frataxin的表达。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-04-17 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102541

Negin Mozafari, Salomé Milagres, Tea Umek, Cristina S J Rocha, Claudia M Vargiu, Fiona Freyberger, Osama Saher, Marek Napierala, Jill S Napierala, Pontus Blomberg, Per T Jørgensen, Tanel Punga, C I Edvard Smith, Jesper Wengel, Rula Zain

{"title":"Anti-gene oligonucleotides targeting Friedreich's ataxia expanded GAA⋅TTC repeats increase Frataxin expression.","authors":"Negin Mozafari, Salomé Milagres, Tea Umek, Cristina S J Rocha, Claudia M Vargiu, Fiona Freyberger, Osama Saher, Marek Napierala, Jill S Napierala, Pontus Blomberg, Per T Jørgensen, Tanel Punga, C I Edvard Smith, Jesper Wengel, Rula Zain","doi":"10.1016/j.omtn.2025.102541","DOIUrl":"10.1016/j.omtn.2025.102541","url":null,"abstract":"Friedreich's ataxia is a progressive, autosomal recessive ataxia caused, in most cases, by homozygous expansion of GAA⋅TTC triplet-repeats in the first intron of the Frataxin gene. GAA⋅TTC repeat expansion results in the formation of a non-B-DNA intramolecular triplex as well as changes in the epigenetic landscape at the Frataxin locus. Expansion of intronic GAA⋅TTC repeats is associated with reduced levels of Frataxin mRNA and protein, resulting in disease development. In our previous study, we demonstrated that DNA-binding anti-gene oligonucleotides specifically targeting the GAA⋅TTC repeat expansion effectively disrupted the formation of intramolecular triplex structures. In this study, we extend these findings by showing that targeting repeat-expanded chromosomal DNA with anti-gene oligonucleotides leads to an increase in Frataxin mRNA and protein levels in cells derived from Friedreich's ataxia patients. We examined numerous anti-gene oligonucleotides and found that the design, length, and their locked nucleic acid composition have a high impact on the effectiveness of the treatment. Collectively, our results demonstrate the unique capability of specifically designed oligonucleotides targeting the GAA⋅TTC DNA repeats to upregulate Frataxin gene expression.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102541"},"PeriodicalIF":6.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248840","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

CLCluster: A redundancy-reduction contrastive learning-based clustering method of cancer subtype based on multi-omics data. CLCluster：一种基于多组学数据的基于冗余减少对比学习的癌症亚型聚类方法。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-04-02 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102534

Hong Wang, Yi Zhang, Wen Li, Zhen Wei, Zhenlong Wang, Mengyuan Yang

{"title":"CLCluster: A redundancy-reduction contrastive learning-based clustering method of cancer subtype based on multi-omics data.","authors":"Hong Wang, Yi Zhang, Wen Li, Zhen Wei, Zhenlong Wang, Mengyuan Yang","doi":"10.1016/j.omtn.2025.102534","DOIUrl":"10.1016/j.omtn.2025.102534","url":null,"abstract":"Alternative splicing (AS) allows one gene to produce several protein variants, offering valuable predictive insights into cancer and facilitating targeted therapies. Although multi-omics data are used to identify cancer subtypes, AS is rarely utilized for this purpose. Here, we propose a redundancy-reduction contrastive learning-based method (CLCluster) based on copy number variation, methylation, gene expression, miRNA expression, and AS for cancer subtype clustering of 33 cancer types. Ablation experiments emphasize the benefits of using AS data to subtype cancer. We identified 2,921 cancer subtype-related AS events associated with patient survival and conducted multiple analyses including open reading frame annotation, RNA binding protein (RBP)-associated AS regulation, and splicing-related anticancer peptides (ACPs) prediction for therapeutic biomarkers. The CLCluster model is more effective in identifying prognostic-relevant cancer subtypes than other models. The effective annotation of cancer subtype related AS events facilitates the identification of therapeutically targetable biomarkers in patients.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102534"},"PeriodicalIF":6.5,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476073","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

miRNA-642a-3p protects β cells from glucolipotoxicity. miRNA-642a-3p保护β细胞免受糖脂毒性。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-03-25 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102498

Sandra Sofia Pinhanços, João Teixeira de Oliveira, C Henrique Alves, Cláudia M Deus, Twan J J de Winter, Sofia Viana, Flávio Reis, Jorge Santos, Mijke Buitinga, Françoise Carlotti, Lino Ferreira, Martin Gotthardt, John Jones, Hugo Fernandes

{"title":"miRNA-642a-3p protects β cells from glucolipotoxicity.","authors":"Sandra Sofia Pinhanços, João Teixeira de Oliveira, C Henrique Alves, Cláudia M Deus, Twan J J de Winter, Sofia Viana, Flávio Reis, Jorge Santos, Mijke Buitinga, Françoise Carlotti, Lino Ferreira, Martin Gotthardt, John Jones, Hugo Fernandes","doi":"10.1016/j.omtn.2025.102498","DOIUrl":"10.1016/j.omtn.2025.102498","url":null,"abstract":"The incidence of type 2 diabetes mellitus (T2DM) is tightly linked to obesity. High levels of circulating glucose and saturated free fatty acids (FFAs), known as glucolipotoxicity (GLT), is implicated in β cell dysfunction and/or death. This study aims to identify miRNAs capable of protecting β cells from GLT-induced cell death (GICD). A library of 2,080 human miRNA mimics was transfected in β cells followed by exposure to GLT. We identified 45 miRNAs capable of protecting β cells from GICD and selected miR-642a-3p for further studies. RNA-seq revealed that miR-642a-3p restored the expression of β cell identity genes and modulated pathways associated with cell survival and lipid metabolism. Moreover, we showed that transfection of β cells with miR-642a-3p protected them from GLT-induced changes in insulin secretion. Compared with the control, hypercaloric-fed mice showed a trend toward decreased expression of GLT-protective miRNAs. Notably, we demonstrated that miR-642a-3p expression was downregulated in human islets isolated from T2DM patients compared with non-diabetic controls. Importantly, in obese patients, the expression of GLT-protective miRNAs in plasma-derived extracellular vesicles was increased in non-diabetic patients. Overall, we have identified a potential dual role for miR-642a-3p as both a biomarker and a facilitator of β cell survival and function, offering a novel theranostic tool for the management of diabetes and/or obesity.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102498"},"PeriodicalIF":6.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476074","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

FUBP3 enhances HIV-1 transcriptional activity and regulates immune response pathways in T cells. FUBP3增强HIV-1转录活性并调节T细胞的免疫应答途径。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-03-25 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102525

Quentin M R Gibaut, Chuan Li, Anqi Cheng, Ines Moranguinho, Luisa P Mori, Susana T Valente

{"title":"FUBP3 enhances HIV-1 transcriptional activity and regulates immune response pathways in T cells.","authors":"Quentin M R Gibaut, Chuan Li, Anqi Cheng, Ines Moranguinho, Luisa P Mori, Susana T Valente","doi":"10.1016/j.omtn.2025.102525","DOIUrl":"10.1016/j.omtn.2025.102525","url":null,"abstract":"Far-upstream element-binding protein 3 (FUBP3) was identified at actively transcribing HIV promoters through chromatin affinity purification and mass spectrometry. Known for regulating cellular processes such as transcription and translation by binding to DNAs and RNAs, FUBP3's role in HIV transcriptional regulation was previously unrecognized. This study reveals that FUBP3 enhances HIV-1 transcriptional activation by interacting with Tat and trans-activation response (TAR)-RNA, critical for boosting viral transcription through recruitment of activating factors that promote RNA polymerase II (RNAPII) elongation. Transcriptomic analysis, chromatin immunoprecipitation, and biochemical assays demonstrated that FUBP3 associates with and stabilizes TAR-RNA, in a Tat-dependent manner, and enhances Tat steady-state levels via interaction with Tat's basic domain. Suppressing FUBP3 decreased HIV-1 transcription and altered expression of host genes linked to T cell activation and inflammation, underscoring its broad regulatory impact. Additionally, FUBP3 was enriched at active promoters, confirming its role in transcriptional regulation at specific genomic locations. These findings highlight FUBP3's critical role in the HIV-1 life cycle and suggest its potential as a therapeutic target in HIV-1 infection. Additionally, this study expands our understanding of FUBP3's functions in oncogenic and inflammatory pathways.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102525"},"PeriodicalIF":6.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12005928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018896","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

Mechanistic intracellular PK/PD modeling to inform development strategies for small interfering RNA therapeutics. 细胞内机制PK/PD建模为小干扰RNA疗法的开发策略提供信息。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-03-17 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102516

Lin Chen, Caroline Bosmajian, Sukyung Woo

{"title":"Mechanistic intracellular PK/PD modeling to inform development strategies for small interfering RNA therapeutics.","authors":"Lin Chen, Caroline Bosmajian, Sukyung Woo","doi":"10.1016/j.omtn.2025.102516","DOIUrl":"10.1016/j.omtn.2025.102516","url":null,"abstract":"Small interfering RNA (siRNA) therapeutics provide a targeted approach to silence disease-related genes, with notable success in liver-targeting applications. However, the quantitative effects of siRNA properties, such as stability and affinity, as well as biological factors like cell proliferation, mRNA turnover, and abundance, on gene silencing, particularly for extrahepatic targets, remain poorly understood. To identify determinants influencing gene knockdown extent and duration, we developed a mechanistic intracellular pharmacokinetic/pharmacodynamic (PK/PD) model for RNAiMAX-delivered siRNA, based on cytoplasmic siRNA disposition, RISC-loaded siRNA exposure, and mRNA knockdown across different targets in MCF7 and BT474 cells. The model highlighted the critical roles of cell proliferation in silencing duration and mRNA turnover rates on knockdown extent. In rapid-dividing cells, mRNA half-life drives knockdown profiles, whereas chemical siRNA stabilization extends silencing in slow-dividing cells. Targets with extremely low or high mRNA abundance pose silencing challenges. While sufficient RISC occupancy is essential, increasing RISC exposure has minimal impact on silencing extent; enhancing siRNA-mRNA target engagement is more effective. The model also defined a quantitative relationship for maximal mRNA knockdown, governed by cell proliferation, mRNA half-life, and RISC-mediated cleavage rates. This mechanistic PK/PD modeling provides insights into optimizing siRNA design and target selection in therapeutic development.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102516"},"PeriodicalIF":6.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12002994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990974","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

Lockpicking FGFR1 with aptamer-based technology. 基于适配体的技术撬锁FGFR1。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-02-27 eCollection Date: 2025-03-11 DOI: 10.1016/j.omtn.2025.102488

Francesca Nonatelli, Fernando Pastor, Fernando Calvo

引用次数: 0

Erratum: In vivo efficacy and safety of systemically administered serinol nucleic acid-modified antisense oligonucleotides in mouse kidney. 勘误：系统给药丝氨酸核酸修饰的反义寡核苷酸在小鼠肾脏的体内有效性和安全性。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-02-25 eCollection Date: 2025-03-11 DOI: 10.1016/j.omtn.2025.102497

Toshiki Tsuboi, Keita Hattori, Takuji Ishimoto, Kentaro Imai, Tomohito Doke, Junichiro Hagita, Jumpei Ariyoshi, Kazuhiro Furuhashi, Noritoshi Kato, Yasuhiko Ito, Yukiko Kamiya, Hiroyuki Asanuma, Shoichi Maruyama

引用次数: 0

Unlocking RNA mysteries: Predicting subcellular localizations with AI. 解开RNA之谜：用人工智能预测亚细胞定位。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-02-21 eCollection Date: 2025-03-11 DOI: 10.1016/j.omtn.2025.102481

Nguyen Quoc Khanh Le

引用次数: 0

Unlocking the potential of allele-specific siRNA therapy: A novel approach for Crouzon syndrome. 解锁等位基因特异性siRNA治疗的潜力：一种治疗Crouzon综合征的新方法。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-02-21 eCollection Date: 2025-03-11 DOI: 10.1016/j.omtn.2025.102484

Federico Di Rocco, Camilla de Laurentis

引用次数: 0

mRNA-1273 is placenta-permeable and immunogenic in the fetus. mRNA-1273在胎儿中具有胎盘渗透性和免疫原性。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-02-17 eCollection Date: 2025-03-11 DOI: 10.1016/j.omtn.2025.102489

Jeng-Chang Chen, Mei-Hua Hsu, Rei-Lin Kuo, Li-Ting Wang, Ming-Ling Kuo, Li-Yun Tseng, Hsueh-Ling Chang, Cheng-Hsun Chiu

{"title":"mRNA-1273 is placenta-permeable and immunogenic in the fetus.","authors":"Jeng-Chang Chen, Mei-Hua Hsu, Rei-Lin Kuo, Li-Ting Wang, Ming-Ling Kuo, Li-Yun Tseng, Hsueh-Ling Chang, Cheng-Hsun Chiu","doi":"10.1016/j.omtn.2025.102489","DOIUrl":"10.1016/j.omtn.2025.102489","url":null,"abstract":"COVID-19 mRNA vaccines are generally recognized as safe for gestational administration. However, their transplacental pharmacokinetics remain obscure. In this study, mRNA-1273 intramuscularly given to pregnant mice rapidly circulated in maternal blood and crossed the placenta within 1 h to spread in the fetal circulation. Although spike mRNA in fetal circulation faded away within 4-6 h, it could accumulate in fetal tissues, mainly the liver and get translated into spike protein. Transplacental mRNA-1273 proved immunogenic in the fetuses, as postnatally equipped with anti-spike immunoglobulin (Ig)M, paternal allotypic anti-spike IgG2a, and heightened anti-spike cellular immunity. Gestationally administered, mRNA-1273 had a dose-dependent effect on its transplacental transfer and immunogenicity in the fetuses, with higher mRNA-1273 doses leading to increased transplacental mRNA-1273 passage and greater serum titers of endogenous anti-spike IgM/IgG generated by the fetuses. Thus, gestationally maternal mRNA-1273 vaccination might endow the newborns with not only passive but also active anti-spike immunity. Our results pose new insights into transplacental capacity of mRNA vaccines and their immunogenic potential in the fetuses, advancing our knowledge of mRNA medicine to protect the unborns against pathogens in perinatal life and broaden our horizons of prenatal mRNA molecular therapy.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 1","pages":"102489"},"PeriodicalIF":6.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657817","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