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

Correction of human non-sense mutation via adenine base editing for Duchenne muscular dystrophy treatment in mouse 通过腺嘌呤碱基编辑纠正人类非有义突变，治疗小鼠杜氏肌营养不良症

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-03-06 DOI: 10.1016/j.omtn.2024.102165

Ming Jin, Jiajia Lin, Haisen Li, Zhifang Li, Dong Yang, Yin Wang, Yuyang Yu, Zhurui Shao, Long Chen, Zhiqiang Wang, Yu Zhang, Xiumei Zhang, Ning Wang, Chunlong Xu, Hui Yang, Wan-Jin Chen, Guoling Li

{"title":"Correction of human non-sense mutation via adenine base editing for Duchenne muscular dystrophy treatment in mouse","authors":"Ming Jin, Jiajia Lin, Haisen Li, Zhifang Li, Dong Yang, Yin Wang, Yuyang Yu, Zhurui Shao, Long Chen, Zhiqiang Wang, Yu Zhang, Xiumei Zhang, Ning Wang, Chunlong Xu, Hui Yang, Wan-Jin Chen, Guoling Li","doi":"10.1016/j.omtn.2024.102165","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102165","url":null,"abstract":"Duchenne muscular dystrophy (DMD) is the most prevalent herediatry disease in men, characterized by dystrophin deficiency, progressive muscle wasting, cardiac insufficiency, and premature mortality, with no effective therapeutic options. Here, we investigated whether adenine base editing can correct pathological non-sense point mutations leading to premature stop codons in the dystrophin gene. We identified 27 causative nonsense mutations in our DMD patient cohort. Treatment with adenine base editor (ABE) could restore dystrophin expression by direct A-to-G editing of pathological nonsense mutations in cardiomyocytes generated from DMD patient-derived induced pluripotent stem cells. We also generated two humanized mouse models of DMD expressing mutation-bearing exons 23 or 30 of human dystrophin gene. Intramuscular administration of ABE, driven by ubiquitous or muscle-specific promoters could correct these non-sense mutations , albeit with higher efficiency in exon 30, restoring dystrophin expression in skeletal fibers of humanized DMD mice. Moreover, a single systemic delivery of ABE with human sgRNA could induce body-wide dystrophin expression and improve muscle function in rotarod tests of humanized DMD mice. These findings demonstrate that ABE with human sgRNAs can confer therapeutic alleviation of DMD in mice, providing a basis for development of adenine base editing therapies in monogenic diseases.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140097467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Trans-amplifying RNA expressing functional miRNA mediates target-specific gene suppression and simultaneous transgene expression 表达功能性 miRNA 的转扩增 RNA 可介导靶标特异性基因抑制和同步转基因表达

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-03-05 DOI: 10.1016/j.omtn.2024.102162

Ayşegül Yıldız, Aida Hasani, Tina Hempel, Nina Köhl, Aline Beicht, René Becker, Stefanie Hubich-Rau, Martin Suchan, Marco A. Poleganov, Ugur Sahin, Tim Beissert

{"title":"Trans-amplifying RNA expressing functional miRNA mediates target-specific gene suppression and simultaneous transgene expression","authors":"Ayşegül Yıldız, Aida Hasani, Tina Hempel, Nina Köhl, Aline Beicht, René Becker, Stefanie Hubich-Rau, Martin Suchan, Marco A. Poleganov, Ugur Sahin, Tim Beissert","doi":"10.1016/j.omtn.2024.102162","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102162","url":null,"abstract":"The co-delivery of microRNAs (miRNAs) and protein-coding RNA presents an opportunity for a combined approach to gene expression and gene regulation for therapeutic applications. Protein delivery is established using long mRNA, self-, and -amplifying RNA (taRNA), whereas miRNA delivery typically uses short synthetic oligonucleotides rather than incorporating it as a precursor into long RNA. Although miRNA delivery into the cell cytoplasm using long genomes of RNA viruses has been described, concerns have remained regarding low processing efficiency. However, miRNA precursors can be released from long cytoplasmic alphaviral RNA by a cytoplasmic fraction of Drosha. taRNA, a promising vector platform for infectious disease vaccination, uses a nonreplicating mRNA expressing an alphaviral replicase to amplify a protein-coding short transreplicon-RNA (STR) in . To investigate the possibility of simultaneously delivering protein expression and gene silencing, we tested whether a taRNA system can carry and release functional miRNA to target cells. Here, we show that mature miRNA is released from STRs and silences specific targets in a replication-dependent manner for several days without compromising the expression of STR-encoded proteins. Our findings suggest that incorporating miRNAs into the taRNA vector platform has the potential for gene regulation alongside the expression of therapeutic genes.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140097652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Modifying miRs for effective reprogramming of fibroblasts to cardiomyocytes 修改 miRs 以有效地将成纤维细胞重编程为心肌细胞

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-02-28 DOI: 10.1016/j.omtn.2024.102160

Xinghua Wang, Syeda S. Baksh, Richard E. Pratt, Victor J. Dzau, Conrad P. Hodgkinson

{"title":"Modifying miRs for effective reprogramming of fibroblasts to cardiomyocytes","authors":"Xinghua Wang, Syeda S. Baksh, Richard E. Pratt, Victor J. Dzau, Conrad P. Hodgkinson","doi":"10.1016/j.omtn.2024.102160","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102160","url":null,"abstract":"Reprogramming scar fibroblasts into cardiomyocytes has been proposed to reverse the damage associated with myocardial infarction. However, the limited improvement in cardiac function calls for enhanced strategies. We reported enhanced efficacy of our miR reprogramming cocktail miR combo (miR-1, miR-133a, miR-208a, and miR-499) via RNA-sensing receptor stimulation. We hypothesized that we could combine RNA-sensing receptor activation with fibroblast reprogramming by chemically modifying miR combo. To test the hypothesis, miR combo was modified to enhance interaction with the RNA-sensing receptor Rig1 via the addition of a 5′-triphosphate (5′ppp) group. Importantly, when compared with unmodified miR combo, 5′ppp-modified miR combo markedly improved reprogramming efficacy . Enhanced reprogramming efficacy correlated with a type-I interferon immune response with strong and selective secretion of interferon β (IFNβ). Antibody blocking studies and media replacement experiments indicated that 5′ppp-miR combo utilized IFNβ to enhance fibroblast reprogramming efficacy. In conclusion, miRs can acquire powerful additional roles through chemical modification that potentially increases their clinical applications.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140097379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Immunostimulatory short non-coding RNAs in the circulation of patients with tuberculosis infection 结核感染患者血液循环中的免疫刺激性非编码短 RNA

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-02-22 DOI: 10.1016/j.omtn.2024.102156

Justin Gumas, Takuya Kawamura, Megumi Shigematsu, Yohei Kirino

引用次数: 0

Protection from cisplatin-induced hearing loss with lentiviral vector-mediated ectopic expression of the anti-apoptotic protein BCL-XL 慢病毒载体介导的抗凋亡蛋白 BCL-XL 异位表达可防止顺铂诱导的听力损失

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-02-19 DOI: 10.1016/j.omtn.2024.102157

Larissa Nassauer, Hinrich Staecker, Peixin Huang, Bryan Renslo, Madeleine Goblet, Jennifer Harre, Athanasia Warnecke, Juliane W. Schott, Michael Morgan, Melanie Galla, Axel Schambach

引用次数: 0

Increasing angiogenesis factors in hypoxic diabetic wounds using siRNA nanotherapeutics 利用 siRNA 纳米疗法增加缺氧性糖尿病伤口的血管生成因子

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-02-19 DOI: 10.1016/j.omtn.2024.102142

Adam Astrada

引用次数: 0

Polymeric nanoparticle-based mRNA vaccine is protective against influenza virus infection in ferrets 基于聚合物纳米粒子的 mRNA 疫苗对雪貂感染流感病毒具有保护作用

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-02-19 DOI: 10.1016/j.omtn.2024.102159

Gijs Hardenberg, Chantal Brouwer, Rachelle van Gemerden, Nicola J. Jones, Anthony C. Marriott, Jaap Rip

引用次数: 0

Single-cell transcriptome profiling implicates the psychological stress-induced disruption of spermatogenesis 单细胞转录组图谱分析显示心理压力导致精子发生紊乱

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-02-19 DOI: 10.1016/j.omtn.2024.102158

Rufeng Li, Yuefeng Du, Kang Li, Xiaofan Xiong, Lingyu Zhang, Chen Guo, Shanfeng Gao, Yufei Yao, Yungang Xu, Juan Yang

引用次数: 0

Metabolic-Pathway-Based Subtyping in Endometrial Carcinoma: An Integrated Study Based on Multi-omics Analysis and Machine Learning Algorithms 基于代谢通路的子宫内膜癌亚型分析：基于多组学分析和机器学习算法的综合研究

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-02-16 DOI: 10.1016/j.omtn.2024.102155

Xiaodie Liu, Wenhui Wang, Xiaolei Zhang, Jing Liang, Dingqing Feng, Yuebo Li, Ming Xue, Bin Ling

{"title":"Metabolic-Pathway-Based Subtyping in Endometrial Carcinoma: An Integrated Study Based on Multi-omics Analysis and Machine Learning Algorithms","authors":"Xiaodie Liu, Wenhui Wang, Xiaolei Zhang, Jing Liang, Dingqing Feng, Yuebo Li, Ming Xue, Bin Ling","doi":"10.1016/j.omtn.2024.102155","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102155","url":null,"abstract":"Endometrial cancer (EC), the second most common malignancy in the female reproductive system, has garnered increasing attention for its genomic heterogeneity, but understanding of its metabolic characteristics is still poor. We explored metabolic dysfunctions in EC through comprehensive multi-omics analysis (RNA-seq datasets from The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), and GEO datasets; the Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteomics; CCLE metabolomics) to develop useful molecular targets for precision therapy. Unsupervised consensus clustering was performed to categorize EC patients into three metabolism-pathways-based subgroups (MPS). These MPS subgroups had distinct clinical prognoses, transcriptomic and genomic alterations, immune microenvironment landscape, and unique patterns of chemotherapy sensitivity. Moreover, the MPS2 subgroup has a better response to immunotherapy. Finally, three machine learning algorithms (LASSO, random forest, and stepwise multivariate Cox regression) were used for developing a prognostic “Metagene” signature based on metabolic molecules. Thus, a thirteen-hub-gene-based classifier was constructed to predict patients’ MPS subtype offering a more accessible and practical approach. This metabolism-based classification system can potentially enhance prognostic predictions and guide clinical strategies for immunotherapy and metabolism-targeted therapy in EC.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139920281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

LSpECifying transgene expression LSpEC 化转基因表达

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-02-16 DOI: 10.1016/j.omtn.2024.102144

Andrea Annoni, Alessio Cantore

引用次数: 0