Molecular Therapy. Nucleic Acids最新文献_第7页

Optimized genomic editing of a common Duchenne muscular dystrophy mutation in patient-derived muscle cells and a new humanized mouse model. 优化患者来源的肌肉细胞中常见杜氏肌营养不良突变的基因组编辑和新的人源化小鼠模型。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-05-16 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102569

Mateusz Z Durbacz, Yu Zhang, Hui Li, Takahiko Nishiyama, Efrain Sanchez- Ortiz, John R McAnally, Damir Alzhanov, Ning Liu, Eric N Olson

{"title":"Optimized genomic editing of a common Duchenne muscular dystrophy mutation in patient-derived muscle cells and a new humanized mouse model.","authors":"Mateusz Z Durbacz, Yu Zhang, Hui Li, Takahiko Nishiyama, Efrain Sanchez- Ortiz, John R McAnally, Damir Alzhanov, Ning Liu, Eric N Olson","doi":"10.1016/j.omtn.2025.102569","DOIUrl":"10.1016/j.omtn.2025.102569","url":null,"abstract":"Duchenne muscular dystrophy (DMD) is a fatal X-linked, recessive disease caused by mutations in the DMD gene encoding dystrophin, a membrane-associated protein necessary for maintaining muscle structure and function. One of the common DMD mutations is the deletion of exon 52 (Δ52), which introduces a premature stop codon in exon 53, preventing the expression of functional dystrophin protein. Patients with this mutation could benefit from skipping or reframing exon 53 to restore the dystrophin open reading frame. In this study, we investigated the efficacy of single-cut CRISPR gene editing with Staphylococcus pyogenes Cas9 (SpCas9)-LRVQR to restore dystrophin expression in patient-derived induced pluripotent stem cells (iPSCs) and a newly generated humanized DMD mouse model. We compared two injection routes for adeno-associated virus (AAV) serotype 9 to deliver gene-editing components to neonatal mice: intraperitoneal (IP) and facial vein (FV) injection. We observed efficient restoration of dystrophin protein expression across multiple skeletal muscle groups and the heart. The AAV9-mediated CRISPR single-cut approach ameliorated key DMD hallmarks, including histopathological phenotypes, impaired grip strength, and elevated serum creatine kinase levels. Our optimized strategies for dystrophin restoration in humanized DMD mice with exon 52 deletion represent a promising treatment for DMD.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102569"},"PeriodicalIF":6.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12167475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302539","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

Differentially expressed ncRNAs as key regulators in infection of human bronchial epithelial cells by the SARS-CoV-2 Delta variant. 差异表达的ncRNAs在SARS-CoV-2 Delta变体感染人支气管上皮细胞中的关键调控作用

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-05-14 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102559

Glory Ranches, Hubert Hackl, Viktoria Zaderer, Melanie Ploner, Wilfried Posch, Doris Wilflingseder, Kai Kummer, Alexander Hüttenhofer

{"title":"Differentially expressed ncRNAs as key regulators in infection of human bronchial epithelial cells by the SARS-CoV-2 Delta variant.","authors":"Glory Ranches, Hubert Hackl, Viktoria Zaderer, Melanie Ploner, Wilfried Posch, Doris Wilflingseder, Kai Kummer, Alexander Hüttenhofer","doi":"10.1016/j.omtn.2025.102559","DOIUrl":"10.1016/j.omtn.2025.102559","url":null,"abstract":"SARS-CoV-2 infection initiates complex interactions at mucosal barriers. In primary human bronchial epithelial cells, we investigated changes in the small RNA transcriptome induced by Delta variant infection. Thereby, we uncovered differential expression of a specific set of microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), vault RNAs, Y RNAs, and long intergenic non-coding RNAs (lincRNAs), which inhibit apoptosis while promoting cell proliferation and viral infection. Conversely, differential expression of 7SL, U2, and RPPH1 RNAs, as well as miR-155-5p and miR-27a-5p, was found to be involved in antiviral signaling. In addition, expression of the protein-coding genes CXCL10, IFIT1, NCOA7, IFIT2, SIX3, and RPSA was increased during infection. Interestingly, the ribosomal protein RPSA has recently been reported to also serve as a viral surface receptor promoting pro-inflammatory cytokine signaling. By investigating these differentially expressed genes also after Omicron BA.2 variant infection, we observed a significantly lower expression of the protein-coding genes CXCL10, IFIT2, and ZC3HAV1. In contrast, expression changes for the majority of non-coding RNAs (ncRNAs) were similar between Delta and Omicron variants with the exception of miR-155-5p and 5'-tRFGlu(TTC), emphasizing their potential as biomarkers for disease severity. Our findings thus highlight distinct molecular responses in SARS-CoV-2-infected cells, revealing specific genes and ncRNAs involved in viral replication, immune response, and apoptosis.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102559"},"PeriodicalIF":6.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12162024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285441","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

Bile acid accumulation induced by miR-122 deficiency in liver parenchyma promotes cancer cell growth in hepatocellular carcinoma. 肝实质miR-122缺乏诱导胆汁酸积累促进肝癌细胞生长。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-05-14 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102560

Jia-Hui Huang, Yi-Hang Li, Juan-Zhen Hong, Ruo-Nan Li, Ruizhi Wang, Zi-Qi Chen, Song-Yang Li, Ying-Lei Chi, Jin-Yu Huang, Ying Zhu

{"title":"Bile acid accumulation induced by miR-122 deficiency in liver parenchyma promotes cancer cell growth in hepatocellular carcinoma.","authors":"Jia-Hui Huang, Yi-Hang Li, Juan-Zhen Hong, Ruo-Nan Li, Ruizhi Wang, Zi-Qi Chen, Song-Yang Li, Ying-Lei Chi, Jin-Yu Huang, Ying Zhu","doi":"10.1016/j.omtn.2025.102560","DOIUrl":"10.1016/j.omtn.2025.102560","url":null,"abstract":"Liver is the central player in maintaining metabolic homeostasis of bile acids (BAs), but how BA is tightly controlled is still largely unknown, and the role of BAs in the development of hepatocellular carcinoma (HCC) remains controversial. Here, we discovered that elevated hepatic BAs were associated with miR-122 downregulation during liver regeneration, steatosis, and fibrosis. In vivo mouse models showed that miR-122 deficiency of liver parenchymal cells (hepatocytes) in paracancerous tissues resulted in significantly increased BA levels and altered hepatic BA spectrum, thus promoting liver tumor burden, which could be abated by administration of BA sequestrant. Mechanistically, miR-122 attenuated BA production by directly targeting BA synthesis gene HSD3B7, thereby inhibiting cancer cell proliferation and HCC growth. Overexpression of HSD3B7 in hepatocytes abolished the inhibitory effect of intrahepatic delivery of miR-122 on cancer cell proliferation in c-Myc/sgTP53-induced HCC model. Consistently, lower miR-122 was associated with elevated levels of BA and HSD3B7 protein in paracancerous tissues from HCC patients and also associated with worse overall survival of HCC patients. These findings provide novel insights into the roles of miR-122-mediated BA regulatory network of liver parenchymal cells of tumor microenvironment during HCC progression, which may provide attractive therapeutic targets for HCC.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102560"},"PeriodicalIF":6.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302534","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

CRISPR antiviral inhibits neurotrophic JC polyomavirus in 2D and 3D culture models through dual-gRNA excision by SaCas9. 通过SaCas9双grna切除，CRISPR抗病毒药物在2D和3D培养模型中抑制神经营养性JC多瘤病毒。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-05-14 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102556

Angela Rocchi, Shuren Liao, Hong Liu, Chen Chen, Senem Çakır, Anna Bellizzi, Hassen S Wollebo, Ilker K Sariyer, Kamel Khalili

{"title":"CRISPR antiviral inhibits neurotrophic JC polyomavirus in 2D and 3D culture models through dual-gRNA excision by SaCas9.","authors":"Angela Rocchi, Shuren Liao, Hong Liu, Chen Chen, Senem Çakır, Anna Bellizzi, Hassen S Wollebo, Ilker K Sariyer, Kamel Khalili","doi":"10.1016/j.omtn.2025.102556","DOIUrl":"10.1016/j.omtn.2025.102556","url":null,"abstract":"Without an effective antiviral, JC virus (JCV) has persisted throughout multiple epochs of immunosuppression, causing the opportunistic demyelinating disease, progressive multifocal leukoencephalopathy (PML). This study proposes a novel therapy using a dual-gRNA, SaCas9, CRISPR antiviral targeting JCV transcription factor, large tumor antigen (LT-Ag), and capsid protein, viral protein 1 (VP1). This treatment was validated using traditional two-dimensional cell culture. A recombinant cell line was produced from SVG astrocytes (SVGA) via lentiviral inoculation and puromycin selection. Following infection, sanger sequencing identified uniform excision of the circular dsDNA genome of JCV, significantly reducing viral load per genomic copy number on qPCR, viral proteins on western blot, and infectivity of viral progeny on adoptive transfer. Following this proof-of-concept using cell lines, translatability of results was advanced using three-dimensional, heterogeneous cerebral organoids (COs). COs were infected and treated with the lentivirus-packaged CRISPR antiviral. As observed in monolayer culture, a truncated genome was confirmed with sequencing, reducing viral load per genomic copy number on qPCR, protein levels on immunofluorescent imaging, and infectivity on adoptive transfer. The high efficacy of this JCV-targeting CRISPR antiviral in the context of cerebral organoids expounds on its value for the currently untreatable JCV and PML.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102556"},"PeriodicalIF":6.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12159223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285440","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

Harnessing endogenous miRNA targeting ZIKV: A cutting-edge strategy to inhibit virus infection. 利用内源性miRNA靶向ZIKV：一种抑制病毒感染的前沿策略

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-05-14 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102562

Rhubia S M Rosa, Soledad Palameta, Jessica M Toscaro, Michael E Miller, Paulo S Lopes-de-Oliveira, Marcio C Bajgelman

{"title":"Harnessing endogenous miRNA targeting ZIKV: A cutting-edge strategy to inhibit virus infection.","authors":"Rhubia S M Rosa, Soledad Palameta, Jessica M Toscaro, Michael E Miller, Paulo S Lopes-de-Oliveira, Marcio C Bajgelman","doi":"10.1016/j.omtn.2025.102562","DOIUrl":"10.1016/j.omtn.2025.102562","url":null,"abstract":"Emerging RNA virus outbreaks, including Zika virus, highlight the urgent need for novel antiviral strategies. Zika virus, a positive-strand RNA virus, causes congenital Zika syndrome, and to date, there are no approved vaccines or antiviral treatments. In this context, microRNAs are small non-coding RNAs that regulate gene expression and show potential as antiviral agents due to their ability to target viral RNA, making them a promising therapeutic approach against Zika syndrome. In this study, we identified endogenous microRNAs that interact with the virus genome using computational algorithms and overexpressed them in VERO cells. Twelve microRNAs reduced viral cytopathic effects by more than 50% in cells infected with a Brazilian Zika virus strain. Additionally, we used a computational platform to select pharmacological compounds capable of modulating endogenous microRNAs in human cells, achieving over 90% inhibition of Zika virus activity. These findings offer a promising path through drug repurposing for antiviral therapy by modulating endogenous microRNAs, with potential applications for other positive-strand RNA viruses.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102562"},"PeriodicalIF":6.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12155756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275426","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

AAVone: A cost-effective, single-plasmid solution for efficient AAV production with reduced DNA impurities. AAVone：一种经济高效的单质粒解决方案，用于高效生产AAV，减少DNA杂质。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-05-14 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102563

Rongze Yang, Ngoc Tam Tran, Taylor Chen, Mengtian Cui, Yuyan Wang, Tapan Sharma, Yu Liu, Jiantao Zhang, Xinxu Yuan, Danmeng Zhang, Cuiping Chen, Zhen Shi, Lemin Wang, Yuling Dai, Haniya Zaidi, Jiarui Liang, May Chen, Dabbu Jaijyan, Huan Hu, Bing Wang, Cheng Xu, Wenhui Hu, Guangping Gao, Daozhan Yu, Phillip W L Tai, Qizhao Wang

{"title":"AAVone: A cost-effective, single-plasmid solution for efficient AAV production with reduced DNA impurities.","authors":"Rongze Yang, Ngoc Tam Tran, Taylor Chen, Mengtian Cui, Yuyan Wang, Tapan Sharma, Yu Liu, Jiantao Zhang, Xinxu Yuan, Danmeng Zhang, Cuiping Chen, Zhen Shi, Lemin Wang, Yuling Dai, Haniya Zaidi, Jiarui Liang, May Chen, Dabbu Jaijyan, Huan Hu, Bing Wang, Cheng Xu, Wenhui Hu, Guangping Gao, Daozhan Yu, Phillip W L Tai, Qizhao Wang","doi":"10.1016/j.omtn.2025.102563","DOIUrl":"10.1016/j.omtn.2025.102563","url":null,"abstract":"Currently, the most common approach for manufacturing good manufacturing practice (GMP)-grade adeno-associated virus (AAV) vectors involves transiently transfecting mammalian cells with three plasmids that carry the essential components for production. Here, we developed an all-in-one, single-plasmid AAV production system, called AAVone, in which the adenovirus helper genes (E2A, E4orf6, and VA RNA), AAV packaging genes (rep and cap), and the vector transgene cassette are consolidated into a single compact plasmid with a 13-kb backbone. The AAVone system achieves a 2- to 4-fold increase in yields, exhibits low batch-to-batch variation, eliminates the need for fine-tuning the ratios of the three plasmids, and simplifies the production process, compared with the traditional triple-plasmid system. AAVs generated by the AAVone system show similar in vitro and in vivo transduction efficiency, but a substantial reduction in DNA impurities from plasmid bacterial backbones and a marked reduction in non-functional snap-back genomes. The AAVone system does not pose a risk for generating replication-competent AAV contaminants. Furthermore, the AAVone system requires significantly less DNAs for AAV production, while achieving favorable full:empty particle ratios and further reducing impurities. In summary, the AAVone platform is a highly efficient, straightforward, cost-effective, and highly consistent AAV production system, making it particularly suitable for manufacturing of GMP-grade AAV vectors.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102563"},"PeriodicalIF":6.1,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12155843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275425","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

Durable HTT silencing using non-evolved dCas9 epigenome editors in patient-derived cells. 在患者来源的细胞中使用非进化的dCas9表观基因组编辑器进行持久的HTT沉默

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-05-14 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102561

Jennifer J Waldo, Julian A N M Halmai, Ankita Singh, Casiana E Gonzalez, Yi-An Chen, Shaylyn A Carthen, Jan A Nolta, Kyle D Fink

{"title":"Durable HTT silencing using non-evolved dCas9 epigenome editors in patient-derived cells.","authors":"Jennifer J Waldo, Julian A N M Halmai, Ankita Singh, Casiana E Gonzalez, Yi-An Chen, Shaylyn A Carthen, Jan A Nolta, Kyle D Fink","doi":"10.1016/j.omtn.2025.102561","DOIUrl":"10.1016/j.omtn.2025.102561","url":null,"abstract":"Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a trinucleotide repeat expansion in exon 1 of the huntingtin (HTT) gene. Nuclease-deficient Cas9 protein (dCas9) epigenetic editing for targeted gene regulation is a promising therapeutic approach for HD through downregulation of the causative gene, HTT. A screen of several dCas9 variants with expanded PAM recognition was fused to KRAB and DNMT3A/L to assess the ability to downregulate total HTT. Surprisingly, only S pdCas9 could significantly downregulate HTT, while expanded PAM recognition variants dxCas9 and dCas9-VQR were less efficient or unable to reduce HTT expression. Using our lead construct with S pdCas9, DNA methylation changes were assessed through reduced representation bisulfite sequencing, showing high on-target increases in DNA methylation and few off-targets. In addition, HTT silencing was mitotically stable for up to 6 weeks in a rapidly dividing cell line. Finally, significant downregulation of HTT was achieved in patient-derived neuronal stem cells, showing the efficacy of this system in a disease-relevant cell type. This approach represents a novel therapeutic pathway for the treatment of HD.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102561"},"PeriodicalIF":6.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12163160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302535","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

CircITSN1/EIF4A3/Itsn1 axis mediates postoperative cognitive dysfunction in aged mice: A novel mechanism and therapeutic target. CircITSN1/EIF4A3/Itsn1轴介导老年小鼠术后认知功能障碍：一个新的机制和治疗靶点。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-05-08 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102555

Changteng Zhang, Xiaoyu Zhu, Rui Gao, Hai Chen, Caiyi Yan, Wangyang Liu, Lina Yang, Xianzheng Zeng, Haoran Yang, Jin Liu, Qi Li, Daqing Ma, Tao Zhu, Chan Chen

{"title":"CircITSN1/EIF4A3/Itsn1 axis mediates postoperative cognitive dysfunction in aged mice: A novel mechanism and therapeutic target.","authors":"Changteng Zhang, Xiaoyu Zhu, Rui Gao, Hai Chen, Caiyi Yan, Wangyang Liu, Lina Yang, Xianzheng Zeng, Haoran Yang, Jin Liu, Qi Li, Daqing Ma, Tao Zhu, Chan Chen","doi":"10.1016/j.omtn.2025.102555","DOIUrl":"10.1016/j.omtn.2025.102555","url":null,"abstract":"Circular RNAs (circRNAs) are stable noncoding RNAs that play a crucial role in neurodegenerative diseases, and they have been implicated in the pathogenesis of postoperative cognitive dysfunction (POCD). However, their underlying molecular mechanisms in POCD remain poorly understood. This study identified hsa_circRNA_061570 as significantly upregulated in plasma after anesthesia/surgery using high-throughput circRNA microarray screening, correlating with cognitive decline. Its murine homolog, circITSN1, was further investigated using shRNA-mediated knockdown in the hippocampus. Behavioral tests (open field, Y maze, and fear conditioning) revealed that circITSN1 suppression improved spatial and contextual memory without affecting motor function. Neuronal damage analysis via Golgi staining demonstrated that circITSN1 knockdown alleviated synaptic and dendritic spine impairments. Mechanistically, circITSN1 directly bound to RNA-binding protein EIF4A3, stabilizing Itsn1 mRNA and activating the JNK inflammatory pathway, thereby increasing pro-inflammatory cytokines. Spatial co-localization of circITSN1 with neuronal markers and EIF4A3 underscored its neuron-specific regulatory role. These findings establish circITSN1 as a critical mediator of neuroinflammation through JNK pathway activation, positioning it as both a diagnostic biomarker and a promising therapeutic target for POCD intervention. The study bridges circRNA biology with neurocognitive pathology, offering novel insights into post-surgical cognitive impairment mechanisms.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102555"},"PeriodicalIF":6.5,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248841","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

Novel mutation SLFN14 T853fs associated with inherited macrothrombocytopenia. 新突变SLFN14 T853fs与遗传性巨血小板减少症相关。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-05-07 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102554

Haixiao Xie, Shiyi Tang, Jianmin Shao, Ming Yang, Huida Tong, Linhua Zhang, Mingzhu Zhong, Xiaomin Yu, Laixi Bi, Yuming Wang, Rongying Ou, Chen Ling, Liqing Zhu

{"title":"Novel mutation SLFN14 T853fs associated with inherited macrothrombocytopenia.","authors":"Haixiao Xie, Shiyi Tang, Jianmin Shao, Ming Yang, Huida Tong, Linhua Zhang, Mingzhu Zhong, Xiaomin Yu, Laixi Bi, Yuming Wang, Rongying Ou, Chen Ling, Liqing Zhu","doi":"10.1016/j.omtn.2025.102554","DOIUrl":"10.1016/j.omtn.2025.102554","url":null,"abstract":"SLFN14-related inherited thrombocytopenia (SLFN14-related IT) is a hereditary disorder involving ribosomopathy and platelet dysfunction. Affected patients exhibit significant bleeding tendencies. To date, five affected pedigrees have been reported, all harboring mutations within the \"ATPase associated with diverse cellular activities\" (AAA) domain. In this study, we identified a novel T853fs variant located in the \"helicase\" domain. SLFN14 expression was markedly reduced in platelets from the patients and in Meg-01 cells transfected with T853fs plasmid. Functional assays revealed a defection of T853fs variant in both arachidonic acid (AA)-induced aggregation and fibrinogen-induced adhesion. Unlike previously reported mutations in the AAA domain, which significantly upregulate ribosomal protein genes and mitochondrial translation pathways, the T853fs mutation identified in this study did not affect mitochondrial translation. Immunofluorescence assay showed that T853fs variant exhibited diffuse cytoplasmic localization. Further RNA sequencing (RNA-seq) analysis revealed the significant regulation of T853fs mutation on pathways related to ion channels and dense granule, which are crucial to platelet function. In conclusion, this study identifies a new SLFN14 mutation and highlights the phenotypic diversity of SLFN14-RT.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102554"},"PeriodicalIF":6.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12159219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285443","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

Antibody and aptamer-based therapies for osteoarthritis: Application of antibodies and promise of aptamers. 基于抗体和适配体的骨关节炎治疗：抗体的应用和适配体的前景。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-05-05 eCollection Date: 2025-06-10 DOI: 10.1016/j.omtn.2025.102552

Huaizhi Chen, Zijian Ye, Jasmijn V Korpershoek, Laura B Creemers, Harrie Weinans, Jaqueline Lourdes Rios

{"title":"Antibody and aptamer-based therapies for osteoarthritis: Application of antibodies and promise of aptamers.","authors":"Huaizhi Chen, Zijian Ye, Jasmijn V Korpershoek, Laura B Creemers, Harrie Weinans, Jaqueline Lourdes Rios","doi":"10.1016/j.omtn.2025.102552","DOIUrl":"10.1016/j.omtn.2025.102552","url":null,"abstract":"Osteoarthritis (OA) is a common degenerative inflammatory joint disease with progressive loss of articular cartilage that undermines patients' quality of life. There are no regulatory-approved, disease-modifying OA medications, despite a great deal of studies done to elucidate OA pathogenesis. Until now, OA pharmacological treatment focused mainly on generalized inhibition of inflammation and pain. Currently, monoclonal antibodies and nucleic-acid aptamers emerge as targeted therapies offering potential alternatives by addressing the complex challenges posed by OA, such as specifically reducing inflammation and pain in the joint targeting specific molecular key players, instead of a systemic and generalized approach like with non-steroidal anti-inflammatory drugs. Aptamers' properties, including structure versatility, reduced immunogenicity, and flexible administration methods, position them as high-potential candidates for OA treatment. This review summarizes results from clinical trials applying monoclonal antibodies to treat OA, preclinical research, and the development of aptamers as a new generation of targeting agents. Meanwhile, it provides a comprehensive comparison of the characteristics, advantages, and limitations of aptamers versus monoclonal antibodies. Notably, the promising applications of aptamers, demonstrated in other inflammatory and degenerative conditions, underscore their potential for OA therapy. We anticipate that the application of aptamer could offer a new way of OA pharmacological intervention.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 2","pages":"102552"},"PeriodicalIF":6.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12145836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248839","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