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

Erratum: Whole-transcriptome analysis of aluminum-exposed rat hippocampus and identification of ceRNA networks to investigate neurotoxicity of Al. 勘误：铝暴露大鼠海马的全转录组分析和 ceRNA 网络的鉴定，以研究铝的神经毒性。

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-06-04 eCollection Date: 2024-06-11 DOI: 10.1016/j.omtn.2024.102232

Chanting He, Xiaoyan Zhao, Yang Lei, Jisheng Nie, Xiaoting Lu, Jing Song, Linping Wang, Huan Li, Fangqu Liu, Yidan Zhang, Qiao Niu

引用次数: 0

Protection of animals against devastating RNA viruses using CRISPR-Cas13s 利用 CRISPR-Cas13s 保护动物免受毁灭性 RNA 病毒的侵害

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-05-31 DOI: 10.1016/j.omtn.2024.102235

Adnan Asadbeigi, Mohammad Reza Bakhtiarizadeh, Mojtaba Saffari, Mohammad Hossein Modarressi, Naser Sadri, Zahra Ziafati Kafi, Hassan Fazilaty, Arash Ghalyanchilangeroudi, Hossein Esmaeili

{"title":"Protection of animals against devastating RNA viruses using CRISPR-Cas13s","authors":"Adnan Asadbeigi, Mohammad Reza Bakhtiarizadeh, Mojtaba Saffari, Mohammad Hossein Modarressi, Naser Sadri, Zahra Ziafati Kafi, Hassan Fazilaty, Arash Ghalyanchilangeroudi, Hossein Esmaeili","doi":"10.1016/j.omtn.2024.102235","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102235","url":null,"abstract":"The intrinsic nature of CRISPR-Cas in conferring immunity to bacteria and archaea has been repurposed to combat pathogenic agents in mammalian and plant cells. In this regard, CRISPR-Cas13 systems have proved their remarkable potential for single-strand RNA viruses targeting. Here, different types of Cas13 orthologs were applied to knockdown foot-and-mouth disease virus (FMDV), a highly contagious disease of a wide variety of species with genetically diverse strains and is widely geographically distributed. Using programmable CRISPR RNAs capable of targeting conserved regions of the viral genome, all Cas13s from CRISPR system type VI (subtype A/B/D) could comprehensively target and repress different serotypes of FMDV virus. This approach has the potential to destroy all strains of a virus as targets the ultra-conserved regions of genome. We experimentally compared the silencing efficiency of CRISPR and RNAi by designing the most effective short hairpin RNAs according to our developed scoring system and observed comparable results. This study showed successful usage of various Cas13 enzymes for suppression of FMDV, which provides a flexible strategy to battle with other animal infectious RNA viruses, an underdeveloped field in the biotechnology scope.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"11 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141520689","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

Deletion of miR-146a enhances therapeutic protein restoration in model of dystrophin exon skipping 在肌营养不良蛋白外显子跳越模型中，缺失 miR-146a 可增强治疗蛋白的恢复能力

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-05-24 DOI: 10.1016/j.omtn.2024.102228

Nikki M. McCormack, Kelsey A. Calabrese, Christina M. Sun, Christopher B. Tully, Christopher R. Heier, Alyson A. Fiorillo

{"title":"Deletion of miR-146a enhances therapeutic protein restoration in model of dystrophin exon skipping","authors":"Nikki M. McCormack, Kelsey A. Calabrese, Christina M. Sun, Christopher B. Tully, Christopher R. Heier, Alyson A. Fiorillo","doi":"10.1016/j.omtn.2024.102228","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102228","url":null,"abstract":"Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by the absence of dystrophin protein. One current DMD therapeutic strategy, exon skipping, produces a truncated dystrophin isoform using phosphorodiamidate morpholino oligomers (PMOs). However, the potential of exon skipping therapeutics has not been fully realized as increases in dystrophin protein have been minimal in clinical trials. Here, we investigate how miR-146a-5p, which is highly elevated in dystrophic muscle, impacts dystrophin protein levels. We find inflammation strongly induces miR-146a in dystrophic, but not wild-type myotubes. Bioinformatics analysis reveals that the dystrophin 3′ UTR harbors an miR-146a binding site, and subsequent luciferase assays demonstrate miR-146a binding inhibits dystrophin translation. In dystrophin-null mice, co-injection of miR-146a reduces dystrophin restoration by an exon 51 skipping PMO. To directly investigate how miR-146a impacts therapeutic dystrophin rescue, we generated with body-wide miR-146a deletion (). Administration of an exon skipping PMO via intramuscular or intravenous injection markedly increases dystrophin protein levels in vs. muscles; skipped dystrophin transcript levels are unchanged, suggesting a post-transcriptional mechanism of action. Together, these data show that miR-146a expression opposes therapeutic dystrophin restoration, suggesting miR-146a inhibition warrants further research as a potential DMD exon skipping co-therapy.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"26 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141256316","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

WITHDRAWN: SPOP Promotes Acute Myeloid Leukemia Initiation and Development Through miR-183-Mediated METAP2 Inhibition 撤回：SPOP 通过 miR-183 介导的 METAP2 抑制作用促进急性髓性白血病的发生和发展

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-05-21 DOI: 10.1016/j.omtn.2024.102219

Jifeng Yu, Yingmei Li, Ling Sun, Lijie Han, Yu Liu, Danfeng Zhang, Haizhou Xing, Xinsheng Xie, Dingming Wan, Zhongxing Jiang

引用次数: 0

WITHDRAWN: The miR-424/miR-503 MicroRNA Cluster Prevents the Malignant Phenotype in Cervical Cancer Cells by Negatively Regulating CCND1 撤回：miR-424/miR-503 微RNA群通过负调控 CCND1 防止宫颈癌细胞的恶性表型

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-05-21 DOI: 10.1016/j.omtn.2024.102218

Xiaomei Chen, Jing Liu, Xuefeng Hao, Lingling Yan, Fengli Gao

引用次数: 0

Precision genome editing offers hope for treatment of β-thalassemia and other genetic disorders 精准基因组编辑为治疗β地中海贫血症和其他遗传疾病带来希望

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-05-15 DOI: 10.1016/j.omtn.2024.102204

Zeeshan Abbas, Abdul Rahman, Bilal Aslam, Saima Aftab, Chunjing Feng, Zulqarnain Baloch

引用次数: 0

A cystic fibrosis gene editing approach that is on target. 囊性纤维化基因编辑方法，目标明确。

IF 6.5 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-05-08 eCollection Date: 2024-06-11 DOI: 10.1016/j.omtn.2024.102197

Joseph J Porter, John D Lueck

引用次数: 0

Precise correction of a spectrum of β-thalassemia mutations in coding and non-coding regions by base editors 通过碱基编辑器精确校正编码区和非编码区的β地中海贫血突变谱

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-05-03 DOI: 10.1016/j.omtn.2024.102205

Kirti Prasad, Nivedhitha Devaraju, Anila George, Nithin Sam Ravi, Joshua Paul P, Gokulnath Mahalingam, Vignesh Rajendiran, Lokesh Panigrahi, Vigneshwaran Venkatesan, Kartik Lakhotiya, Yogapriya Periyasami, Aswin Anand Pai, Yukio Nakamura, Ryo Kurita, Poonkuzhali Balasubramanian, Saravanabhavan Thangavel, Shaji R. Velayudhan, Gregory A. Newby, Srujan Marepally, Alok Srivastava, Kumarasamypet M. Mohankumar

{"title":"Precise correction of a spectrum of β-thalassemia mutations in coding and non-coding regions by base editors","authors":"Kirti Prasad, Nivedhitha Devaraju, Anila George, Nithin Sam Ravi, Joshua Paul P, Gokulnath Mahalingam, Vignesh Rajendiran, Lokesh Panigrahi, Vigneshwaran Venkatesan, Kartik Lakhotiya, Yogapriya Periyasami, Aswin Anand Pai, Yukio Nakamura, Ryo Kurita, Poonkuzhali Balasubramanian, Saravanabhavan Thangavel, Shaji R. Velayudhan, Gregory A. Newby, Srujan Marepally, Alok Srivastava, Kumarasamypet M. Mohankumar","doi":"10.1016/j.omtn.2024.102205","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102205","url":null,"abstract":"β-thalassemia/HbE results from mutations in the β-globin locus that impede the production of functional adult hemoglobin. Base editors (BEs) could facilitate the correction of the point mutations with minimal or no indel creation, but its efficiency and bystander editing for the correction of β-thalassemia mutations in coding and non-coding regions remains unexplored. Here, we screened BE variants in HUDEP-2 cells for their ability to correct a spectrum of β-thalassemia mutations that were integrated into the genome as fragments of . The identified targets were introduced into their endogenous genomic location using BEs and Cas9/homology-directed repair (HDR) to create cellular models with β-thalassemia. These β-thalassemia models were then used to assess the efficiency of correction in the native locus and functional β-globin restoration. Most bystander edits produced near target sites did not interfere with adult hemoglobin expression and are not predicted to be pathogenic. Further, the effectiveness of BE was validated for the correction of the pathogenic HbE variant in severe β/β-thalassaemia patient cells. Overall, our study establishes a novel platform to screen and select optimal BE tools for therapeutic genome editing by demonstrating the precise, efficient, and scarless correction of pathogenic point mutations spanning multiple regions of including the promoter, intron, and exons.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"20 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140939370","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

Sequencing-guided design of genetically encoded small RNAs targeting CAG repeats for selective inhibition of mutant huntingtin 以 CAG 重复序列为目标的基因编码小 RNA 的测序指导设计，用于选择性抑制突变杭汀蛋白

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-04-29 DOI: 10.1016/j.omtn.2024.102206

Mansi A. Parasrampuria, Adam A. White, Ramadevi Chilamkurthy, Adrian A. Pater, Fatima El-Azzouzi, Katy N. Ovington, Philip J. Jensik, Keith T. Gagnon

{"title":"Sequencing-guided design of genetically encoded small RNAs targeting CAG repeats for selective inhibition of mutant huntingtin","authors":"Mansi A. Parasrampuria, Adam A. White, Ramadevi Chilamkurthy, Adrian A. Pater, Fatima El-Azzouzi, Katy N. Ovington, Philip J. Jensik, Keith T. Gagnon","doi":"10.1016/j.omtn.2024.102206","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102206","url":null,"abstract":"Huntington’s disease (HD) is an incurable neurodegenerative disorder caused by genetic expansion of a CAG repeat sequence in one allele of the (HTT) gene. Reducing expression of the mutant HTT (mutHTT) protein has remained a clear therapeutic goal, but reduction of wild-type HTT is undesirable, as it compromises gene function and potential therapeutic efficacy. One promising allele-selective approach involves targeting the CAG repeat expansion with steric binding small RNAs bearing central mismatches. However, successful genetic encoding requires consistent placement of mismatches to the target within the small RNA guide sequence, which involves 5′ processing precision by cellular enzymes. Here, we used small RNA sequencing (RNA-seq) to monitor the processing precision of a limited set of CAG repeat-targeted small RNAs expressed from multiple scaffold contexts. Small RNA-seq identified expression constructs with high-guide strand 5′ processing precision and promising allele-selective inhibition of mutHTT. Transcriptome-wide mRNA-seq also identified an allele-selective small RNA with a favorable off-target profile. These results support continued investigation and optimization of genetically encoded repeat-targeted small RNAs for allele-selective HD gene therapy and underscore the value of sequencing methods to balance specificity with allele selectivity during the design and selection process.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"42 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140939373","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

Aberrant spliceosome activity via elevated intron retention and upregulation and phosphorylation of SF3B1 in chronic lymphocytic leukemia 慢性淋巴细胞白血病中通过内含子保留率升高、SF3B1 上调和磷酸化引起的剪接体活性异常

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-04-26 DOI: 10.1016/j.omtn.2024.102202

Manoj Kumar Kashyap, Hiren Karathia, Deepak Kumar, Roberto Vera Alvarez, Jose Vicente Forero-Forero, Eider Moreno, Juliana Velez Lujan, Carlos Ivan Amaya-Chanaga, Newton Medeiros Vidal, Zhe Yu, Emanuela M. Ghia, Paula A. Lengerke-Diaz, Daniel Achinko, Michael Y. Choi, Laura Z. Rassenti, Leonardo Mariño-Ramírez, Stephen M. Mount, Sridhar Hannenhalli, Thomas J. Kipps, Januario E. Castro

{"title":"Aberrant spliceosome activity via elevated intron retention and upregulation and phosphorylation of SF3B1 in chronic lymphocytic leukemia","authors":"Manoj Kumar Kashyap, Hiren Karathia, Deepak Kumar, Roberto Vera Alvarez, Jose Vicente Forero-Forero, Eider Moreno, Juliana Velez Lujan, Carlos Ivan Amaya-Chanaga, Newton Medeiros Vidal, Zhe Yu, Emanuela M. Ghia, Paula A. Lengerke-Diaz, Daniel Achinko, Michael Y. Choi, Laura Z. Rassenti, Leonardo Mariño-Ramírez, Stephen M. Mount, Sridhar Hannenhalli, Thomas J. Kipps, Januario E. Castro","doi":"10.1016/j.omtn.2024.102202","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102202","url":null,"abstract":"Splicing factor 3b subunit 1 (SF3B1) is the largest subunit and core component of the spliceosome. Inhibition of SF3B1 was associated with an increase in broad intron retention (IR) on most transcripts, suggesting that IR can be used as a marker of spliceosome inhibition in chronic lymphocytic leukemia (CLL) cells. Furthermore, we separately analyzed exonic and intronic mapped reads on annotated RNA-sequencing transcripts obtained from B cells ( = 98 CLL patients) and healthy volunteers ( = 09). We measured intron/exon ration to use that as a surrogate for alternative RNA splicing (ARS) and found that 66% of CLL-B cell transcripts had significant IR elevation compared with normal B cells (NBCs) and that correlated with mRNA downregulation and low expression levels. Transcripts with highest IR levels belonged to biological pathways associated with gene expression and RNA splicing. A >2-fold increase of active pSF3B1 in CLL-B cells compared with NBCs. Additionally, when the CLL-B cells were treated with macrolides (pladienolide-B), a significant decrease in pSF3B1, but not total SF3B1 protein was observed. These findings suggest that IR/ARS is increased in CLL, which is associated with SF3B1 phosphorylation and susceptibility to SF3B1 inhibitors. These data provide additional support to the relevance of ARS in carcinogenesis and evidence of pSF3B1 participation in this process.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"7 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140889393","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