Molecular Therapy最新文献_第6页

In vivo-directed evolution identifies AAV-WM04 as a next-generation vector for potent and sustained hearing restoration in DFNB9. 体内定向进化确定AAV-WM04是DFNB9中有效和持续听力恢复的下一代载体。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-10-07 Epub Date: 2026-07-13 DOI: 10.1016/j.ymthe.2026.07.021

Yong Tao, Cenfeng Chu, Zhenzhe Cheng, Shan Yin, Yilin Sun, Ying Chen, Huifang Zhang, Shuyue Bao, Boyu Yang, Baoyi Feng, Xianyu Huang, Yao Lu, Qiuxiang Yang, Xuegao Mao, Qifang Zhou, Chenxi Jin, Zhuo Duan, Guisheng Zhong, Hao Wu

{"title":"In vivo-directed evolution identifies AAV-WM04 as a next-generation vector for potent and sustained hearing restoration in DFNB9.","authors":"Yong Tao, Cenfeng Chu, Zhenzhe Cheng, Shan Yin, Yilin Sun, Ying Chen, Huifang Zhang, Shuyue Bao, Boyu Yang, Baoyi Feng, Xianyu Huang, Yao Lu, Qiuxiang Yang, Xuegao Mao, Qifang Zhou, Chenxi Jin, Zhuo Duan, Guisheng Zhong, Hao Wu","doi":"10.1016/j.ymthe.2026.07.021","DOIUrl":"10.1016/j.ymthe.2026.07.021","url":null,"abstract":"Efficient and cell-specific gene delivery to cochlear inner hair cells (IHCs) remains a major challenge for inner ear gene therapy. Here, we identify and characterize a novel adeno-associated virus (AAV)2-derived capsid, AAV-WM04, that enables highly efficient and selective IHC transduction at low doses. Using an in-vivo-directed evolution strategy, we generated a randomized AAV2 capsid library with 9 amino acid insertions and performed iterative selection in the adult mouse cochlea. Next-generation sequencing revealed enrichment of several variants, among which AAV-WM04 exhibited superior packaging efficiency and pronounced IHC tropism. AAV-WM04 achieved near-complete IHC transduction throughout the cochlear axis in adult mice, outperforming clinically relevant vectors with minimal off-target expression and no detectable ototoxicity. Selective IHC transduction was observed in non-human primates following local delivery, providing proof-of-concept evidence supporting the translational potential of AAV-WM04. Therapeutically, AAV-WM04 enabled efficient dual-AAV trans-splicing delivery of the large OTOF gene, resulting in uniform full-length otoferlin expression in IHCs. In a humanized OtofQ829X/Q829X mouse model, AAV-WM04 restored auditory function across a broad frequency range at relatively low doses and achieved sustained hearing recovery. These findings establish AAV-WM04 as a next-generation IHC-targeted vector with high efficiency, safety, and cross-species applicability for precision gene therapy of hereditary hearing loss.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"5726-5744"},"PeriodicalIF":11.4,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148437556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Tissue-specific silencing of synthetic mRNAs by de-targeting elements maps vaccination-competent tissues and allows Cas9 de-immunization. 通过去靶向元件对合成mrna进行组织特异性沉默，绘制疫苗耐受组织，并允许Cas9去免疫。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-10-07 Epub Date: 2026-07-29 DOI: 10.1016/j.ymthe.2026.07.050

Guendalina Froechlich, Annagiulia Scognamiglio, Simone Totaro, Linda Nocchi, Emilio Pellino, Andrea Campanile, Luigia Infante, Giulio Miano, Alessandra Centore, Francesco Molfetta, Alessandra Napolano, Anna Morena D'Alise, Silvia Parisi, Alfredo Nicosia, Emanuele Sasso, Nicola Zambrano

{"title":"Tissue-specific silencing of synthetic mRNAs by de-targeting elements maps vaccination-competent tissues and allows Cas9 de-immunization.","authors":"Guendalina Froechlich, Annagiulia Scognamiglio, Simone Totaro, Linda Nocchi, Emilio Pellino, Andrea Campanile, Luigia Infante, Giulio Miano, Alessandra Centore, Francesco Molfetta, Alessandra Napolano, Anna Morena D'Alise, Silvia Parisi, Alfredo Nicosia, Emanuele Sasso, Nicola Zambrano","doi":"10.1016/j.ymthe.2026.07.050","DOIUrl":"10.1016/j.ymthe.2026.07.050","url":null,"abstract":"The clinical success of mRNA/lipid nanoparticle (LNP)-based vaccines has established a leading platform for in vivo nucleic acid delivery, yet the relationship between biodistribution, tissue-specific translation, and immune activation remains poorly defined. Here, we systematically investigate the anatomical determinants of immune responses elicited by mRNA/LNPs. Using a gold-standard LNP formulation, we map exogenous mRNA biodistribution and functionally interrogate the contribution of distinct organs to both humoral and cellular immunity. To achieve this, we engineered mRNAs containing 3' UTR-embedded de-targeting elements as target sites for endogenous tissue-specific microRNAs, enabling selective silencing of antigen expression in defined anatomical compartments. This approach allowed us to causally link sites of translation with immune outputs. Applying this strategy to a spike-based vaccine model, we identify muscle and spleen as the most immunologically competent tissues required for robust immune priming. These findings provide a framework for the rational design of next-generation mRNA/LNP formulations with enhanced targeting precision, enabling dose sparing and reduced off-target effects. Furthermore, we extended this concept to genome editing by preventing mRNA-Cas9 expression in immune-active tissues, thereby reducing its immunogenicity and toxicity. Collectively, our work establishes a unifying strategy to optimize both potency and safety of mRNA-based therapeutics.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"6028-6038"},"PeriodicalIF":11.4,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Hepatotoxicity in clinical gene therapy for hemophilia A: Cellular stress and the immune system. 血友病A基因治疗的肝毒性：细胞应激和免疫系统。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-10-07 Epub Date: 2026-09-24 DOI: 10.1016/j.ymthe.2026.09.009

Roland W Herzog, Radoslaw Kaczmarek

引用次数: 0

A new capless self-amplifying RNA. 一种新的无帽自我扩增RNA。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-10-07 Epub Date: 2026-09-25 DOI: 10.1016/j.ymthe.2026.09.011

Patrick B Arbuthnot, Kristie M Bloom, Abdullah Ely

引用次数: 0

Cryo-thermal therapy reprograms myeloid cells into CCL5+ mature phenotype to increase T-cell infiltration and potentiates anti-PD-1 therapy 低温热疗法将骨髓细胞重编程为CCL5+成熟表型，以增加t细胞浸润并增强抗pd -1治疗

IF 12.4 1区医学

Molecular Therapy Pub Date : 2026-10-01 DOI: 10.1016/j.ymthe.2026.09.037

Yuankai Hao,Zelu Zhang,Shicheng Wang,Ke Wang,Xiaohui Liu,Ping Liu

引用次数: 0

Targeting the miR-3156-3p/K+ channel axis suppresses viral release and paralysis in enterovirus D68 infection 靶向miR-3156-3p/K+通道轴抑制肠病毒D68感染中的病毒释放和瘫痪

IF 12.4 1区医学

Molecular Therapy Pub Date : 2026-09-30 DOI: 10.1016/j.ymthe.2026.09.038

Yueh-Te Lin, Yu-An Kung, Yu-Nong Gong, Huan-Jung Chiang, Kuei-Ching Hsiung, Hou-Chen Lee, Wen-Fang Tang, Chung-Guei Huang, Jim-Tong Horng, Shin-Ru Shih

{"title":"Targeting the miR-3156-3p/K+ channel axis suppresses viral release and paralysis in enterovirus D68 infection","authors":"Yueh-Te Lin, Yu-An Kung, Yu-Nong Gong, Huan-Jung Chiang, Kuei-Ching Hsiung, Hou-Chen Lee, Wen-Fang Tang, Chung-Guei Huang, Jim-Tong Horng, Shin-Ru Shih","doi":"10.1016/j.ymthe.2026.09.038","DOIUrl":"https://doi.org/10.1016/j.ymthe.2026.09.038","url":null,"abstract":"Viruses rely on egress machinery to exit cells, a step that is crucial for their transmission. While non-enveloped RNA viruses, such as enteroviruses, are typically associated with the lytic release pathway, emerging evidence suggests they can also be packaged within vesicles for non-lytic release. However, the molecular mechanisms that regulate viral release remain unclear. Here, we performed a genome-wide CRISPR–Cas9 screen in A549 cells and identified the microRNA hsa-miR-3156-1 as a critical host factor for enterovirus infection. Both the primary and mature forms of miR-3156-1 were upregulated following infection, with miR-3156-3p acting as a positive regulator of viral infection by directly targeting the 3′-untranslated regions of the K<ce:sup loc=\"post\">+</ce:sup> channel-associated genes <ce:italic>KCNV1</ce:italic>, <ce:italic>KCNJ2</ce:italic>, <ce:italic>KCNK3</ce:italic>, and <ce:italic>KCNK5</ce:italic>, thereby causing plasma membrane depolarization and Ca<ce:sup loc=\"post\">2+</ce:sup> influx, which increase viral release. Pre-administration of a miR-3156-3p antagomir alleviated virus-associated acute flaccid paralysis in an ICR neonatal mouse model. Our findings reveal how the miR-3156-3p/K<ce:sup loc=\"post\">+</ce:sup> channel axis controls enterovirus release, highlighting potential prophylactic targets.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"113 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149084305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

PII: S1525-0016(26)00784-7

IF 12.4 1区医学

Molecular Therapy Pub Date : 2026-09-30 DOI: 10.1016/j.ymthe.2026.09.015

引用次数: 0

Receptor-ligand matching for precision allogeneic NK cell cancer therapies. 受体-配体匹配用于精确的异基因NK细胞癌治疗。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-09-30 DOI: 10.1016/j.ymthe.2026.09.036

Pablo Castro-Córdova, Isidora P Torres, Felipe Tapia-Rybertt, Joaquín Jerez, Maroun Khoury

{"title":"Receptor-ligand matching for precision allogeneic NK cell cancer therapies.","authors":"Pablo Castro-Córdova, Isidora P Torres, Felipe Tapia-Rybertt, Joaquín Jerez, Maroun Khoury","doi":"10.1016/j.ymthe.2026.09.036","DOIUrl":"10.1016/j.ymthe.2026.09.036","url":null,"abstract":"Allogeneic natural killer (NK) cell therapies have a favorable safety profile. NK cell cytotoxicity is the result of interactions between activating and inhibitory receptors and tumor-cell ligands expressed in the tumoral cell. This complex, donor-dependent interaction could explain variable persistence and limited durability across clinical trials. Here, we discuss an emergent framework for improving NK cell efficacy through systemic receptor-ligand matching grounded in NK licensing and donor-recipient immunogenetics, particularly KIR/HLA class I interactions, integrated with tumor ligand landscapes such as stress-induced NKG2D ligands. This review synthesizes how inhibitory and activating receptor repertoires calibrate NK functional competence, why identical KIR/HLA configurations yield context-dependent outcomes across malignancies and treatments, and how tumor immune evasion can decouple ligand expression from NK recognition. Based on this evidence hierarchy, we propose a biomarker-driven stratification framework to guide decisions on donor selection, redosing, and combination therapy. We further discuss how emerging machine learning classifiers and multiscale computational models could extend this framework to the clinical scale. Finally, we propose that the systematic incorporation of receptor-ligand immunogenetics into the design of an adoptive NK cell clinical trial is a necessary and tractable step toward improving the mechanistic interpretability, clinical development, and reproducibility of allogeneic NK cell therapies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Anti-CD19-engineered exosomes enable B cell-targeted anti-BAFF mRNA delivery to alleviate lupus progression 抗cd19工程外泌体使B细胞靶向抗baff mRNA递送减轻狼疮进展

IF 12.4 1区医学

Molecular Therapy Pub Date : 2026-09-29 DOI: 10.1016/j.ymthe.2026.08.040

Linda Zeng,Jingxian Shu,Shuping Zhong,Xin Dong,Yongjian Wu,Xi Huang

引用次数: 0

Protein trans-splicing: Solving the challenge of gene therapy for large genes 蛋白质反式剪接：解决大基因基因治疗的挑战

IF 12.4 1区医学

Molecular Therapy Pub Date : 2026-09-29 DOI: 10.1016/j.ymthe.2026.09.017

Rachel R. Stine,James J. Dowling

引用次数: 0