Molecular Therapy最新文献_第9页

Intrinsic/proximal cell surface marker logic-gated extracellular targeted protein degradation in specific cell population. 内在/近端细胞表面标记逻辑门控细胞外靶向蛋白降解在特定细胞群。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-05-07 DOI: 10.1016/j.ymthe.2025.05.002

Yafeng Wang,Guiquan Zhang,Ping Rong,Panpan Guo,Shisheng Huang,Yang Hang,Pei Wang,Lin Tang,Xiaojing Li,Xiaojun Tang,Shuai Ding,Xingxu Huang,Jianghuai Liu,Lingyun Sun

{"title":"Intrinsic/proximal cell surface marker logic-gated extracellular targeted protein degradation in specific cell population.","authors":"Yafeng Wang,Guiquan Zhang,Ping Rong,Panpan Guo,Shisheng Huang,Yang Hang,Pei Wang,Lin Tang,Xiaojing Li,Xiaojun Tang,Shuai Ding,Xingxu Huang,Jianghuai Liu,Lingyun Sun","doi":"10.1016/j.ymthe.2025.05.002","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.05.002","url":null,"abstract":"Molecular tether-mediated extracellular targeted protein degradation (eTPD) presents an innovative technology and underlies a promising drug modality. However, to precisely implement eTPD within specific cell compartments remains a significant challenge. As eTPD depends on the degrader molecule expression and activity, we first seek to expand the panel of potential eTPD degraders. To this end, more than fifty receptors with variable tissue distributions are screened for identification of those with substantial endocytic rates. We subsequently assemble the bispecific, \"Selected endocytic carrier-targeting chimeras (SecTAC)\", and validate their efficacies to program the target cells to internalize membrane/extracellular protein cargoes (or nucleic acids). Moreover, administration of a SecTAC for removal of excessive IgG via a currently validated, emerging degrader (CD71) leads to evident therapeutic effect in a mouse lupus model. To further enhance cell-targeting specificity, we next develop logic-gated eTPD (LOG-eTPD) based on combination of chimeras that indirectly couple cargo and degrader via another cell surface gating marker. Particularly, we find that a selective surface marker from the neighboring cells may also be exploited as input for LOG-eTPD in a therapeutically relevant context. Taken together, the present work has laid strong foundation for developing eTPD agents that combine high potency with precision and safety.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"48 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926388","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

Template-assisted sequence knock-in rescues skeletal and cardiac muscle function in a deletion model of Duchenne muscular dystrophy. 在杜氏肌营养不良缺失模型中，模板辅助序列敲入可挽救骨骼肌和心肌功能。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-05-07 DOI: 10.1016/j.ymthe.2025.05.005

Sina Fatehi,Matthew J Rok,Ryan M Marks,Emily Huynh,Natalie Kozman,Hong Anh Truong,Lijun Chi,Bei Yan,Enzhe Khazeeva,Paul Delgado-Olguin,Evgueni A Ivakine,Ronald D Cohn

{"title":"Template-assisted sequence knock-in rescues skeletal and cardiac muscle function in a deletion model of Duchenne muscular dystrophy.","authors":"Sina Fatehi,Matthew J Rok,Ryan M Marks,Emily Huynh,Natalie Kozman,Hong Anh Truong,Lijun Chi,Bei Yan,Enzhe Khazeeva,Paul Delgado-Olguin,Evgueni A Ivakine,Ronald D Cohn","doi":"10.1016/j.ymthe.2025.05.005","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.05.005","url":null,"abstract":"Duchenne muscular dystrophy (DMD) poses challenges in therapy design due to dystrophin's complex role in maintaining muscle function since the restoration of truncated protein products has failed to completely address the disease's pathophysiology in clinical trials. As ∼70% of patients harbour deletions, strategies enabling targeted DNA insertion to restore full-length dystrophin protein are essential. Here, we present template-assisted sequence knock-in (TASK), a strategy that we employed to specifically correct the Dmd Δ52-54 mutation in a murine model. By co-delivering a repair template and the Cas9 nuclease using AAV9s, the splice-competent sequence for Dmd exons 52-54 was integrated into the residual intron 54 locus, resulting in the systemic restoration of full-length dystrophin at therapeutically relevant levels in the heart and across all skeletal muscles, leading to significant functional improvements. TASK demonstrates the highest efficiency of exogenous DNA knock-in reported to date, achieving rescue of key dystrophic hallmarks in a deletion model of DMD.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"16 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926390","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

Safety and efficacy of gene therapy for RAG1-deficient SCID. 基因治疗rag1缺陷SCID的安全性和有效性。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-03-18 DOI: 10.1016/j.ymthe.2025.02.044

Frank J T Staal, Karin Pike-Overzet, Sander de Kivit, Lisa Ott de Bruin, Lucia Mamede, Martine Pergent, Johan Prevot, Michael Rothe, Axel Schambach, Arjan Lankester

引用次数: 0

Spatial Multi-Omics Reveals the Potential Involvement of SPP1+ Fibroblasts in Determining Metabolic Heterogeneity and Promoting Metastatic Growth of Colorectal Cancer Liver Metastasis. 空间多组学揭示SPP1+成纤维细胞在决定结直肠癌肝转移代谢异质性和促进转移生长中的潜在参与。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-05-07 DOI: 10.1016/j.ymthe.2025.05.004

Yuzhen Gao,Xiuping Zhang,Shenglong Xia,Qing Chen,Qinchao Tong,Shaobo Yu,Rui An,Cheng Cheng,Wenbo Zou,Leilei Liang,Xinyou Xie,Zhangfa Song,Rong Liu,Jun Zhang

{"title":"Spatial Multi-Omics Reveals the Potential Involvement of SPP1+ Fibroblasts in Determining Metabolic Heterogeneity and Promoting Metastatic Growth of Colorectal Cancer Liver Metastasis.","authors":"Yuzhen Gao,Xiuping Zhang,Shenglong Xia,Qing Chen,Qinchao Tong,Shaobo Yu,Rui An,Cheng Cheng,Wenbo Zou,Leilei Liang,Xinyou Xie,Zhangfa Song,Rong Liu,Jun Zhang","doi":"10.1016/j.ymthe.2025.05.004","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.05.004","url":null,"abstract":"This study aims to investigate key microscopic regions involved in colorectal cancer liver metastasis (CRLM), focusing on the crucial role of cancer-associated fibroblasts (CAFs) in promoting tumor progression and providing molecular and metabolism-level insights for its diagnosis and treatment using multi-omics. We followed 12 fresh surgical samples from 2 untreated CRLM patients. Among these, 4 samples were used for spatial transcriptomics (ST), 4 for spatial metabolomics, and 4 for single-cell RNA sequencing (scRNA-seq). Additionally, 92 frozen tissue samples from 40 patients were collected. 7 patients were used for immunofluorescence and RT-qPCR, while 33 patients were used for untargeted metabolomics. ST revealed that the spatial regions of CRLM consists of 7 major components, with fibroblast-dominated regions being the most prominent. These regions are characterized by diverse cell-cell interactions and immunosuppressive, and tumor growth-promoting environments. scRNA-seq identified that SPP1+ fibroblasts interact with CD44+ tumor cells, as confirmed through immunofluorescence. Spatial metabolomics revealed suberic acid and tetraethylene glycol as specific metabolic components of this structure, which was further validated by untargeted metabolomics. In conclusion, a SPP1+fibroblast-rich spatial region with metabolic reprogramming capabilities and immunosuppressive properties was identified in CRLM, which potentially facilitates metastatic outgrowth through interactions with tumor cells.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"12 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926387","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

Addressing barriers to clinical translation of extracellular vesicle therapeutics. 解决细胞外囊泡疗法临床翻译的障碍。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-02-25 DOI: 10.1016/j.ymthe.2025.02.020

Steven M Jay

引用次数: 0

Small RNAs as therapeutic agents: From catalytic motifs to regulatory pathways. 作为治疗药物的小 RNA：从催化元件到调控途径。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-04-02 DOI: 10.1016/j.ymthe.2025.03.053

John J Rossi, Saumya Das

引用次数: 0

GMP manufacturing of cell and gene therapy products: Challenges, opportunities, and pathways forward. 细胞和基因治疗产品的GMP生产：挑战、机遇和前进的途径。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-02-25 DOI: 10.1016/j.ymthe.2025.02.022

Brian Fury, Gerhard Bauer

{"title":"GMP manufacturing of cell and gene therapy products: Challenges, opportunities, and pathways forward.","authors":"Brian Fury, Gerhard Bauer","doi":"10.1016/j.ymthe.2025.02.022","DOIUrl":"10.1016/j.ymthe.2025.02.022","url":null,"abstract":"Cell and gene therapy (CGT) products have been emerging as life-saving and life-changing therapies over the last 20 years. The United States has been a forerider in the development of these therapeutic products and has also developed the pertinent manufacturing methods for these complicated \"living medicines.\" California has emerged as a prominent hub for CGT manufacturing, hosting a variety of good manufacturing practice (GMP) facilities. These facilities are pivotal in advancing CGT products from phase 1 to phase 3 clinical trials and, eventually, to commercialization. Despite California's strategic advantages, including its biotech ecosystem and access to venture capital, numerous challenges hinder its full potential. These include funding disparities, expertise limitations, stringent regulatory demands, and a mismatch between facility utilization and demand. This review explores these factors more in depth and provides a comprehensive analysis of the current state of GMP manufacturing for CGTs in California. The example of the current situation in the state of California may also serve as an analogy for other states; we chose California due to our decades of experience manufacturing CGT products in this state.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1886-1888"},"PeriodicalIF":12.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12126763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516170","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

Current trends in gene therapy to treat inherited disorders of the brain. 基因疗法治疗遗传性脑部疾病的最新趋势。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-04-02 DOI: 10.1016/j.ymthe.2025.03.057

Zaneta Matuszek, Brandon L Brown, Carolyn M Yrigollen, Megan S Keiser, Beverly L Davidson

引用次数: 0

AAV vector development, back to the future. AAV载体发展，回到未来。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-04-03 DOI: 10.1016/j.ymthe.2025.03.064

Lester Suarez-Amaran, Liujiang Song, Anna P Tretiakova, Sheila A Mikhail, Richard Jude Samulski

{"title":"AAV vector development, back to the future.","authors":"Lester Suarez-Amaran, Liujiang Song, Anna P Tretiakova, Sheila A Mikhail, Richard Jude Samulski","doi":"10.1016/j.ymthe.2025.03.064","DOIUrl":"10.1016/j.ymthe.2025.03.064","url":null,"abstract":"Adeno-associated virus (AAV) has become a pivotal tool in gene therapy, providing a safe and efficient platform for long-term transgene expression. This review presents a comprehensive analysis of AAV's historical development, from its initial identification as a \"contaminant\" to its current clinical applications. We examine the molecular evolution of AAV, detailing advancements in vector engineering, rational design, directed evolution platforms, and computational modeling, which have expanded its therapeutic potential across diverse disease areas. Additionally, we explore AAV genome regulation, with a particular focus on inverted terminal repeats (ITRs) and AAV capsid-genome interactions, which play a crucial role in vector transduction efficiency and host adaptation. An assessment of past and present clinical trials as well as future directions is provided to illustrate the field's trajectory. Finally, another unique milestone in AAV research is also reported; namely, a pool of AAV libraries has been successfully administered to human decedents and analyzed, representing a transformative step in AAV evolution and selection for human applications. These studies should pave the way for more refined AAV vector optimization, accelerating the development of next-generation gene therapies with enhanced clinical translatability, potentially accelerating the gene therapy revolution.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1903-1936"},"PeriodicalIF":12.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12126818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788668","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

Therapeutic application of extracellular vesicles in human diseases. 细胞外囊泡在人类疾病中的治疗应用。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-04-03 DOI: 10.1016/j.ymthe.2025.04.002

Allancer Nunes, Tianpeng Zhang, Xiaodong Mu, Paul D Robbins

引用次数: 0