Molecular Therapy最新文献_第10页

Genetically reprogrammed exosomes for cancer immunotherapy.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-05 Epub Date: 2025-02-25 DOI: 10.1016/j.ymthe.2025.02.009

Wenxing Gu, Qingchang Tian, Tian Xie, Xiaoyuan Chen

引用次数: 0

In situ blockade of TNF-TNFR2 axis via oncolytic adenovirus improves antitumor efficacy in solid tumors. 通过溶瘤腺病毒原位阻断 TNF-TNFR2 轴可提高实体瘤的抗肿瘤疗效。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-05 Epub Date: 2025-01-23 DOI: 10.1016/j.ymthe.2025.01.033

Xiaozhen Kang, Yifeng Han, Mengdi Wu, Yuxin Li, Peng Qian, Chuning Xu, Zhengyun Zou, Jie Dong, Jiwu Wei

引用次数: 0

Retraction Notice to: Hypoxia-induced lncHILAR promotes renal cancer metastasis via ceRNA for the miR-613/206/ 1-1-3p/Jagged-1/Notch/CXCR4 signaling pathway.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-05 Epub Date: 2025-01-31 DOI: 10.1016/j.ymthe.2025.01.044

Guanghui Hu, Junjie Ma, Jin Zhang, Yonghui Chen, Huan Liu, Yiran Huang, Junhua Zheng, Yunfei Xu, Wei Xue, Wei Zhai

引用次数: 0

Optimizing CAR-T treatment: A T²EVOLVE guide to raw and starting material selection. 优化 CAR-T 治疗：T2EVOLVE 原料和起始材料选择指南》。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-05 Epub Date: 2024-11-12 DOI: 10.1016/j.ymthe.2024.11.017

Sergio Navarro, Carole Moukheiber, Susana Inogés Sancho, Marta Ruiz Guillén, Ascensión López-Díaz de Cerio, Carmen Sanges, Toshimitsu Tanaka, Sylvain Arnould, Javier Briones, Harry Dolstra, Michael Hudecek, Rashmi Choudhary, Inga Schapitz, Manel Juan, Nina Worel, Delphine Ammar, Maik Luu, Mirko Müller, Bernd Schroeder, Hélène Negre, Paul Franz

{"title":"Optimizing CAR-T treatment: A T2EVOLVE guide to raw and starting material selection.","authors":"Sergio Navarro, Carole Moukheiber, Susana Inogés Sancho, Marta Ruiz Guillén, Ascensión López-Díaz de Cerio, Carmen Sanges, Toshimitsu Tanaka, Sylvain Arnould, Javier Briones, Harry Dolstra, Michael Hudecek, Rashmi Choudhary, Inga Schapitz, Manel Juan, Nina Worel, Delphine Ammar, Maik Luu, Mirko Müller, Bernd Schroeder, Hélène Negre, Paul Franz","doi":"10.1016/j.ymthe.2024.11.017","DOIUrl":"10.1016/j.ymthe.2024.11.017","url":null,"abstract":"Chimeric antigen receptor (CAR)-T cell products, classified as Advanced Therapy Medicinal Products (ATMPs), have shown promising outcomes in cancer immunotherapy. The quality of raw and starting materials used in manufacturing is critical to ensure the efficacy and safety of CAR-T cell products and depends primarily on the selection of the right materials and the right suppliers. It is essential to consider a long-term strategy when selecting raw and starting materials to prevent delays in the supply of innovative, high-quality, and safe therapies to patients. A thorough assessment will allow developers not only to select suppliers who comply with regulatory requirements but also to ensure a sustainable supply of materials throughout the development and the commercial phases. A careful selection of materials and suppliers can avoid the need of comparability studies due to changes in the supply of materials, impacting costs and causing significant delays in development and treatment readiness for patients. This work, coordinated by the T2EVOLVE IMI consortium, provides guidance for the selection and handling of raw and starting materials. By following these suggestions, developers can ensure that they use high quality raw and starting materials through the product development and life cycle, resulting in safe and effective CAR-T therapies for patients.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"847-865"},"PeriodicalIF":12.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11897765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624260","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

Targeting the TRIM21-PD-1 axis potentiates immune checkpoint blockade and CAR-T cell therapy.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-05 Epub Date: 2025-02-03 DOI: 10.1016/j.ymthe.2025.01.047

Jie Shi, Zijian Zhang, Hsin-Yi Chen, Yingmeng Yao, Shanwen Ke, Kechun Yu, Jiangzhou Shi, Xiangling Xiao, Chuan He, Bolin Xiang, Yishuang Sun, Minling Gao, Xixin Xing, Haisheng Yu, Xiyong Wang, Wei-Chien Yuan, Bugi Ratno Budiarto, Shih-Yu Chen, Tongcun Zhang, Yu-Ru Lee, Haichuan Zhu, Jinfang Zhang

{"title":"Targeting the TRIM21-PD-1 axis potentiates immune checkpoint blockade and CAR-T cell therapy.","authors":"Jie Shi, Zijian Zhang, Hsin-Yi Chen, Yingmeng Yao, Shanwen Ke, Kechun Yu, Jiangzhou Shi, Xiangling Xiao, Chuan He, Bolin Xiang, Yishuang Sun, Minling Gao, Xixin Xing, Haisheng Yu, Xiyong Wang, Wei-Chien Yuan, Bugi Ratno Budiarto, Shih-Yu Chen, Tongcun Zhang, Yu-Ru Lee, Haichuan Zhu, Jinfang Zhang","doi":"10.1016/j.ymthe.2025.01.047","DOIUrl":"10.1016/j.ymthe.2025.01.047","url":null,"abstract":"Dysregulation of T cells is a major limitation for the clinical success of T cell-based cancer immunotherapies, such as immune checkpoint blockade and chimeric antigen receptor (CAR)-T cell therapy. Understanding the underlying mechanisms for regulating T cell functions can facilitate designing therapeutic strategies to improve immunotherapies. Here, we report that TRIM21 impairs CD8+ T cell activation and anti-tumor immunity. Mechanistically, TRIM21 catalyzes the K63-linked ubiquitination on programmed cell death-1 (PD-1) at K233, leading to stabilization of PD-1 through antagonizing its K48-linked ubiquitination and degradation. Thus, Trim21 knockout (KO) significantly decreases PD-1 expression and enhances the activation of cytotoxic CD8+ T cells, which sensitizes tumors to anti-CTLA-4 immunotherapy. Notably, Trim21 KO anti-CD19 CAR-T cells exhibit improved anti-tumor efficacy. These results reveal the molecular mechanism by which TRIM21-mediated K63-linked ubiquitination on PD-1 restrains the activation of CD8+ T cells, highlighting that targeting the TRIM21-PD-1 axis as a potential therapeutic strategy to potentiate cancer immunotherapy.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1073-1090"},"PeriodicalIF":12.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11897759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190044","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

Long-read RNA sequencing: A transformative technology for exploring transcriptome complexity in human diseases. 长读 RNA 测序：探索人类疾病转录组复杂性的变革性技术。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-05 Epub Date: 2024-11-19 DOI: 10.1016/j.ymthe.2024.11.025

Isabelle Heifetz Ament, Nicole DeBruyne, Feng Wang, Lan Lin

引用次数: 0

Visualizing lipid nanoparticle trafficking for mRNA vaccine delivery in non-human primates. 非人类灵长类动物mRNA疫苗递送的脂质纳米颗粒运输可视化

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-05 Epub Date: 2025-01-10 DOI: 10.1016/j.ymthe.2025.01.008

Maureen Buckley, Mariluz Araínga, Laura Maiorino, Ivan S Pires, B J Kim, Katarzyna Kaczmarek Michaels, Jonathan Dye, Kashif Qureshi, Yiming J Zhang, Howard Mak, Jon M Steichen, William R Schief, Francois Villinger, Darrell J Irvine

{"title":"Visualizing lipid nanoparticle trafficking for mRNA vaccine delivery in non-human primates.","authors":"Maureen Buckley, Mariluz Araínga, Laura Maiorino, Ivan S Pires, B J Kim, Katarzyna Kaczmarek Michaels, Jonathan Dye, Kashif Qureshi, Yiming J Zhang, Howard Mak, Jon M Steichen, William R Schief, Francois Villinger, Darrell J Irvine","doi":"10.1016/j.ymthe.2025.01.008","DOIUrl":"10.1016/j.ymthe.2025.01.008","url":null,"abstract":"mRNA delivered using lipid nanoparticles (LNPs) has become an important subunit vaccine modality, but mechanisms of action for mRNA vaccines remain incompletely understood. Here, we synthesized a metal chelator-lipid conjugate enabling positron emission tomography (PET) tracer labeling of LNP/mRNA vaccines for quantitative visualization of vaccine trafficking in live mice and non-human primates (NHPs). Following intramuscular injection, we observed LNPs distributing through injected muscle tissue, simultaneous with rapid trafficking to draining lymph nodes (dLNs). Deltoid injection of LNPs mimicking human vaccine administration led to stochastic LNP delivery to three different sets of dLNs. LNP uptake in dLNs was confirmed by histology, and cellular analysis of tissues via flow cytometry identified antigen-presenting cells as the primary immune cell type responsible for early LNP uptake and mRNA translation. These results provide insights into the biodistribution of mRNA vaccines administered at clinically relevant doses, injection volumes, and injection sites in an important large animal model for vaccine development.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1105-1117"},"PeriodicalIF":12.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11897755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142966031","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

Focused ultrasound and microbubble-mediated delivery of CRISPR-Cas9 ribonucleoprotein to human induced pluripotent stem cells. 聚焦超声和微泡介导的CRISPR-Cas9核糖核蛋白向人诱导多能干细胞的传递。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-05 Epub Date: 2025-01-10 DOI: 10.1016/j.ymthe.2025.01.013

Kyle Hazel, Davindra Singh, Stephanie He, Zakary Guertin, Mathieu C Husser, Brandon Helfield

{"title":"Focused ultrasound and microbubble-mediated delivery of CRISPR-Cas9 ribonucleoprotein to human induced pluripotent stem cells.","authors":"Kyle Hazel, Davindra Singh, Stephanie He, Zakary Guertin, Mathieu C Husser, Brandon Helfield","doi":"10.1016/j.ymthe.2025.01.013","DOIUrl":"10.1016/j.ymthe.2025.01.013","url":null,"abstract":"CRISPR-Cas9 ribonucleoproteins (RNPs) have been heavily considered for gene therapy due to their high on-target efficiency, rapid activity, and lack of insertional mutagenesis relative to other CRISPR-Cas9 delivery formats. Genetic diseases such as hypertrophic cardiomyopathy currently lack effective treatment strategies and are prime targets for CRISPR-Cas9 gene editing technology. However, current in vivo delivery strategies for Cas9 pose risks of unwanted immunogenic responses. This proof-of-concept study aimed to demonstrate that focused ultrasound (FUS) in combination with microbubbles can be used to deliver Cas9-sgRNA (single-guide RNA) RNPs and functionally edit human induced pluripotent stem cells (hiPSCs) in vitro, a model system that can be expanded to cardiovascular research via hiPSC-derived cardiomyocytes. Here, we first determine acoustic conditions suitable for the viable delivery of large proteins to hiPSCs with clinical Definity microbubble agents using our customized experimental platform. From here, we delivered Cas9-sgRNA RNP complexes targeting the EGFP (enhanced green fluorescent protein) gene to EGFP-expressing hiPSCs for EGFP knockout. Simultaneous acoustic cavitation detection during treatment confirmed a strong correlation between microbubble disruption and viable FUS-mediated protein delivery in hiPSCs. This study shows for the first time the potential for an FUS-mediated technique for targeted and precise CRISPR-Cas9 gene editing in human stem cells.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"986-996"},"PeriodicalIF":12.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11897754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142966000","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

Functional rescue of F508del-CFTR through revertant mutations introduced by CRISPR base editing. 通过CRISPR碱基编辑引入的反向突变对F508del-CFTR的功能修复。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-05 Epub Date: 2025-01-10 DOI: 10.1016/j.ymthe.2025.01.011

Irene Carrozzo, Giulia Maule, Carmelo Gentile, Alessandro Umbach, Matteo Ciciani, Daniela Guidone, Martina De Santis, Gianluca Petris, Luis Juan Vicente Galietta, Daniele Arosio, Anna Cereseto

{"title":"Functional rescue of F508del-CFTR through revertant mutations introduced by CRISPR base editing.","authors":"Irene Carrozzo, Giulia Maule, Carmelo Gentile, Alessandro Umbach, Matteo Ciciani, Daniela Guidone, Martina De Santis, Gianluca Petris, Luis Juan Vicente Galietta, Daniele Arosio, Anna Cereseto","doi":"10.1016/j.ymthe.2025.01.011","DOIUrl":"10.1016/j.ymthe.2025.01.011","url":null,"abstract":"Cystic fibrosis (CF) is a life-shortening autosomal recessive disease caused by mutations in the CFTR gene, resulting in functional impairment of the encoded ion channel. F508del mutation, a trinucleotide deletion, is the most frequent cause of CF, affecting approximately 80% of persons with CF (pwCFs). Even though current pharmacological treatments alleviate the F508del-CF disease symptoms, there is no definitive cure. Here, we leveraged revertant mutations (RMs) in cis with F508del to rescue CFTR protein folding and restore its function. We developed CRISPR base editing strategies to efficiently and precisely introduce the desired mutations in the F508del locus. Both editing and CFTR function recovery were verified in CF cellular models, including primary epithelial cells derived from pwCFs. The efficacy of the CFTR recovery strategy was validated in cultures of pseudostratified epithelia from pwCF cells showing full recovery of ion transport. Additionally, we observed an additive effect by combining our strategy with small molecules that enhance F508del activity, thus paving the way to combinatorial therapies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"970-985"},"PeriodicalIF":12.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11897810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142966028","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

Scalable control of stem cell fate by riboswitch-regulated RNA viral vector without genomic integration. 无基因组整合的核糖体开关调节RNA病毒载体对干细胞命运的可扩展控制。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-05 Epub Date: 2025-01-10 DOI: 10.1016/j.ymthe.2025.01.005

Narae Kim, Yohei Yokobayashi

引用次数: 0