Molecular Therapy最新文献_第5页

Efficient and selective kidney targeting by chemically modified carbohydrate conjugates. 通过化学修饰的碳水化合物共轭物高效、选择性地靶向肾脏。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-11-12 DOI: 10.1016/j.ymthe.2024.10.020

Vikas Kumar, Aniket Wahane, Ming Shen Tham, Stefan Somlo, Anisha Gupta, Raman Bahal

{"title":"Efficient and selective kidney targeting by chemically modified carbohydrate conjugates.","authors":"Vikas Kumar, Aniket Wahane, Ming Shen Tham, Stefan Somlo, Anisha Gupta, Raman Bahal","doi":"10.1016/j.ymthe.2024.10.020","DOIUrl":"10.1016/j.ymthe.2024.10.020","url":null,"abstract":"We investigated a renal tubule-targeting carbohydrate (RENTAC) that can selectively deliver small-molecule and nucleic acid analogs to the proximal convoluted tubules of the kidney following systemic delivery in mice. We comprehensively evaluated anti-miR-21-peptide nucleic acid-RENTAC, and fluorophore-RENTAC conjugates in cell culture and in vivo. We established that RENTAC conjugates showed megalin- and cubilin-dependent endocytic uptake in the immortalized kidney cell line. In vivo biodistribution studies confirmed the retention of RENTAC conjugates in the kidneys for several days compared with other organs. Immunofluorescence staining confirmed the selective distribution of the RENTAC conjugates in proximal convoluted tubules. We further demonstrated proximal convoluted tubule targeting features of RENTAC conjugates in a folic acid-induced kidney fibrosis mouse model. As a biological readout, we targeted miR-33 using antisense peptide nucleic acid (PNA) 33-RENTAC conjugates in the fibrotic kidney disease model. The targeted delivery of PNA 33-RENTAC resulted in slower fibrosis progression and decreased collagen deposition. We also confirmed that the RENTAC ligand did not exert any adverse reactions. Thus, we established that the RENTAC ligand can be used for broad clinical applications targeting the kidneys selectively.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4383-4400"},"PeriodicalIF":12.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624241","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

Retraction Notice to: Inhibition of Multiple Protective Signaling Pathways and Ad.5/3 Delivery Enhances mda-7/IL-24 Therapy of Malignant Glioma. 撤稿通知：抑制多种保护性信号通路和 Ad.5/3 递送可增强 mda-7/IL-24 对恶性胶质瘤的治疗。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-08-29 DOI: 10.1016/j.ymthe.2024.08.020

Hossein A Hamed, Adly Yacoub, Margaret A Park, Patrick J Eulitt, Rupesh Dash, Devanand Sarkar, Igor P Dmitriev, Maciej S Lesniak, Khalid Shah, Steven Grant, David T Curiel, Paul B Fisher, Paul Dent

引用次数: 0

PD-L1: From cancer immunotherapy to therapeutic implications in multiple disorders. PD-L1：从癌症免疫疗法到多种疾病的治疗意义。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-09-28 DOI: 10.1016/j.ymthe.2024.09.026

Daeun Lee, Minjeong Cho, Eunseo Kim, Youngbin Seo, Jong-Ho Cha

{"title":"PD-L1: From cancer immunotherapy to therapeutic implications in multiple disorders.","authors":"Daeun Lee, Minjeong Cho, Eunseo Kim, Youngbin Seo, Jong-Ho Cha","doi":"10.1016/j.ymthe.2024.09.026","DOIUrl":"10.1016/j.ymthe.2024.09.026","url":null,"abstract":"The PD-L1/PD-1 signaling pathway is the gold standard for cancer immunotherapy. Therapeutic antibodies targeting PD-1, such as nivolumab (Opdivo) and pembrolizumab (Keytruda), and PD-L1, including atezolizumab (Tecentriq), durvalumab (Imfinzi), and avelumab (Bavencio) have received Food and Drug Administration approval and are currently being used to treat various cancers. Traditionally, PD-L1 is known as an immune checkpoint protein that binds to the PD-1 receptor on its surface to inhibit the activity of T cells, which are the primary effector cells in antitumor immunity. However, it also plays a role in cancer progression, which goes beyond traditional understanding. Here, we highlight the multifaceted mechanisms of action of PD-L1 in cancer cell proliferation, transcriptional regulation, and systemic immune suppression. Moreover, we consider the potential role of PD-L1 in the development and pathogenesis of diseases other than cancer, explore PD-L1-focused therapeutic approaches for these diseases, and assess their clinical relevance. Through this review, we hope to provide deeper insights into the PD-L1/PD-1 signaling pathway and present a broad perspective on potential therapeutic approaches for cancer and other diseases.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4235-4255"},"PeriodicalIF":12.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350560","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

Reversion of metabolic dysfunction-associated steatohepatitis by skeletal muscle-directed FGF21 gene therapy. 骨骼肌引导的 FGF21 基因疗法可逆转代谢功能障碍相关性脂肪性肝炎。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-28 DOI: 10.1016/j.ymthe.2024.10.023

Veronica Jimenez, Victor Sacristan, Claudia Jambrina, Maria Luisa Jaen, Estefania Casana, Sergio Muñoz, Sara Marcó, Maria Molas, Miquel Garcia, Ignasi Grass, Xavier León, Ivet Elias, Albert Ribera, Gemma Elias, Victor Sanchez, Laia Vilà, Alba Casellas, Tura Ferre, Jordi Rodó, Ana Carretero, Marti Pumarola, Marc Navarro, Anna Andaluz, Xavier Moll, Sonia Añor, Sylvie Franckhauser, Mercedes Vergara, Assumpta Caixàs, Fatima Bosch

{"title":"Reversion of metabolic dysfunction-associated steatohepatitis by skeletal muscle-directed FGF21 gene therapy.","authors":"Veronica Jimenez, Victor Sacristan, Claudia Jambrina, Maria Luisa Jaen, Estefania Casana, Sergio Muñoz, Sara Marcó, Maria Molas, Miquel Garcia, Ignasi Grass, Xavier León, Ivet Elias, Albert Ribera, Gemma Elias, Victor Sanchez, Laia Vilà, Alba Casellas, Tura Ferre, Jordi Rodó, Ana Carretero, Marti Pumarola, Marc Navarro, Anna Andaluz, Xavier Moll, Sonia Añor, Sylvie Franckhauser, Mercedes Vergara, Assumpta Caixàs, Fatima Bosch","doi":"10.1016/j.ymthe.2024.10.023","DOIUrl":"10.1016/j.ymthe.2024.10.023","url":null,"abstract":"The highly prevalent metabolic dysfunction-associated steatohepatitis (MASH) is associated with liver steatosis, inflammation, and hepatocyte injury, which can lead to fibrosis and may progress to hepatocellular carcinoma and death. New treatment modalities such as gene therapy may be transformative for MASH patients. Here, we describe that one-time intramuscular administration of adeno-associated viral vectors of serotype 1 (AAV1) encoding native fibroblast growth factor 21 (FGF21), a key metabolic regulator, resulted in sustained increased circulating levels of the factor, which mediated long-term (>1 year) MASH and hepatic fibrosis reversion and halted development of liver tumors in obese male and female mouse models. AAV1-FGF21 treatment also counteracted obesity, adiposity, and insulin resistance, which are significant drivers of MASH. Scale-up to large animals successfully resulted in safe skeletal muscle biodistribution and biological activity in key metabolic tissues. Moreover, as a step toward the clinic, circulating FGF21 levels were characterized in obese, insulin-resistant and MASH patients. Overall, these results underscore the potential of the muscle-directed AAV1-FGF21 gene therapy to treat MASH and support its clinical translation.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4285-4302"},"PeriodicalIF":12.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569300","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

Passing on the Molecular Therapy baton. 传递分子疗法的接力棒

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-11-15 DOI: 10.1016/j.ymthe.2024.11.005

Roland W Herzog

引用次数: 0

A tumor-conditional IL-15 safely synergizes with immunotherapy to enhance antitumor immune responses. 一种肿瘤条件性 IL-15 可安全地与免疫疗法协同增强抗肿瘤免疫反应。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-28 DOI: 10.1016/j.ymthe.2024.10.021

Wenqiang Shi, Wei Xu, Luyao Song, Qiongya Zeng, Gen Qi, Ying Qin, Zhikun Li, Xianglei Liu, Zheng Jiao, Yonggang Zhao, Nan Liu, Huili Lu

{"title":"A tumor-conditional IL-15 safely synergizes with immunotherapy to enhance antitumor immune responses.","authors":"Wenqiang Shi, Wei Xu, Luyao Song, Qiongya Zeng, Gen Qi, Ying Qin, Zhikun Li, Xianglei Liu, Zheng Jiao, Yonggang Zhao, Nan Liu, Huili Lu","doi":"10.1016/j.ymthe.2024.10.021","DOIUrl":"10.1016/j.ymthe.2024.10.021","url":null,"abstract":"It is a challenge to invigorate tumor-infiltrating lymphocytes without causing immune-related adverse events, which also stands as a primary factor contributing to resistance against cancer immunotherapies. Interleukin (IL)-15 can potently promote expansion and activation of T cells, but its clinical use has been limited by dose-limiting toxicities. In this study, we develop a tumor-conditional IL-15 (pro-IL-15), which masks IL-15 with steric hindrance caused by Fc fragment and IL-15Rα-sushi domain. Upon reaching the tumor site, it can be cleaved by tumor-associated proteases to release an IL-15 superagonist, resulting in potent antitumor activities. Systemic delivery of pro-IL-15 demonstrates significantly reduced toxicity but uncompromised antitumor efficacy. Pro-IL-15 can yield better effectors and vitalize terminally exhausted CD8+ T cells to overcome checkpoint blockade resistance. Moreover, pro-IL-15 promotes chemotaxis and activation of adoptive T cells, leading to eradication of advanced solid tumors and durable cures. Furthermore, pro-IL-15 shows promise for synergizing with other immunotherapies like IL-12 and oncolytic virus by improving the CD8/Treg ratio and interferon-γ levels, resulting in substantial regression of both local and metastatic cold tumors. Collectively, our results suggest that pro-IL-15 represents a compelling strategy for overcoming resistance to current immunotherapies while avoiding toxicities.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4482-4496"},"PeriodicalIF":12.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569249","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

Ex vivo-generated human CD1c⁺ regulatory B cells by a chemically defined system suppress immune responses and alleviate graft-versus-host disease. 通过化学定义系统在体内生成的人 CD1c+ 调节性 B 细胞可抑制免疫反应并缓解移植物抗宿主疾病。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-26 DOI: 10.1016/j.ymthe.2024.10.026

Yingying Bao, Jialing Liu, Zhishan Li, Yueming Sun, Junhua Chen, Yuanchen Ma, Gang Li, Tao Wang, Huanyi Liu, Xiaoran Zhang, Rong Yan, Zhenxia Yao, Xiaolu Guo, Rui Fang, Jianqi Feng, Wenjie Xia, Andy Peng Xiang, Xiaoyong Chen

{"title":"Ex vivo-generated human CD1c+ regulatory B cells by a chemically defined system suppress immune responses and alleviate graft-versus-host disease.","authors":"Yingying Bao, Jialing Liu, Zhishan Li, Yueming Sun, Junhua Chen, Yuanchen Ma, Gang Li, Tao Wang, Huanyi Liu, Xiaoran Zhang, Rong Yan, Zhenxia Yao, Xiaolu Guo, Rui Fang, Jianqi Feng, Wenjie Xia, Andy Peng Xiang, Xiaoyong Chen","doi":"10.1016/j.ymthe.2024.10.026","DOIUrl":"10.1016/j.ymthe.2024.10.026","url":null,"abstract":"IL-10+ regulatory B cells (Bregs) show great promise in treating graft-versus-host disease (GVHD), a life-threatening complication of post-hematopoietic stem cell transplantation. However, obtaining high-quality human IL-10+ Bregs in vitro remains a challenge due to the lack of unique specific markers and the triggering of pro-inflammatory cytokine expression. Here, by uncovering the critical signaling pathways in Breg induction by mesenchymal stromal cells (MSCs), we first established an efficient Breg induction system based on MSCs and GSK-3β blockage (CHIR-99021), which had a robust capacity to induce IL-10+ Bregs while suppressing tumor necrosis factor α (TNF-α) expression. Furthermore, these Breg populations could be identified and enriched by CD1c+. Mechanistically, MSCs induced the expansion of Bregs through the PKA-mediated phosphorylation of cAMP response element-binding protein (CREB). Thus, we developed a chemically defined inducing protocol by PKA-CREB agonist, instead of MSCs, which can also effectively induce CD1c+ Bregs with lower TNF-α expression. Importantly, induced CD1c+ Bregs suppressed the proliferation of peripheral blood mononuclear cells and the inflammatory cytokine secretion of T cells. When adoptively transferred into a humanized mouse model of GVHD, induced CD1c+ Bregs effectively alleviated GVHD. Overall, we established an efficient ex vivo induction system for human Bregs, which has implications for developing novel Bregs-based therapies for GVHD.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4372-4382"},"PeriodicalIF":12.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569275","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

Recombinant adeno-associated virus as a delivery platform for ocular gene therapy: A comprehensive review. 重组腺相关病毒作为眼部基因治疗的传递平台：全面回顾。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-28 DOI: 10.1016/j.ymthe.2024.10.017

Jiang-Hui Wang, Wei Zhan, Thomas L Gallagher, Guangping Gao

{"title":"Recombinant adeno-associated virus as a delivery platform for ocular gene therapy: A comprehensive review.","authors":"Jiang-Hui Wang, Wei Zhan, Thomas L Gallagher, Guangping Gao","doi":"10.1016/j.ymthe.2024.10.017","DOIUrl":"10.1016/j.ymthe.2024.10.017","url":null,"abstract":"Adeno-associated virus (AAV) has emerged as a leading platform for in vivo gene therapy, particularly in ocular diseases. AAV-based therapies are characterized by low pathogenicity and broad tissue tropism and have demonstrated clinical success, as exemplified by voretigene neparvovec-rzyl (Luxturna) being the first gene therapy to be approved by the U.S. Food and Drug Administration to treat RPE65-associated Leber congenital amaurosis (LCA). However, several challenges remain in the development of AAV-based gene therapies, including immune responses, limited cargo capacity, and the need for enhanced transduction efficiency, especially for intravitreal delivery to photoreceptors and retinal pigment epithelium cells. This review explores the biology of AAVs in the context of gene therapy, innovations in capsid engineering, and clinical advancements in AAV-based ocular gene therapy. We highlight ongoing clinical trials targeting inherited retinal diseases and acquired conditions, discuss immune-related limitations, and examine novel strategies for enhancing AAV vector performance to address current barriers.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4185-4207"},"PeriodicalIF":12.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569299","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

Gene editing efficiencies and hematopoietic stem cell fitness in sickle cell disease: A balancing act. 镰状细胞病的基因编辑效率和造血干细胞适应性：平衡之术

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-11-19 DOI: 10.1016/j.ymthe.2024.11.009

John Strouboulis, Panicos Shangaris

引用次数: 0

Safety and efficacy studies of CRISPR-Cas9 treatment of sickle cell disease highlights disease-specific responses. 在临床相关条件下进行的 CRISPR/Cas9 治疗镰状细胞病的安全性和有效性研究突出了疾病特异性反应。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-07-22 DOI: 10.1016/j.ymthe.2024.07.015

Giacomo Frati, Megane Brusson, Gilles Sartre, Bochra Mlayah, Tristan Felix, Anne Chalumeau, Panagiotis Antoniou, Giulia Hardouin, Jean-Paul Concordet, Oriana Romano, Giandomenico Turchiano, Annarita Miccio

{"title":"Safety and efficacy studies of CRISPR-Cas9 treatment of sickle cell disease highlights disease-specific responses.","authors":"Giacomo Frati, Megane Brusson, Gilles Sartre, Bochra Mlayah, Tristan Felix, Anne Chalumeau, Panagiotis Antoniou, Giulia Hardouin, Jean-Paul Concordet, Oriana Romano, Giandomenico Turchiano, Annarita Miccio","doi":"10.1016/j.ymthe.2024.07.015","DOIUrl":"10.1016/j.ymthe.2024.07.015","url":null,"abstract":"Fetal hemoglobin (HbF) reactivation expression through CRISPR-Cas9 is a promising strategy for the treatment of sickle cell disease (SCD). Here, we describe a genome editing strategy leading to reactivation of HbF expression by targeting the binding sites (BSs) for the lymphoma-related factor (LRF) repressor in the γ-globin promoters. CRISPR-Cas9 treatment in healthy donor (HD) and patient-derived HSPCs resulted in a high frequency of LRF BS disruption and potent HbF synthesis in their erythroid progeny. LRF BS disruption did not impair HSPC engraftment and differentiation but was more efficient in SCD than in HD cells. However, SCD HSPCs showed a reduced engraftment and a myeloid bias compared with HD cells. We detected off-target activity and chromosomal rearrangements, particularly in SCD samples (likely because of the higher overall editing efficiency) but did not impact the target gene expression and HSPC engraftment and differentiation. Transcriptomic analyses showed that the editing procedure results in the up-regulation of genes involved in DNA damage and inflammatory responses, which was more evident in SCD HSPCs. This study provides evidence of efficacy and safety for an editing strategy based on HbF reactivation and highlights the need of performing safety studies in clinically relevant conditions, i.e., in patient-derived HSPCs.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4337-4352"},"PeriodicalIF":12.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141752179","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