Molecular Therapy最新文献_第2页

Gene supplementation with precise transgene expression rescues hearing loss in a mouse model with an Mpzl2 East Asian founder variant. 在Mpzl2东亚始祖变异体小鼠模型中，精确转基因表达的基因补充可挽救听力损失。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-10-06 DOI: 10.1016/j.ymthe.2025.10.005

Seung Hyun Jang,Hyeong Gi Song,Sun Young Joo,Jung Ah Kim,Se Jin Kim,Jae Young Choi,Jinsei Jung,Heon Yung Gee

{"title":"Gene supplementation with precise transgene expression rescues hearing loss in a mouse model with an Mpzl2 East Asian founder variant.","authors":"Seung Hyun Jang,Hyeong Gi Song,Sun Young Joo,Jung Ah Kim,Se Jin Kim,Jae Young Choi,Jinsei Jung,Heon Yung Gee","doi":"10.1016/j.ymthe.2025.10.005","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.10.005","url":null,"abstract":"Hearing loss is the most common sensory organ disorder, with genetic factors substantially contributing to the disease. Among the 87 genes responsible for autosomal recessive nonsyndromic hearing loss, mutations in MPZL2 have been frequently linked to mild-to-moderate autosomal recessive hearing loss (DFNB111). Here, we present multiple families whose hearing loss arose from biallelic mutations in the MPZL2 gene and found that the MPZL2 p.Q74* mutation may be a founder allele among East Asians. Furthermore, we generated an Mpzl2 p.Q74* knock-in mouse model that exhibited autosomal recessive, progressive, ski-sloping hearing loss with Deiter's cell degeneration. Gene supplementation using AAV-DJ or AAV-PHP.eB to deliver human MPZL2 (hMPZL2) under control of the CAG promoter induced ototoxicity, whereas employing an alternative EF1α promoter with AAV-DJ (DJ-EF1α-hMPZL2) circumvented this issue, restoring long-term auditory function and Deiter's cell survival in Mpzl2Q74∗/Q74∗ mice for up to 24 weeks. Overall, this study provides the foundational steps for developing a safe and effective biological treatment for DFNB111 and underscores the importance of precise regulation of target cells and transgene expression in AAV-based treatments.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"56 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240930","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

Innate Immune Cells in Chimeric Antigen Receptor Therapy. 嵌合抗原受体治疗中的先天免疫细胞。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-10-06 DOI: 10.1016/j.ymthe.2025.10.003

Marius Jassaud,Lydia Ziane-Chaouche,Marie Duhamel,Michel Salzet

{"title":"Innate Immune Cells in Chimeric Antigen Receptor Therapy.","authors":"Marius Jassaud,Lydia Ziane-Chaouche,Marie Duhamel,Michel Salzet","doi":"10.1016/j.ymthe.2025.10.003","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.10.003","url":null,"abstract":"Chimeric antigen receptor (CAR) therapies have revolutionized cancer treatment, particularly with the success of CAR-T cells in hematologic malignancies. However, their application to solid tumors remains limited by major challenges, including cytokine release syndrome (CRS), neurotoxicity, poor tumor infiltration, antigen heterogeneity, and high manufacturing costs. These limitations have prompted growing interest in alternative immune effector cells. Innate immune cells - such as natural killer (NK) cells, macrophages, invariant natural killer T (iNKT) cells, gamma delta (γδ) T cells, dendritic cells (DCs) and neutrophils - offer distinct advantages. They are associated with a lower risk of graft-versus-host disease (GvHD), possess intrinsic tumor-homing and cytotoxic properties, and are suitable for off-the-shelf therapeutic platforms. This review explores the biological rationale and clinical potential of CAR-engineered innate immune cells, highlighting key findings from preclinical and clinical studies. Finally, we discuss combinatorial strategies and future directions that could shape the next generation of CAR-based therapies for solid tumors.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"19 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240932","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

PAD4 promotes macrophage migration to aggravate tubulointerstitial injury in diabetic kidney disease. PAD4促进巨噬细胞迁移，加重糖尿病肾病小管间质损伤。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-10-06 DOI: 10.1016/j.ymthe.2025.10.009

Yunjie Xiong,Ruolin Li,Xiangjun Chen,Chuan Peng,Qinglian Zeng,Shuangshuang Zhu,Furong He,Jinshan Wu,Jiangyun Lei,Miaoyun Chen,Shiyun Tong,Yue Sun,Yong Xu,Wei Huang,Shumin Yang,Qifu Li,Jinbo Hu,Linqiang Ma

{"title":"PAD4 promotes macrophage migration to aggravate tubulointerstitial injury in diabetic kidney disease.","authors":"Yunjie Xiong,Ruolin Li,Xiangjun Chen,Chuan Peng,Qinglian Zeng,Shuangshuang Zhu,Furong He,Jinshan Wu,Jiangyun Lei,Miaoyun Chen,Shiyun Tong,Yue Sun,Yong Xu,Wei Huang,Shumin Yang,Qifu Li,Jinbo Hu,Linqiang Ma","doi":"10.1016/j.ymthe.2025.10.009","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.10.009","url":null,"abstract":"Peptidyl Arginine Deiminase 4 (PAD4) is an enzyme predominantly expressed in myeloid cells, and its role in diabetic kidney disease (DKD) remains unknown. We functionally characterized 48 PADI4 variants identified among 469,779 participants from UK Biobank and examined their associations with renal function. We found that most PADI4 variants causes loss of function, which was significantly associated with higher estimated glomerular filtration rate. We observed an enhanced PAD4 expression in renal tubulointerstitium among DKD patients and animal models of DKD. Both PAD4 deficiency in macrophages and PAD4 inhibitor GSK484 significantly alleviated renal tubulointerstitial injury by reducing macrophage infiltration in diabetic mice models. Mechanistically, PAD4 interacted with p65 to promote its binding to Cmklr1 promoter and induce the expression of Cmklr1, which led to an enhanced macrophage migration. These findings demonstrate the crucial role of PAD4-mediated macrophage migration in tubulointerstitial injury of DKD.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"74 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235748","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

CD8 co-receptor modulates the specificity profile of the 1G4 TCR against NY-ESO-1. CD8共受体调节1G4 TCR对NY-ESO-1的特异性。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-10-06 DOI: 10.1016/j.ymthe.2025.10.006

Heather F Jones,Zita Aretz,Ron S Gejman,Tara Cicic,David A Scheinberg

引用次数: 0

Langerhans Cell-targeted Protein Delivery Enhances Antigen-Specific Cellular Immune Response. 朗格汉斯细胞靶向蛋白递送增强抗原特异性细胞免疫反应。

IF 12 1区医学

Molecular Therapy Pub Date : 2025-10-04 DOI: 10.1016/j.ymthe.2025.10.008

Ramona Rica, Klara Klein, Litty Johnson, Gabriele Carta, Mirza Sarcevic, Freyja Langer, Christoph Rademacher, Robert Wawrzinek, Federica Quattrone, Florian Sparber

引用次数: 0

M2 Macrophage Exosomes Reverse Cardiac Functional Decline in Mice with Diet-Induced Myocardial Infarction by Suppressing Type 1 Interferon Signaling in Myeloid Cells. M2巨噬细胞外泌体通过抑制髓细胞中1型干扰素信号逆转饮食性心肌梗死小鼠心功能下降

IF 12 1区医学

Molecular Therapy Pub Date : 2025-10-04 DOI: 10.1016/j.ymthe.2025.10.010

Martin Ng, Alex S Gao, Tuan Anh Phu, Ngan K Vu, Robert L Raffai

{"title":"M2 Macrophage Exosomes Reverse Cardiac Functional Decline in Mice with Diet-Induced Myocardial Infarction by Suppressing Type 1 Interferon Signaling in Myeloid Cells.","authors":"Martin Ng, Alex S Gao, Tuan Anh Phu, Ngan K Vu, Robert L Raffai","doi":"10.1016/j.ymthe.2025.10.010","DOIUrl":"10.1016/j.ymthe.2025.10.010","url":null,"abstract":"Effective treatment strategies to alleviate heart failure that develops as a consequence of myocardial infarction (MI) remain an unmet need in cardiovascular medicine. In this study, we uncover that exosomes produced by human THP-1 macrophages cultured with the cytokine IL-4 (THP1-IL4-exo), reverse cardiac functional decline in mice that developed MI in response to diet-induced occlusive coronary atherosclerosis. Therapeutic benefits of THP1-IL4-exo stem from their ability to drive transcriptional reprogramming of inflammatory responses in myeloid cells. Notably, repeated infusions of THP1-IL4-exo led to the suppression of Type 1 Interferon signaling in circulating Ly-6Chi monocytes as well as in myeloid cells within the bone marrow and cardiac tissue. In vitro studies with primary macrophages stimulated with double-stranded DNA confirmed an ability for THP1-IL4-exo to confer suppression of Type 1 Interferon-mediated immune activation and inflammation. Collectively, these benefits contribute to the control of myelopoiesis, cardiac myeloid cell recruitment, and preserve populations of resident cardiac macrophages that together mitigate cardiac inflammation, adverse ventricular remodeling, and heart failure. Our findings introduce THP1-IL4-exo, one form of M2-macrophage exosomes, as novel anti-inflammatory and tissue repair therapeutics to preserve cardiac function post-MI.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.0,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233082","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

RNA Inosine Sensor-Guided TadA Mutational Scanning for Toxicity Minimization of Adenine Base Editors. RNA肌苷传感器引导的TadA突变扫描对腺嘌呤碱基编辑器的毒性最小化。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-10-04 DOI: 10.1016/j.ymthe.2025.10.011

Cheng Zhang,Ziliang Chen,Jixin Cao,Zui Zhang,Wei-Ke Li,Xinyi Zhang,Junying Chen,Jun Liu,Zhou Yuan,Feng Gao,Zehao Shi,Xing-Ming Zhao,Jingqi Chen,Changyou Zhan,Tian-Lin Cheng

{"title":"RNA Inosine Sensor-Guided TadA Mutational Scanning for Toxicity Minimization of Adenine Base Editors.","authors":"Cheng Zhang,Ziliang Chen,Jixin Cao,Zui Zhang,Wei-Ke Li,Xinyi Zhang,Junying Chen,Jun Liu,Zhou Yuan,Feng Gao,Zehao Shi,Xing-Ming Zhao,Jingqi Chen,Changyou Zhan,Tian-Lin Cheng","doi":"10.1016/j.ymthe.2025.10.011","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.10.011","url":null,"abstract":"The TadA component of adenine base editors (ABEs) induces widespread RNA off-target edits and raises safety concerns for their applications. However, the extent of RNA-editing-related toxicity remains elusive, and high-throughput engineering of ABEs focusing on RNA editing activities remains challenging. Here we demonstrate that RNA off-target editing of classical ABEs leads to substantial toxicity in vitro and in vivo. We then design a rapid, cost-effective and sensitive fluorescent RNA inosine sensor to accelerate RNA off-target editing evaluation and high-throughput screening in mammalian cells. Deep mutation scanning with the RNA sensor identifies various TadA8e mutants displaying minimized RNA editing activity, with the representative H52L/D53R mutant compatible with both SpCas9 and the compact IscB nickase. We show that the engineered ABEs could efficiently target clinically relevant sites in vitro and in vivo with enhanced precision, thereby providing promising tools for applications in which RNA-editing-related toxicity should be carefully evaluated and minimized.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"63 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229107","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

Real-World Outcomes of Delandistrogene Moxeparvovec Gene Therapy: Motor Outcomes and Emerging Safety Concerns. Delandistrogene moxparvovec基因治疗的实际结果：运动结果和新出现的安全性问题。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-10-04 DOI: 10.1016/j.ymthe.2025.10.007

Dennis J Keselman,Juliana C Small,Tiffany Seneviratne,Sarah McCague,Taylor L Kaschak,Sabrina W Yum,Andrea O'Brien,John F Brandsema,Tamir Diamond,Kathleen M Loomes,Kimberly Y Lin,Carol A Wittlieb-Weber,Oscar H Mayer,Scott G Daniel,Amy T Waldman,Benjamin J Samelson-Jones,Susan E Matesanz,Lindsey A George

{"title":"Real-World Outcomes of Delandistrogene Moxeparvovec Gene Therapy: Motor Outcomes and Emerging Safety Concerns.","authors":"Dennis J Keselman,Juliana C Small,Tiffany Seneviratne,Sarah McCague,Taylor L Kaschak,Sabrina W Yum,Andrea O'Brien,John F Brandsema,Tamir Diamond,Kathleen M Loomes,Kimberly Y Lin,Carol A Wittlieb-Weber,Oscar H Mayer,Scott G Daniel,Amy T Waldman,Benjamin J Samelson-Jones,Susan E Matesanz,Lindsey A George","doi":"10.1016/j.ymthe.2025.10.007","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.10.007","url":null,"abstract":"Delandistrogene moxeparvovec is currently the only commercially approved gene therapy for Duchenne muscular dystrophy (DMD). Herein we report real-world data of 11 ambulatory DMD patients, ages 4-6, treated with commercial delandistrogene moxeparvovec. Patients were prospectively and uniformally monitored for 1 year post-gene-transfer for safety and motor outcomes. Nine patients experienced 15 treatment-related toxicities; 4 required escalation of corticosteroids. Side effects included gastrointestinal symptoms (n=7), liver enzyme abnormalities (n=4), acute liver injury (n=2), and troponin-I elevations (n=3). In both patients with acute liver injury, troponin-I elevations occurred in close temporal association beginning 8-9 weeks post-gene-transfer that were responsive to corticosteroids. The clinical courses of these two patients was at least partially consistent with a cellular immune response to the AAV capsid. Troponin-I elevations were asymptomatic and without acute functional changes on echocardiogram. The cohort had improvements in year 1 motor function assessments relative to baseline, including a statistically significant median 4-point increase in North Star Ambulatory Assessment score; however, important confounding factors, e.g. baseline corticosteroid use, limit interpretation and will be important to control for in future real-world data sets. Additional follow-up is required to determine long-term safety and motor outcomes with unclear generalizability of our results.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"570 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229109","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

Overcoming Barriers to Commercially Pre-Viable Gene and Cell Therapies for Rare and Ultra-Rare Diseases. 克服商业上可行的基因和细胞治疗罕见和超罕见疾病的障碍。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-10-04 DOI: 10.1016/j.ymthe.2025.09.049

David Barrett,Paula M Cannon,Federico Mingozzi,Matthew Porteus,Isabelle Rivière,Terence R Flotte

{"title":"Overcoming Barriers to Commercially Pre-Viable Gene and Cell Therapies for Rare and Ultra-Rare Diseases.","authors":"David Barrett,Paula M Cannon,Federico Mingozzi,Matthew Porteus,Isabelle Rivière,Terence R Flotte","doi":"10.1016/j.ymthe.2025.09.049","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.049","url":null,"abstract":"Gene and cell therapies offer transformative potential for patients with rare and ultra-rare diseases. However, many treatments stall despite demonstration of safety and efficacy in pre-clinical studies and early-stage clinical trials. This market failure creates a barrier where otherwise successful therapies are unable to reach patients due to commercial non-viability. In March 2025, ASGCT held a workshop, \"Establishing and Maintaining Access to Gene and Cell Therapy for Rare and Ultrarare Diseases,\" focusing on developing actionable paths forward to ensure that successful gene therapies reach patients regardless of commercial viability. The field faces ongoing and deep-seated challenges; addressing them will require coordinated action across private companies, regulatory agencies, and non-profit organizations to explore non-traditional business models. During the workshop and described here, ASGCT reviewed a matrix of solutions encompassing regulatory innovations, manufacturing efficiencies, financial modeling, and patient-focused frameworks to ensure that efficacious gene and cell therapies reach the patients who need them. Strategies included the creation of a temporary repository for deprioritized gene and cell therapy programs offering support while working to identify new sponsors to continue clinical trials and the creation of a consortium of developers focused on accelerating timelines and reducing costs.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"32 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229108","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

Recombinant Orf viral vectors: A novel vaccine platform. 重组Orf病毒载体：一种新的疫苗平台。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-10-02 DOI: 10.1016/j.ymthe.2025.09.039

Pablo Penaloza-MacMaster

引用次数: 0