Molecular Therapy最新文献_第8页

Galectin-9 inhibition of the MIF-CD74/CD44 pathway suppresses chronic arthritis. 半乳糖凝集素-9抑制MIF-CD74/CD44通路抑制慢性关节炎。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-08-11 DOI: 10.1016/j.ymthe.2025.08.016

Meiling Li,Min-Kyung Nam,Jung Gon Kim,Juyeon Kang,Se-Hyeon Park,Su-Hyun Lee,Chaerin Kim,David Song,Jingchun Jin,Seung-Ah Yoo,Richard Bucala,Wan-Uk Kim

{"title":"Galectin-9 inhibition of the MIF-CD74/CD44 pathway suppresses chronic arthritis.","authors":"Meiling Li,Min-Kyung Nam,Jung Gon Kim,Juyeon Kang,Se-Hyeon Park,Su-Hyun Lee,Chaerin Kim,David Song,Jingchun Jin,Seung-Ah Yoo,Richard Bucala,Wan-Uk Kim","doi":"10.1016/j.ymthe.2025.08.016","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.08.016","url":null,"abstract":"The destructive potential of rheumatoid arthritis (RA) lies in the aggressive behavior of fibroblast-like synoviocyte (FLSs), which actively contribute to the erosion of cartilage and bone and may persist even in the face of apparent clinical remission. Therapeutic approaches targeting RA-FLSs have been developed to treat RA; however, there are no clinically approved drugs available at present. Here, single-cell RNA sequencing of RA-FLSs identified a distinct MIF-high subset with mitochondrial and ER dysfunction. MIF-high conditions led to increased survival, proliferation, and migration of FLSs, along with upregulation of CD44 and the CD44v6 isoform expression. We next explored whether a stable, recombinant form of galectin-9 C10-HPPY (designated as sGal-9), which acts as a CD44 blockade, regulates the MIF-induced aggressive phenotype of RA-FLSs. We found that sGal-9 remarkably reduced the increased proliferation, migration, invasion of RA-FLSs by inhibiting the MIF-CD44 pathway. Moreover, both local and systemic administration of sGal-9 substantially inhibited excessive cartilage and bone destruction by RA-FLSs in a xenotransplantation arthritis model and alleviated the severity of collagen-induced arthritis in mice, comparable to Enbrel and Tofacitinib. Conclusively, these data suggest that sGal-9 is effective at repressing destructive phenotypes of RA-FLSs as a novel anti-MIF agent.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"745 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144825758","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

Direct In Vivo Reprogramming to Relieve Tissue Ischemia via Induced Vasculogenesis. 直接体内重编程通过诱导血管生成来缓解组织缺血。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-08-09 DOI: 10.1016/j.ymthe.2025.08.013

Mervin C Yoder,Chandan K Sen

{"title":"Direct In Vivo Reprogramming to Relieve Tissue Ischemia via Induced Vasculogenesis.","authors":"Mervin C Yoder,Chandan K Sen","doi":"10.1016/j.ymthe.2025.08.013","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.08.013","url":null,"abstract":"There is an ongoing need for innovative cell and regenerative medicine therapies to promote vascular repair and regeneration to meet the growing global health concern of ischemic cardiovascular diseases. Direct reprogramming of somatic cells into an induced pluripotent state caused scientists to reconsider prior theories of cell differentiation and develop approaches to directly reprogram cells in vivo into other states or fates to adaptively replace cells lost to aging or disease. While direct in vivo reprogramming of fibroblast to cardiomyocytes, neurons, or pancreatic beta islet cell states has been studied since 2008, direct in vivo reprogramming of fibroblasts into induced vasculogenic cells was not reported until 2017. This review provides a brief overview of the field of in vitro direct reprogramming of fibroblasts into induced endothelial cells over the past decade and identifies key similarities and differences in approaches. The primary focus of this review is to discuss in detail 4 published reports of direct in vivo reprogramming of fibroblasts into vasculogenic cell states and identify a series of questions for future studies that will clarify the reprogrammed cells and potential for using these approaches for translation into larger preclinical models or human subjects.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"738 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812868","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

Preclinical development and a phase I trial of IMC001, an EpCAM-targeted CAR-T cell therapy, in patients with advanced gastric cancer. IMC001是一种epcam靶向CAR-T细胞疗法，用于晚期胃癌患者的临床前开发和I期试验。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-08-09 DOI: 10.1016/j.ymthe.2025.08.014

Weijia Fang,Zhengmao Lu,Jingyu Ge,Shuangshuang Zhang,Rui Zheng,Weiwei Yin,Ruidong Hao,Minmin Sun,Tianhang Luo

{"title":"Preclinical development and a phase I trial of IMC001, an EpCAM-targeted CAR-T cell therapy, in patients with advanced gastric cancer.","authors":"Weijia Fang,Zhengmao Lu,Jingyu Ge,Shuangshuang Zhang,Rui Zheng,Weiwei Yin,Ruidong Hao,Minmin Sun,Tianhang Luo","doi":"10.1016/j.ymthe.2025.08.014","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.08.014","url":null,"abstract":"Autologous EpCAM-targeted CAR-T cell therapy (IMC001) was developed for advanced gastric cancer (GC). This study evaluated the specificity, efficacy, and safety of IMC001 in preclinical models and a phase I dose-escalation/expansion trial in patients who had failed at least two lines of therapy. IMC001 specifically recognized EpCAM and exhibited potent anti-tumor activity in EpCAM-positive tumor cells, xenograft models, and patient-derived organoids. From August 2021 to May 2023, 12 advanced GC patients received IMC001. All patients experienced grade 3 or 4 treatment-related adverse events, mainly lymphopenia related to lymphodepletion, with no treatment-related deaths. Five patients experienced cytokine release syndrome (n=3, grade 3-4) and two patients experienced immune-related hepatitis (n=1, grade 3 in middle-dose group; n=1, grade 4 in high-dose group). Partial responses were observed in 33.3% (1/3) of low-dose patients and 40% (2/5) of middle-dose patients, achieving an objective response rate of 30% and a disease control rate of 70%. Median progression-free survival and overall survival were 4.5 and 8.4 months, respectively. One patient underwent conversion surgery at week 27 and remains alive 31.5 months post-infusion. These findings demonstrate an acceptable safety profile and promising efficacy of IMC001 in advanced GC, supporting further clinical development for refractory GC patients.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"15 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812865","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

METTL5 deficiency induces oligoasthenoteratozoospermia via impaired 18S rRNA m6A methylation in humans and mice. 在人和小鼠中，METTL5缺乏通过18S rRNA m6A甲基化受损诱导少弱异卵精子症。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-08-08 DOI: 10.1016/j.ymthe.2025.08.009

Mengya Zhang,Xueguang Zhang,Chen Tan,Ting Jiang,Zheng Cao,Yufei Chen,Feng Qiao,Gelin Huang,Chaoye Ma,Huixia Li,Mei Ye,Lei Wang,Liandong Zuo,Jun Yu,Xiaofeng Li,Yunfang Zhang,Yue-Qiu Tan,Shuibin Lin,Wenming Xu,Hao Chen

{"title":"METTL5 deficiency induces oligoasthenoteratozoospermia via impaired 18S rRNA m6A methylation in humans and mice.","authors":"Mengya Zhang,Xueguang Zhang,Chen Tan,Ting Jiang,Zheng Cao,Yufei Chen,Feng Qiao,Gelin Huang,Chaoye Ma,Huixia Li,Mei Ye,Lei Wang,Liandong Zuo,Jun Yu,Xiaofeng Li,Yunfang Zhang,Yue-Qiu Tan,Shuibin Lin,Wenming Xu,Hao Chen","doi":"10.1016/j.ymthe.2025.08.009","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.08.009","url":null,"abstract":"Recent studies have highlighted RNA modifications as integral regulators of gene expression during spermatogenesis. Ribosomal RNAs (rRNAs) are the most abundant RNA in the cells, while the function and clinical relevance of rRNA modifications in spermatogenesis remain poorly understood. Here, we identified 4 pathogenic heterozygous variants of METTL5 in 1427 patients with male infertility characterized as oligoasthenoteratozoospermia (OAT). The pathogenic variants of METTL5 led to the significantly decreased expression level of METTL5. Null-mutation of 18S rRNA methyltransferase Mettl5 led to male infertility attributed to oligoasthenoteratozoospermia (OAT) during spermiogenesis, presenting defects in both the sperm head and tail. Notwithstanding the absence of notable changes in global translation after Mettl5 loss, we observed a compromised translational efficiency of mRNAs encoding proteins crucial for spermiogenesis, including Gk2, Akap4, Fsip2, Odf2, and Pgk2. Intriguingly, therapeutic interventions via intra-cytoplasmic sperm injection (ICSI) in OAT couples with these variants resulted in successful pregnancies. These insights not only identify METTL5-mediated 18S rRNA m6A modification as a novel genetic determinant for OAT but also offer a new target to the genetic counseling, clinical diagnosis and potential treatment strategies for male infertility.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"15 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805687","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

mRNA prime-boost vaccination promotes clonal continuity in germinal center reactions and broadens SARS-CoV-2 variant coverage. mRNA预增强疫苗可促进生发中心反应的克隆连续性，并扩大SARS-CoV-2变体的覆盖范围。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-08-08 DOI: 10.1016/j.ymthe.2025.08.008

Matias Ciancaglini,Jonas Fixemer,Cemre Seven,Mirela Dimitrova,Davide Finozzi,Denice Weklak,Anna Lena Kastner,Franziska Jönsson,Ingrid Wagner,Ilena Vincenti,Anneli Peters,Maddy L Newby,Max Crispin,Doron Merkler,Florian Kreppel,Daniel D Pinschewer

{"title":"mRNA prime-boost vaccination promotes clonal continuity in germinal center reactions and broadens SARS-CoV-2 variant coverage.","authors":"Matias Ciancaglini,Jonas Fixemer,Cemre Seven,Mirela Dimitrova,Davide Finozzi,Denice Weklak,Anna Lena Kastner,Franziska Jönsson,Ingrid Wagner,Ilena Vincenti,Anneli Peters,Maddy L Newby,Max Crispin,Doron Merkler,Florian Kreppel,Daniel D Pinschewer","doi":"10.1016/j.ymthe.2025.08.008","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.08.008","url":null,"abstract":"mRNA- and adenovirus-based (rAd) SARS-CoV-2 vaccines have been widely used in various homologous and heterologous prime-boost combinations. It remains unknown, however, which vaccination regimens effectively promote B cell clonal continuity, i.e. the participation of individual B cell clones in durable GC reactions to prime and subsequent boost. Here we characterize SARS-CoV-2-specific GC B cell dynamics in vaccinated mice. While rAd/mRNA prime-boost elicited SARS-CoV-2-neutralizing antibody (nAb) titers equivalent to those induced by mRNA/mRNA, the latter provided broader nAb coverage of variants-of-concern. B cell fate-mapping experiments revealed that mRNA/mRNA afforded higher clonal continuity between primary and secondary GC reactions than rAd/mRNA, which was associated with similarly sized but more durable GC responses upon mRNA prime. Homologous rAd/rAd prime-boost resulted in vector backbone-biased antibody responses and limited clonal continuity of SARS-CoV-2-specific B cells. Our study suggests that high clonal continuity as observed during mRNA homologous prime boost is key for vaccination regimens against rapidly evolving pathogens.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"27 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805703","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

Gene therapy downregulating CaV1.3 reverses motor disability in aged parkinsonian male and female macaques. 下调CaV1.3的基因治疗可逆转老年帕金森雄性和雌性猕猴的运动障碍。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-08-08 DOI: 10.1016/j.ymthe.2025.07.049

Mikko Airavaara,Safak Er

引用次数: 0

Targeting NLRP3/caspase-1/GSDMD to treat inner ear injury from labyrinthine hemorrhage. 靶向NLRP3/caspase-1/GSDMD治疗迷路出血内耳损伤。

IF 12 1区医学

Molecular Therapy Pub Date : 2025-08-08 DOI: 10.1016/j.ymthe.2025.07.052

J Qi, L Zhang, Y Lu, R Chai

引用次数: 0

Cancer interrupted: A story of oncolytic HSV-induced killing. 癌症中断：一个溶瘤性单纯疱疹病毒导致死亡的故事。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-08-08 DOI: 10.1016/j.ymthe.2025.07.047

Upasana Sahu,Balveen Kaur

引用次数: 0

Highly conserved brain vascular receptor ALPL mediates transport of engineered AAV vectors across the blood-brain barrier. 高度保守的脑血管受体ALPL介导工程AAV载体穿越血脑屏障的运输。

IF 12 1区医学

Molecular Therapy Pub Date : 2025-08-06 Epub Date: 2025-05-08 DOI: 10.1016/j.ymthe.2025.04.046

Tyler C Moyer, Brett A Hoffman, Weitong Chen, Ishan Shah, Xiao-Qin Ren, Tatiana Knox, Jiachen Liu, Wei Wang, Jiangyu Li, Hamza Khalid, Anupriya S Kulkarni, Munachiso Egbuchulam, Joseph Clement, Alexis Bloedel, Matthew Child, Rupinderjit Kaur, Emily Rouse, Kristin Graham, Damien Maura, Zachary Thorpe, Ambreen Sayed-Zahid, Charlotte Hiu-Yan Chung, Alexander Kutchin, Amy Johnson, Johnny Yao, Jeffrey Thompson, Nilesh Pande, Mathieu E Nonnenmacher

{"title":"Highly conserved brain vascular receptor ALPL mediates transport of engineered AAV vectors across the blood-brain barrier.","authors":"Tyler C Moyer, Brett A Hoffman, Weitong Chen, Ishan Shah, Xiao-Qin Ren, Tatiana Knox, Jiachen Liu, Wei Wang, Jiangyu Li, Hamza Khalid, Anupriya S Kulkarni, Munachiso Egbuchulam, Joseph Clement, Alexis Bloedel, Matthew Child, Rupinderjit Kaur, Emily Rouse, Kristin Graham, Damien Maura, Zachary Thorpe, Ambreen Sayed-Zahid, Charlotte Hiu-Yan Chung, Alexander Kutchin, Amy Johnson, Johnny Yao, Jeffrey Thompson, Nilesh Pande, Mathieu E Nonnenmacher","doi":"10.1016/j.ymthe.2025.04.046","DOIUrl":"10.1016/j.ymthe.2025.04.046","url":null,"abstract":"<p><p>Delivery of systemically administered therapeutics to the central nervous system (CNS) is restricted by the blood-brain barrier (BBB). Bioengineered adeno-associated virus (AAV) capsids have been shown to penetrate the BBB with great efficacy in mouse and non-human primate models, but their translational potential is often limited by species selectivity and undefined mechanisms of action. Here, we apply our RNA-guided TRACER AAV capsid evolution platform to generate VCAP-102, an AAV9 variant with markedly increased brain tropism following intravenous delivery in both rodents and primates. Relative to AAV9, VCAP-102 demonstrates 20- to 400-fold increased gene transfer across multiple brain regions. We identify alkaline phosphatase (ALPL) as the primary receptor used by VCAP-102 to cross the BBB and demonstrate that direct binding of VCAP-102 to human ALPL can initiate receptor-mediated transcytosis in a cell barrier model. Our work identifies VCAP-102 as a cross-species CNS gene delivery vector with a strong potential for clinical translation and establishes ALPL as a brain delivery shuttle capable of efficient BBB transport to maximize CNS delivery of biotherapeutics.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3902-3916"},"PeriodicalIF":12.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010275","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

Guarding glomeruli from immune injury. 保护肾小球免受免疫损伤。

IF 12 1区医学

Molecular Therapy Pub Date : 2025-08-06 Epub Date: 2025-07-28 DOI: 10.1016/j.ymthe.2025.07.018

Emma M Navratil, Lauryn J Renze, Robert F Mullins

引用次数: 0