Molecular Therapy最新文献_第9页

Intranasal replicon SARS-CoV-2 vaccine produces protective respiratory and systemic immunity and prevents viral transmission. 鼻内复制子SARS-CoV-2疫苗产生保护性呼吸道和全身免疫，并防止病毒传播。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-09 DOI: 10.1016/j.ymthe.2025.04.007

Madeleine F Jennewein, Michael D Schultz, Samuel Beaver, Peter Battisti, Julie Bakken, Derek Hanson, Jobaida Akther, Fen Zhou, Raodoh Mohamath, Jasneet Singh, Noah Cross, Darshan N Kasal, Matthew R Ykema, Sierra Reed, Davies Kalange, Isabella R Cheatwood, Jennifer L Tipper, Jeremy B Foote, R Glenn King, Aaron Silva-Sanchez, Kevin S Harrod, Davide Botta, Alana Gerhardt, Corey Casper, Troy D Randall, Frances E Lund, Emily A Voigt

{"title":"Intranasal replicon SARS-CoV-2 vaccine produces protective respiratory and systemic immunity and prevents viral transmission.","authors":"Madeleine F Jennewein, Michael D Schultz, Samuel Beaver, Peter Battisti, Julie Bakken, Derek Hanson, Jobaida Akther, Fen Zhou, Raodoh Mohamath, Jasneet Singh, Noah Cross, Darshan N Kasal, Matthew R Ykema, Sierra Reed, Davies Kalange, Isabella R Cheatwood, Jennifer L Tipper, Jeremy B Foote, R Glenn King, Aaron Silva-Sanchez, Kevin S Harrod, Davide Botta, Alana Gerhardt, Corey Casper, Troy D Randall, Frances E Lund, Emily A Voigt","doi":"10.1016/j.ymthe.2025.04.007","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.04.007","url":null,"abstract":"While mRNA vaccines have been effective in combating SARS-CoV-2, the waning of vaccine-induced antibody responses and lack of vaccine-induced respiratory tract immunity contribute to ongoing infection and transmission. In this work, we compare and contrast intranasal (i.n.) and intramuscular (i.m.) administration of a SARS-CoV-2 replicon vaccine delivered by a nanostructured lipid carrier (NLC). Both i.m. and i.n. vaccines induce potent systemic serum neutralizing antibodies, bone marrow-resident immunoglobulin G-secreting cells, and splenic T cell responses. The i.n. vaccine additionally induces robust respiratory mucosal immune responses, including SARS-CoV-2-reactive lung-resident memory T cell populations. As a booster following previous i.m. vaccination, the i.n. vaccine also elicits the development of mucosal virus-specific T cells. Both the i.m.- and i.n.-administered vaccines durably protect hamsters from infection-associated morbidity upon viral challenge, significantly reducing viral loads and preventing challenged hamsters from transmitting virus to naive cagemates. This replicon-NLC vaccine's potent systemic immunogenicity, and additional mucosal immunogenicity when delivered i.n., may be key for combating SARS-CoV-2 and other respiratory pathogens.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019281","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

DNA based Immunotherapy for Cancer: in vivo Approaches for Recalcitrant Targets. 基于DNA的癌症免疫治疗：难治性靶点的体内方法。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-04-09 DOI: 10.1016/j.ymthe.2025.04.008

Pratik S Bhojnagarwala,Joshua Jose,Shushu Zhao,David B Weiner

{"title":"DNA based Immunotherapy for Cancer: in vivo Approaches for Recalcitrant Targets.","authors":"Pratik S Bhojnagarwala,Joshua Jose,Shushu Zhao,David B Weiner","doi":"10.1016/j.ymthe.2025.04.008","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.04.008","url":null,"abstract":"Immunotherapy has revolutionized cancer treatment which complements traditional therapies including surgery, chemotherapy, radiation and targeted therapies. Immunotherapy redirects the patient's immune system against tumors via several immune mediated approaches. Over the past few years, therapeutic immunization, which enable the patient's T cells to better recognize and kill tumors, have been increasingly tested in the clinic with several approaches demonstrating treatment improvements. There has been a renewed interest in cancer vaccines due to advances in tumor-antigen identification, immune response optimization, novel adjuvants, next-generation vaccine delivery platforms and antigen designs. The Covid-19 pandemic accelerated progress in nucleic acid-based vaccine manufacturing, which spurred broader interest in mRNA or plasmid platforms. Enhanced DNA vaccine designs including optimized leader sequences, RNA and codon optimizations, improved formulations and delivery via adaptive electroporation using stereotactic intramuscular/intradermal methods have improved T cell responses to plasmid-delivered tumor-antigens. Additionally, advancements for direct in vivo delivery of DNA-encoded mono/bispecific antibodies offer novel tumor-targeting strategies. This review summarizes recent clinical data for therapeutic cancer vaccines utilizing the DNA platform, including vaccines targeting common tumor-associated and viral antigens and neoantigen vaccines using nucleic acid technologies. We also summarize preclinical data using DNA-launched monoclonal/bispecific antibodies, underscoring their potential as a novel cancer therapy tool.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"13 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822563","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 delivery of SUMO1-derived peptide rescues neuronal degeneration and motor deficits in a mouse model of Parkinson's disease. 在rAAV-α-synuclein-A53T帕金森病小鼠模型中，sumo1衍生肽的基因传递可拯救神经元变性和运动缺陷。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-05 DOI: 10.1016/j.ymthe.2025.04.005

Zhaohui Liang, Suresh Kanna Murugappan, Yuxuan Li, Man Nga Lai, Yajing Qi, Yi Wang, Ho Yin Edwin Chan, Marianne M Lee, Michael K Chan

{"title":"Gene delivery of SUMO1-derived peptide rescues neuronal degeneration and motor deficits in a mouse model of Parkinson's disease.","authors":"Zhaohui Liang, Suresh Kanna Murugappan, Yuxuan Li, Man Nga Lai, Yajing Qi, Yi Wang, Ho Yin Edwin Chan, Marianne M Lee, Michael K Chan","doi":"10.1016/j.ymthe.2025.04.005","DOIUrl":"10.1016/j.ymthe.2025.04.005","url":null,"abstract":"Developing α-synuclein aggregation inhibitors is challenging because its aggregation process involves several microscopic steps and heterogeneous intermediates. Previously, we identified a SUMO1-derived peptide, SUMO1(15-55), that exhibits tight binding to monomeric α-synuclein via SUMO-SUMO-interacting motif (SIM) interactions, and effectively blocks the initiation of aggregation and formation of toxic aggregates in vitro. In cellular and Drosophila models, SUMO1(15-55) was efficacious in protecting neuronal cells from α-synuclein-induced neurotoxicity and neuronal degeneration. Given the demonstrated ability of SUMO1(15-55) to sequester α-synuclein monomers thereby blocking oligomer formation, we sought to evaluate whether it could be equally effective against the aggregation-prone familial mutant α-synuclein-A53T. Herein, we show that SUMO1(15-55) selectively binds to monomeric α-synuclein-A53T, inhibits primary nucleation, and prevents the formation of structured protofibrils in vitro, thereby protecting neuronal cells from protofibril-induced cell death. We further demonstrate that larval feeding of a designed His10-SUMO1(15-55) that exhibits enhanced sub-stoichiometric suppression of α-synuclein-A53T aggregation in vitro can ameliorate Parkinson's disease (PD)-related symptoms in α-synuclein-A53T transgenic Drosophila models, while its rAAV-mediated gene delivery can relieve the PD-related histological and behavioral deficiencies in an rAAV-α-synuclein-A53T mouse PD model. Our findings suggest that gene delivery of His10-SUMO1(15-55) may serve as a clinical therapy for a spectrum of α-synuclein-aggregation associated synucleinopathies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795762","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

An engineered mitoCBE facilitates efficient mitochondrial DNA editing and modified mitochondrial transfer. 工程mitoCBE促进高效的线粒体DNA编辑和修改线粒体转移。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-03 DOI: 10.1016/j.ymthe.2025.03.051

Jie Liu, Jun Chen, Shisheng Huang, Junfan Guo, Xiangyang Li, Ying Yan, Ruijing Chen, Guanglei Li, Ming Liu, Jiao Wei, Xingxu Huang, Yunbo Qiao

{"title":"An engineered mitoCBE facilitates efficient mitochondrial DNA editing and modified mitochondrial transfer.","authors":"Jie Liu, Jun Chen, Shisheng Huang, Junfan Guo, Xiangyang Li, Ying Yan, Ruijing Chen, Guanglei Li, Ming Liu, Jiao Wei, Xingxu Huang, Yunbo Qiao","doi":"10.1016/j.ymthe.2025.03.051","DOIUrl":"10.1016/j.ymthe.2025.03.051","url":null,"abstract":"Double-stranded DNA cytosine deaminase DddA orthologs from multiple types of bacteria have been fused with the transcription-activator-like effector system for mitochondrial DNA (mtDNA) base editing, while the efficiencies remain limited and its nuclear off-targeting activity cannot be ignored yet. Here we identified a DddA ortholog from Burkholderia gladioli (BgDddA) and generated nuclear or mtDNA cytosine base editors (mitoCBEs), exhibiting higher C⋅G-to-T⋅A editing frequencies compared with canonical DdCBE, and fusion with transactivator Rta remarkably improved editing efficiencies by up to 6.4-fold at non-TC targets. Referring to DddA11, we further introduced six substitutions into BgDddA and generated mitoCBE3.2, which efficiently induced disease-associated mtDNA mutations in mouse and human cell lines at both TC and non-TC targets with efficiency reaching up to 99.2%. Using mitoCBE3.2, single clones containing homoplasmic mtDNA mutations or premature stop codons associated with human diseases were generated, and the functions of these mutations have been evaluated upon the treatment of reactive oxygen species inducers. Importantly, mitochondria harboring these homoplasmic mutations were transplanted into wild-type cells, enabling precise base conversions, without the risk of nuclear gene off-targets. Thus, we have engineered an efficient mitoCBE using BgDddA, facilitating mitochondrial disease modeling and potential mutation correction with the aid of mitochondrial transplantation.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779713","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

The advent of clinical self-amplifying RNA vaccines. 临床自我扩增RNA疫苗的出现。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-03 DOI: 10.1016/j.ymthe.2025.03.060

Irafasha C Casmil, Jongwoo Jin, Eun-Jeong Won, Cynthia Huang, Suiyang Liao, Hyunjoo Cha-Molstad, Anna K Blakney

{"title":"The advent of clinical self-amplifying RNA vaccines.","authors":"Irafasha C Casmil, Jongwoo Jin, Eun-Jeong Won, Cynthia Huang, Suiyang Liao, Hyunjoo Cha-Molstad, Anna K Blakney","doi":"10.1016/j.ymthe.2025.03.060","DOIUrl":"10.1016/j.ymthe.2025.03.060","url":null,"abstract":"Self-amplifying RNA (saRNA) technology is an emerging platform for vaccine development, offering significant advantages over conventional mRNA vaccines. By enabling intracellular amplification of RNA, saRNA facilitates robust antigen expression at lower doses, thereby enhancing both immunogenicity and cost-effectiveness. This review examines the latest advancements in saRNA vaccine development, highlighting its applications in combating infectious diseases. This includes viral pathogens such as SARS-CoV-2, influenza, and emerging zoonotic threats. We discuss the design and optimization of saRNA vectors to maximize antigen expression while minimizing adverse immune responses. Recent studies demonstrating the safety, efficacy, and scalability of saRNA-based vaccines in clinical settings are also discussed. We address challenges related to delivery systems, stability, and manufacturing, along with novel strategies being developed to mitigate these challenges. As the global demand for rapid, flexible, and scalable vaccine platforms grows, saRNA presents a promising solution with enhanced potency and durability. This review emphasizes the transformative potential of saRNA vaccines to shape the future of immunization strategies, particularly in response to pandemics and other global health threats.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788691","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

Viral and cellular insulators promote sustained HSV vector-mediated transgene expression in brain. 病毒和细胞绝缘体可促进 HSV 载体介导的转基因在大脑中的持续表达

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2025-02-28 DOI: 10.1016/j.ymthe.2025.02.039

Selene Ingusci, Justus B Cohen, Joseph C Glorioso

{"title":"Viral and cellular insulators promote sustained HSV vector-mediated transgene expression in brain.","authors":"Selene Ingusci, Justus B Cohen, Joseph C Glorioso","doi":"10.1016/j.ymthe.2025.02.039","DOIUrl":"10.1016/j.ymthe.2025.02.039","url":null,"abstract":"We have developed a gene therapy platform based on non-toxic, high-capacity replication-defective (rd) herpes simplex virus type 1 (HSV-1) vectors. We previously determined that transgene expression from rdHSV-1 vectors requires strategic placement of insulators-small DNA elements that overcome the host's epigenetic silencing of foreign DNA-to maintain transgenes in euchromatin regions. Transgene expression was rescued by replacing either the latency associated transcript (LAT) or the the infected cell protein 4 (ICP4) gene with the transgene cassette close to naturally occurring viral insulators. The ICP4 locus was more permissive for transgene expression than the LAT locus in neurons in vitro. Following in vivo brain delivery, transgene expression from both loci lasted for at least 4 months. However, the level of expression tended to decline over time. To enhance transgene expression, we designed a novel insulator environment by combining cellular insulators with the resident viral insulators. In combination, these elements provided significantly higher levels of transgene expression in the brain than the viral insulators alone, lasting for at least 11.7 months. This new cassette design extends transgene activity in neurons compared with previous designs and holds promise for gene therapy applications in treating brain disorders.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1420-1433"},"PeriodicalIF":12.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531681","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 BCL11B in CAR-engineered lymphoid progenitors drives NK-like cell development with prolonged anti-leukemic activity. 靶向BCL11B在car工程淋巴样祖细胞驱动nk样细胞发育具有持久的抗白血病活性。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2025-02-15 DOI: 10.1016/j.ymthe.2025.02.024

Franziska Baatz, Arnab Ghosh, Jessica Herbst, Saskia Polten, Johann Meyer, Manuel Rhiel, Tobias Maetzig, Robert Geffers, Michael Rothe, Antonella Lucia Bastone, Philipp John-Neek, Jörg Frühauf, Britta Eiz-Vesper, Agnes Bonifacius, Christine S Falk, Constantin V Kaisenberg, Toni Cathomen, Axel Schambach, Marcel R M van den Brink, Michael Hust, Martin G Sauer

{"title":"Targeting BCL11B in CAR-engineered lymphoid progenitors drives NK-like cell development with prolonged anti-leukemic activity.","authors":"Franziska Baatz, Arnab Ghosh, Jessica Herbst, Saskia Polten, Johann Meyer, Manuel Rhiel, Tobias Maetzig, Robert Geffers, Michael Rothe, Antonella Lucia Bastone, Philipp John-Neek, Jörg Frühauf, Britta Eiz-Vesper, Agnes Bonifacius, Christine S Falk, Constantin V Kaisenberg, Toni Cathomen, Axel Schambach, Marcel R M van den Brink, Michael Hust, Martin G Sauer","doi":"10.1016/j.ymthe.2025.02.024","DOIUrl":"10.1016/j.ymthe.2025.02.024","url":null,"abstract":"Chimeric antigen receptor (CAR)-induced suppression of the transcription factor B cell CLL/lymphoma 11B (BCL11B) propagates CAR-induced killer (CARiK) cell development from lymphoid progenitors. Here, we show that CRISPR-Cas9-mediated Bcl11b knockout in human and murine early lymphoid progenitors distinctively modulates this process either alone or in combination with a CAR. Upon adoptive transfer into hematopoietic stem cell recipients, Bcl11b-edited progenitors mediated innate-like antigen-independent anti-leukemic immune responses. With CAR expression allowing for additional antigen-specific responses, the progeny of double-edited lymphoid progenitors acquired prolonged anti-leukemic activity in vivo. These findings give important insights into how Bcl11b targeting can be used to tailor anti-leukemia functionality of CAR-engineered lymphoid progenitor cells.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1584-1607"},"PeriodicalIF":12.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425833","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

A universal viral capsid protein based one step RNA synthesis and packaging system for rapid and efficient mRNA vaccine development. 一种基于通用病毒衣壳蛋白的一步RNA合成和包装系统，用于快速高效的mRNA疫苗开发。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2025-02-28 DOI: 10.1016/j.ymthe.2025.02.037

Jiayue Su, Jinsong Zhang, Xiangning Feng, Jinsong Liu, Shan Gao, Xinrui Liu, Mingwei Yang, Zeliang Chen

{"title":"A universal viral capsid protein based one step RNA synthesis and packaging system for rapid and efficient mRNA vaccine development.","authors":"Jiayue Su, Jinsong Zhang, Xiangning Feng, Jinsong Liu, Shan Gao, Xinrui Liu, Mingwei Yang, Zeliang Chen","doi":"10.1016/j.ymthe.2025.02.037","DOIUrl":"10.1016/j.ymthe.2025.02.037","url":null,"abstract":"The success of coronavirus disease 2019 mRNA vaccines highlights the transformative potential of mRNA technology. Current mRNA vaccine development involves complex steps, including plasmid construction, RNA transcription, 5' capping, poly(A) tailing, and lipid nanoparticle encapsulation, yet challenges in vaccine accessibility persist. Here, we present an innovative mRNA platform leveraging the self-assembly capabilities of the MS2 bacteriophage viral capsid protein (VCP). A dual-promoter plasmid has been designed where one promoter drives VCP expression while the other transcribes target RNA containing pac sites, enabling rapid mRNA self-assembly in Escherichia coli. Using an ovalbumin (OVA)-based tumor model, we validate the efficacy of this system. Tumor growth is significantly inhibited, accompanied by robust immune activation. Flow cytometry analyses reveal increased frequencies of OVA-specific CD8+, as well as activated and memory T cells. Additionally, the MS2-OVA vaccine favorably modulated the tumor immunosuppressive microenvironment by reducing myeloid-derived suppressor cells, while sustained antibody responses demonstrated the platform's ability to induce durable humoral immunity. These findings establish the feasibility of one-step mRNA synthesis and packaging in E. coli, providing a versatile and rapid platform for mRNA vaccine development, with broad implications for addressing global vaccination challenges.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1720-1734"},"PeriodicalIF":12.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531701","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

Dysregulation of astrocyte-derived matrix gla protein impairs dendritic spine development in pyridoxine-dependent epilepsy. 星形胶质细胞衍生基质Gla蛋白的失调损害吡哆醇依赖性癫痫的树突脊柱发育。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2025-02-20 DOI: 10.1016/j.ymthe.2025.02.027

Junjie Wu, Dezhe Qin, Ziqi Liang, Qiang Liu, Min Wang, Ye Guo, Weixiang Guo

{"title":"Dysregulation of astrocyte-derived matrix gla protein impairs dendritic spine development in pyridoxine-dependent epilepsy.","authors":"Junjie Wu, Dezhe Qin, Ziqi Liang, Qiang Liu, Min Wang, Ye Guo, Weixiang Guo","doi":"10.1016/j.ymthe.2025.02.027","DOIUrl":"10.1016/j.ymthe.2025.02.027","url":null,"abstract":"In spite of adequate seizure control, approximately 75% of pyridoxine-dependent epilepsy (PDE) patients with ALDH7A1 mutation still suffer from intellectual disability. However, the mechanisms underlying brain dysfunction in PDE patients are still unknown even when seizure control is achieved. In this study, we show that mice with specific deletion of Aldh7a1 from astrocytes, but not neurons, exhibit PDE, and have defective dendritic spine development and cognitive impairment when seizure occurrence is well controlled. Mechanistically, ALDH7A1 deficiency leads to dysregulation of astrocyte-derived matrix gla protein (MGP), one of the vitamin K-dependent proteins, thereby impairing dendritic spine development and synaptic transmission. Notably, supplementation of menaquinone-7, a form of vitamin K, promotes MGP activation and rescues defective dendritic spine development, abnormal synaptic transmission, and cognitive impairment in Aldh7a1-deficient mice. Therefore, our findings not only unravel the important role of ALDH7A1 in astrocytes contributing to the pathogenesis of PDE, but also provide a potential therapeutic intervention to ameliorate cognitive impairment in PDE beyond pyridoxine treatment.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1785-1802"},"PeriodicalIF":12.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468132","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

Impaired megakaryopoiesis due to aberrant macrophage polarization via BTK/Rap1/NF-κB pathway in sepsis-induced thrombocytopenia. 脓毒症所致血小板减少症中巨噬细胞异常极化通过BTK/Rap1/NF-κB通路导致巨核生成受损

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2024-12-30 DOI: 10.1016/j.ymthe.2024.12.048

Ziyan Zhang, Meng Zhou, Yaqiong Tang, Jiaqian Qi, Xiaoyan Xu, Peng Wang, Haohao Han, Tingting Pan, Xiaofei Song, Shuhui Jiang, Xueqian Li, Chengyuan Gu, Zhenzhen Yao, Qixiu Hou, Mengting Guo, Siyi Lu, Depei Wu, Yue Han

{"title":"Impaired megakaryopoiesis due to aberrant macrophage polarization via BTK/Rap1/NF-κB pathway in sepsis-induced thrombocytopenia.","authors":"Ziyan Zhang, Meng Zhou, Yaqiong Tang, Jiaqian Qi, Xiaoyan Xu, Peng Wang, Haohao Han, Tingting Pan, Xiaofei Song, Shuhui Jiang, Xueqian Li, Chengyuan Gu, Zhenzhen Yao, Qixiu Hou, Mengting Guo, Siyi Lu, Depei Wu, Yue Han","doi":"10.1016/j.ymthe.2024.12.048","DOIUrl":"10.1016/j.ymthe.2024.12.048","url":null,"abstract":"Sepsis-induced thrombocytopenia (SIT) is a widely accepted predictor of poor prognosis during sepsis, while the mechanism of SIT remains elusive. In this study, we revealed that SIT patients and septic mice exhibited higher levels of pro-inflammatory macrophages and phosphorylated Bruton's tyrosine kinase (p-BTK) expression in macrophages, which were closely correlated with platelet counts. Treatment with the BTK inhibitor BGB-3111 in SIT mice resulted in enhanced production of megakaryocytes and platelets. Depletion of macrophages in SIT mice and coculture experiments further confirmed the critical role of macrophages in the improvement of platelet count induced by BGB-3111. By performing single-cell RNA sequencing on bone marrow-derived cells from SIT mice, we not only confirmed the connection between macrophages and megakaryocytes influenced by BTK but also identified a potential mediation through the Rap1 signaling pathway in macrophages. Subsequent experiments in macrophages demonstrated that inhibition of BTK signaling impeded the pro-inflammatory polarization of macrophages by targeting the Rap1/NF-κB signaling pathway. In conclusion, our study highlights the crucial role of macrophages in SIT, and inhibiting phosphorylation of BTK in macrophages may alleviate SIT through the Rap1/NF-κB signaling pathway.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1769-1784"},"PeriodicalIF":12.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915312","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