Molecular TherapyPub Date : 2025-09-03Epub Date: 2025-06-09DOI: 10.1016/j.ymthe.2025.05.021
Nikolaos I Vlachogiannis, Maria Polycarpou-Schwarz, Aikaterini-Paraskevi Avdi, Simon Tual-Chalot, Konstantinos Stellos
{"title":"Targeting RNA adenosine editing and modification enzymes for RNA therapeutics.","authors":"Nikolaos I Vlachogiannis, Maria Polycarpou-Schwarz, Aikaterini-Paraskevi Avdi, Simon Tual-Chalot, Konstantinos Stellos","doi":"10.1016/j.ymthe.2025.05.021","DOIUrl":"10.1016/j.ymthe.2025.05.021","url":null,"abstract":"<p><p>Adenosine-to-inosine (A-to-I) RNA editing, and N6 methyladenosine (m6A) are among the most abundant modifications in eukaryotic messenger RNA, affecting various aspects of RNA metabolism and cellular function, including proliferation, differentiation, responses to stressors, and cell death. Recent preclinical evidence suggests that both modifications play a significant role in multiple disorders, including infections, chronic inflammatory diseases, and cancer, sparking great interest in their therapeutic potential. Structural characterization of ADARs (adenosine deaminases acting on RNA) and key m6A enzymes has enabled the development of small molecule inhibitors modulating their expression, enzymatic activity, or binding to target RNAs. Herein, we review preclinical evidence supporting the therapeutic benefits of targeting ADARs and m6A enzymes in diverse disease contexts. Small molecule inhibitors of RNA modification enzymes have shown potent anti-proliferative and pro-apoptotic effects in cancer cells, and have successfully inhibited tumor growth in vivo, without evident toxicity, while their combination with immuno-/chemotherapeutics displayed synergistic anti-neoplastic action. Adenosine RNA editing via recruitment of endogenous ADARs and usage of guide RNAs showed remarkable efficacy in correcting G-to-A point mutations and restoring the associated protein expression with limited off-target activity. Future studies are warranted to evaluate the safety and clinical efficacy of RNA editing or modification-targeting therapeutics in patients.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4044-4090"},"PeriodicalIF":12.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266805","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}
Molecular TherapyPub Date : 2025-09-03Epub Date: 2025-05-27DOI: 10.1016/j.ymthe.2025.05.026
Bin Li, Xudong Zhu, Jingyu Ge, Hangyu Zhang, Yang Gao, Xuanwen Bao, Xiaomeng Dai, Zhicheng Du, Xiaoxuan Tu, Zhou Tong, Qihan Fu, Dongxue Hu, Weihong Tian, Yi Zheng, Lulu Liu, Peng Zhao, Weijia Fang, Shu Wang, Dongrui Wang
{"title":"Intraperitoneal infusion of NKG2D CAR-NK cells induces endogenous CD8<sup>+</sup> T cell activation in patients with advanced colorectal cancer.","authors":"Bin Li, Xudong Zhu, Jingyu Ge, Hangyu Zhang, Yang Gao, Xuanwen Bao, Xiaomeng Dai, Zhicheng Du, Xiaoxuan Tu, Zhou Tong, Qihan Fu, Dongxue Hu, Weihong Tian, Yi Zheng, Lulu Liu, Peng Zhao, Weijia Fang, Shu Wang, Dongrui Wang","doi":"10.1016/j.ymthe.2025.05.026","DOIUrl":"10.1016/j.ymthe.2025.05.026","url":null,"abstract":"<p><p>Peritoneal metastasis (PM) is a prevalent mode of metastasis in colorectal cancer (CRC) with rapid disease progression and limited treatment options. Locoregional infusion of immune cells have been explored in different types of solid tumors, but the feasibility and safety of locoregional chimeric antigen receptor-natural killer (CAR-NK) cells in treating CRC-PM is still unknown. We report the results of a phase 1 dose-escalation clinical trial (NCT05213195) using intraperitoneal infusion of NKG2D CAR-NK cells in heavily-pretreated patients with CRC-PM, and the immune-modulatory effect of CAR-NK cells was also illustrated using multi-omics analysis and functional validation. Locoregional NKG2D CAR-NK cell therapy showed preliminary efficacy and tolerable toxicity in this study. Of nine patients, three achieved stable disease, and the disease control rate was 33.3%. Notably, CD8<sup>+</sup> T cells post CAR-NK infusion showed the enrichment of a subset co-expressing CD38 and human leukocyte antigen (HLA)-DR, which were highly clonal and also associated with a cytotoxic phenotype. This activated CD38<sup>+</sup> HLA-DR<sup>+</sup> T cell subset, together with their effector phenotype and function, was induced and maintained by the secretome of activated CAR-NK cells. Our data provide evidence supporting the feasibility of locoregionally infused CAR-NK cells to treat patients with CRC-PM, and indicate peripheral immune activation after locoregional CAR-NK therapy.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4509-4528"},"PeriodicalIF":12.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174194","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}
{"title":"Essential role of CD56<sup>dim</sup>NKG2C<sup>+</sup> NK cells trained by SARS-CoV-2 vaccines in protecting against COVID-19.","authors":"Huiwen Zheng, Yanli Chen, Jing Li, Yifan Zhang, Heng Li, Xin Zhao, Zhanlong He, Yun Liao, Zihan Zhang, Haijing Shi, Fengmei Yang, Yunguang Hu, Yadong Li, Jiali Li, Yuping Zhao, Xinglong Zhang, Jingsi Yang, Qihan Li, Longding Liu","doi":"10.1016/j.ymthe.2025.05.031","DOIUrl":"10.1016/j.ymthe.2025.05.031","url":null,"abstract":"<p><p>The adaptive immune protection elicited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination has been proven to control the severity of novel coronavirus disease 2019 (COVID-19). However, the contributions of innate lymphoid cells formed from immunization are poorly defined in vaccine evaluation. Here, we highlight how the natural killer (NK) and macrophage (Mϕ) cells' response, primed by the inactivated COVID-19 vaccine, is crucial to preventing lung injury. We propose that a specific subset of NK cells, marked CD56<sup>dim</sup>CD16<sup>+</sup>NKG2C<sup>+</sup>, along with M2-like Mϕ, CD8<sup>+</sup> T cells, are important in defending against SARS-CoV-2. Our studies using a rhesus macaque model showed that this orchestration of protection was depicted as a trajectory of adaptive NK and Mϕ cell responses from circulating peripheral blood mononuclear cells to the lungs. Through single-cell RNA sequencing and mass cytometry (cytometry by time-of-flight) analysis, we also identified the significance of adaptive CD56<sup>dim</sup>CD16<sup>+</sup>CD57<sup>+</sup>NKG2C<sup>+</sup> NK cells and classical monocytes with chemotaxis traits in orchestrating T cell immunity in humans. Interestingly, our findings show a deficiency of these adaptive cells in older participants post-booster vaccination, leading to potentially inadequate protection. This study discusses the evaluation of vaccines at the innate immune level, which can contribute to the development of successful vaccines.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4488-4508"},"PeriodicalIF":12.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226036","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}
Molecular TherapyPub Date : 2025-09-03Epub Date: 2025-06-14DOI: 10.1016/j.ymthe.2025.06.027
María José Limeres, Rocio Gambaro, Malin Svensson, Silvia Fraude-El Ghazi, Leah Pretsch, Daniel Frank, German A Islan, Ignacio Rivero Berti, Matthias Bros, Ying K Tam, Hiromi Muramatsu, Norbert Pardi, Stephan Gehring, Maximiliano L Cacicedo
{"title":"mRNA-LNP vaccines against hepatitis B virus induce protective immune responses in preventive and chronic mouse challenge models.","authors":"María José Limeres, Rocio Gambaro, Malin Svensson, Silvia Fraude-El Ghazi, Leah Pretsch, Daniel Frank, German A Islan, Ignacio Rivero Berti, Matthias Bros, Ying K Tam, Hiromi Muramatsu, Norbert Pardi, Stephan Gehring, Maximiliano L Cacicedo","doi":"10.1016/j.ymthe.2025.06.027","DOIUrl":"10.1016/j.ymthe.2025.06.027","url":null,"abstract":"<p><p>Over 300 million people worldwide suffer from chronic hepatitis B virus (HBV) infections that can cause serious liver damage and hepatocellular carcinoma. Ineffective innate and adaptive immune responses characterize these chronic infections, making the development of a therapeutic vaccine an urgent medical need. While current vaccines can prevent HBV infections, they are ineffective in treating chronic disease. This study investigated lipid nanoparticle (LNP)-formulated nucleoside-modified mRNA vaccines encoding hepatitis B surface antigen (HBsAg) for prophylactic and therapeutic applications. We found that HBsAg mRNA-LNP vaccines induced robust humoral and cellular immune responses, outperforming the protein-based vaccine approved for human use. The incorporation of a major histocompatibility complex class I (MHC class I) signal peptide further enhanced Th1-biased responses preventing HBV infections in a mouse model. Importantly, mRNA-LNP vaccination led to seroconversion, HBsAg clearance, and strong T cell responses in a chronically infected mouse model. These findings highlight the potential of mRNA-LNP as an alternative and effective vaccine modality for HBV prophylaxis and therapeutic use in treating chronic infections.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4156-4174"},"PeriodicalIF":12.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432868/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302566","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}
Molecular TherapyPub Date : 2025-09-02DOI: 10.1016/j.ymthe.2025.08.049
Byunghwa Noh,Ramu Gopalappa,Haiyue Lin,Heon Yung Gee,Jae Young Choi,Hyongbum Henry Kim,Jinsei Jung
{"title":"Engineered virus-like particles for in vivo gene editing ameliorate hearing loss in murine DFNA2 model.","authors":"Byunghwa Noh,Ramu Gopalappa,Haiyue Lin,Heon Yung Gee,Jae Young Choi,Hyongbum Henry Kim,Jinsei Jung","doi":"10.1016/j.ymthe.2025.08.049","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.08.049","url":null,"abstract":"Although gene editing therapy is applicable to human diseases, its efficiency and safety require further investigation. Further, non-virus-mediated gene editor delivery is challenging in the inner ear. Here, engineered virus-like particles (eVLPs) were used for inner-ear delivery of SpCas9 and single-guided RNA to delete the Kcnq4 dominant-negative mutant allele, which causes progressive hearing loss in a non-syndromic hearing loss murine model. eVLP-delivered SpCas9 was administered to the inner ears of Kcnq4W277S/+ mice to target the Kcnq4-expressing outer hair cells (OHCs). Hearing loss was significantly alleviated 7 weeks after eVLP administration. OHC survival improved significantly, and OHC-innervating neurite (connected to type II spiral ganglion neuronal body) loss was ameliorated. Finally, OHC membrane potential was hyperpolarized with eVLP gene editor treatment in Kcnq4-mutant mice, indicating that their OHCs were healthier and more stable than those of uninjected mice. Our findings suggest that eVLPs are feasible inner ear gene editor deliverers to treat hearing loss.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"19 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144960202","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}
Molecular TherapyPub Date : 2025-09-02DOI: 10.1016/j.ymthe.2025.08.050
Giulio S Tomassy,Wei Fan,Shuwen Cao,Zhengyu Luo,Alessandro Magli,Tracy Zhang,Kristen Boyle,Robert Jackson,Brenda Richards,Dongyu Liu,Franck Rapaport,Shameer Khader,Edith L Pfister,Catherine O'Riordan,Amy Frederick,Jennifer Sullivan,James Cao,Nageswara Rao Kollu,Basel T Assaf,Martin Goulet,Christian Mueller
{"title":"Development of an AAV-delivered microRNA gene therapy for Myotonic Dystrophy Type 1.","authors":"Giulio S Tomassy,Wei Fan,Shuwen Cao,Zhengyu Luo,Alessandro Magli,Tracy Zhang,Kristen Boyle,Robert Jackson,Brenda Richards,Dongyu Liu,Franck Rapaport,Shameer Khader,Edith L Pfister,Catherine O'Riordan,Amy Frederick,Jennifer Sullivan,James Cao,Nageswara Rao Kollu,Basel T Assaf,Martin Goulet,Christian Mueller","doi":"10.1016/j.ymthe.2025.08.050","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.08.050","url":null,"abstract":"Myotonic dystrophy type 1 (DM1), characterized by life-threatening muscle weakness, compromised respiration, and often cardiac conduction abnormalities, is the most common form of adult muscular dystrophy it is. DM1 is caused by a CTG repeat expansion in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene resulting in aggregation of DMPK mRNA into insoluble ribonuclear foci which sequester RNA-binding proteins. Redistribution of essential splicing factors causes mis-splicing of factors responsible for muscle differentiation. Targeting the disease at its root by reducing DMPK RNA promises to reduce RNA foci and pathogenesis. Here, we present an AAV-RNAi based strategy for DMPK reduction based on a muscle-targeted platform comprising an AAV capsid with high muscle transduction efficiency, a promoter with strong activity in muscle, and a DMPK-targeting artificial miRNA. In cellular and animal models of DM1 we show that AAV delivery of an artificial miRNA targeting DMPK reduces DMPK RNA levels, and improves molecular, pathological, and clinically relevant disease hallmarks. In non-human primates, we show AAV-amiRDMPK/SAR446268 treatment is well tolerated and results in a dose-dependent downregulation of DMPK mRNA (up to 90%) in all major muscle groups. Together, our data provide evidence of the efficacy and safety of SAR446268.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"79 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144960234","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}
Molecular TherapyPub Date : 2025-09-02DOI: 10.1016/j.ymthe.2025.08.044
Seung Hyun Jang, Jae Won Roh, Kyung Seok Oh, Sun Young Joo, Jung Ah Kim, Se Jin Kim, Jae Young Choi, Jinsei Jung, Yeonjoon Kim, Jinwoong Bok, Heon Yung Gee
{"title":"Antisense oligonucleotide therapy mitigates autosomal dominant progressive hearing loss in a murine model of human DFNA2.","authors":"Seung Hyun Jang, Jae Won Roh, Kyung Seok Oh, Sun Young Joo, Jung Ah Kim, Se Jin Kim, Jae Young Choi, Jinsei Jung, Yeonjoon Kim, Jinwoong Bok, Heon Yung Gee","doi":"10.1016/j.ymthe.2025.08.044","DOIUrl":"10.1016/j.ymthe.2025.08.044","url":null,"abstract":"<p><p>Hearing loss is the most common sensory disorder, with a substantial proportion caused by genetic mutations. KCNQ4, a voltage-gated potassium channel highly expressed in cochlear outer hair cells, is a common genetic etiology implicated in autosomal dominant progressive hearing loss (DFNA2). The dominant-negative KCNQ4 p.W276S (c.827G>C) mutation represents a mutational hotspot in DFNA2, yet no effective treatments exist. Here, we developed allele-preferential antisense oligonucleotides (ASOs) targeting this dominant-negative KCNQ4 mutation. In a systemic in vitro screen, ASO-123 demonstrated a knockdown of mutant Kcnq4 while preserving wild-type transcripts. In a Kcnq4 p.W277S knockin mouse model mimicking DFNA2, ASO-123 preferentially suppressed mutant transcripts, attenuated progressive hearing loss, and improved outer hair cell survival while enhancing their electrophysiologic function. Comprehensive transcriptomic analyses further validated the efficacy of ASO-123. Thus, our findings establish ASO-based therapy as a promising strategy for treating hereditary hearing loss caused by dominant-negative KCNQ4 mutations.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.0,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961809","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}
Molecular TherapyPub Date : 2025-09-02DOI: 10.1016/j.ymthe.2025.08.043
Evandro Bezerra,Ludmila Lupu,Marcos de Lima,Lena Pfaller,Alison Neal,Nelly R Hajizadeh,Qiuhong Zhao,Martin Beibel,Catherine Chung,Myriam Lemmens,Austin Sim,Mevion Oertli,Timothy Voorhees,Rebecca Bohnert,Nathan Denlinger,Yoann Gilbart,Lara Bontadelli,Laura Monovich,Jennifer Willert,Daniel Stover,Jingbo Gao,Li Li,Stefan Reinker,Ulrike Naumann,Hans D Menssen,Daniel Jones,Silvana Libertini,Jonathan E Brammer
{"title":"Isolated oral CD30+/CD4+ CAR+ T-cell lymphoma in long-term remission after radiotherapy.","authors":"Evandro Bezerra,Ludmila Lupu,Marcos de Lima,Lena Pfaller,Alison Neal,Nelly R Hajizadeh,Qiuhong Zhao,Martin Beibel,Catherine Chung,Myriam Lemmens,Austin Sim,Mevion Oertli,Timothy Voorhees,Rebecca Bohnert,Nathan Denlinger,Yoann Gilbart,Lara Bontadelli,Laura Monovich,Jennifer Willert,Daniel Stover,Jingbo Gao,Li Li,Stefan Reinker,Ulrike Naumann,Hans D Menssen,Daniel Jones,Silvana Libertini,Jonathan E Brammer","doi":"10.1016/j.ymthe.2025.08.043","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.08.043","url":null,"abstract":"A Chimeric Antigen Receptor (CAR) positive CD30+/CD4+ T-cell lymphoma (TCL) manifested as a single oral ulceration 22 months after treatment with tisagenlecleucel (tisa-cel), an anti-CD19 CAR T-cell based therapy. TCL showed lentiviral integration in ANKHD1-EIF4EBP3, loss of function of TET2, and NTRK1 copy number gain, suggesting that genetic alterations unrelated to insertional mutagenesis contributed to lymphomagenesis. The patient remains in remission two years after radiotherapy. This is the only CAR+TCL case reported at Ohio State University James Comprehensive Cancer Center, out of 288 patients treated with CAR T-cells.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"38 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144960235","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}
Molecular TherapyPub Date : 2025-09-02DOI: 10.1016/j.ymthe.2025.08.051
Zherui Zhang, Jie Huang, Zhenye Li, Chenglin Deng, Hongqing Zhang, Bo Zhang, Yanan Zhang
{"title":"An alphavirus vaccine development utilizing RNA replication-defective strategy.","authors":"Zherui Zhang, Jie Huang, Zhenye Li, Chenglin Deng, Hongqing Zhang, Bo Zhang, Yanan Zhang","doi":"10.1016/j.ymthe.2025.08.051","DOIUrl":"10.1016/j.ymthe.2025.08.051","url":null,"abstract":"<p><p>Alphaviruses are arthropod-borne viruses that cause widespread disease. However, many pathogenic alphaviruses are classified as risk group 3 human pathogens, which hampers the development of vaccines and therapeutic agents targeting alphavirus infections. In this study, we developed an RNA replication-defective Venezuelan equine encephalitis virus that has a complete nsP4 gene deletion (VEEV-ΔnsP4). A BHK cell line expressing nsP4 (BHK<sub>nsP4</sub>) was selected for trans-complementation to support the replication cycle of VEEV-ΔnsP4. The VEEV-ΔnsP4 replicates only in BHK<sub>nsP4</sub> cells and is immunologically similar to its parental wild type. Significantly, VEEV-ΔnsP4 is highly attenuated and a single dose immunization can protect mice from a lethal challenge. Furthermore, the RNA replication-defective vaccine strategy has been successfully employed for Chikungunya virus (CHIKV), Western equine encephalitis virus (WEEV) and Eastern equine encephalitis virus (EEEV). Overall, our study highlights the potential of the nsP4 trans-complementation system as a safe and effective platform for alphavirus vaccines development.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.0,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961844","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}
{"title":"An alphavirus vaccine development utilizing RNA replication-defective strategy.","authors":"Zherui Zhang,Jie Huang,Zhenye Li,Chenglin Deng,Hongqing Zhang,Bo Zhang,Yanan Zhang","doi":"10.1016/j.ymthe.2025.08.051","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.08.051","url":null,"abstract":"Alphaviruses are arthropod-borne viruses that cause widespread disease. However, many pathogenic alphaviruses are classified as risk group 3 human pathogens, which hampers the development of vaccines and therapeutic agents targeting alphavirus infections. In this study, we developed a RNA replication-defective Venezuelan equine encephalitis virus that has a complete nsP4 gene deletion (VEEV-△nsP4). A BHK cell line expressing nsP4 (BHKnsP4) was selected for trans-complementation to support the replication cycle of VEEV-△nsP4. The VEEV-△nsP4 only replicates in BHKnsP4 cells and is immunologically similar to its parental wild type. Significantly, VEEV-△nsP4 is highly attenuated and a single dose immunization can protect mice from a lethal challenge. Furthermore, the RNA replication-defective vaccine strategy has been successfully employed for Chikungunya virus (CHIKV), Western equine encephalitis virus (WEEV) and Eastern equine encephalitis virus (EEEV). Overall, our study highlights the potential of the nsP4 trans-complementation system as a safe and effective platform for alphavirus vaccines development.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"29 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144960200","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}
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