Gene Therapy最新文献

RNAi targeting heparin cofactor II promotes hemostasis in a canine model of acquired hemophilia A. 靶向肝素辅助因子II的RNAi促进犬获得性血友病a模型的止血。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-05-24 DOI: 10.1038/s41434-025-00541-w

Yuyang Zhang, Tingting Liu, Haiming Kou, Huafang Wang, Yu Hu, Liang V Tang

{"title":"RNAi targeting heparin cofactor II promotes hemostasis in a canine model of acquired hemophilia A.","authors":"Yuyang Zhang, Tingting Liu, Haiming Kou, Huafang Wang, Yu Hu, Liang V Tang","doi":"10.1038/s41434-025-00541-w","DOIUrl":"https://doi.org/10.1038/s41434-025-00541-w","url":null,"abstract":"Heparin cofactor II (HCII) is a critical anticoagulant protein that inactivates thrombin. In our previous mouse studies, we demonstrated that GalNAc-HCII, a small interfering RNA (siRNA) targeting HCII conjugated with N-acetylgalactosamine (GalNAc), exhibited promising therapeutic effects in hemophilia A mouse models. Further evaluation in large animal models, especially with FVIII inhibitors, is essential before GalNAc-HCII can proceed to clinical trials. In this study, we successfully established, for the first time, an acquired hemophilia A canine model by multiple intravenous injections of a rabbit-dog chimeric neutralizing anti-canine FVIII antibody. In the control group, the Beagle dogs exhibited spontaneous bleeding symptoms accompanied by prolonged activated partial thromboplastin time (APTT). After administration, GalNAc-HCII (0.8 and 1.6 mg/kg) demonstrated potent, dose-dependent, and durable HCII inhibitory effects. After 5 days, in normal dogs, GalNAc-HCII reduced HCII levels to 32.67% ± 3.07% and 10.62% ± 1.74% with 0.8 and 1.6 mg/kg GalNAc-HCII, respectively. In hemophilic dogs, GalNAc-HCII treatment significantly improved hemostatic function. Specifically, in the carotid artery thrombosis model, the thrombus formation time was shortened [29.7 ± 2.08 min (0.8 mg/kg) and 18.0 ± 1.0 min (1.6 mg/kg) vs. 40 min (control), P < 0.01]; in the knee joint puncture-induced bleeding model, joint bleeding and synovitis were alleviated; and in the saphenous vein bleeding model, the number of hemostatic events increased. Furthermore, repeated administration of GalNAc-HCII effectively reduced the prolonged APTT. This study demonstrates the efficacy of GalNAc-HCII in hemophilic dogs, suggesting it as a promising novel therapeutic option for patients with hemophilia, including those with FVIII inhibitors.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 oncolytic virus NDV-anti-VEGFR2 enhances radiotherapy sensitivity in NSCLC by targeting VEGF signaling and impairing DNA repair. 重组溶瘤病毒ndv -抗vegfr2通过靶向VEGF信号和损伤DNA修复增强NSCLC的放疗敏感性。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-05-17 DOI: 10.1038/s41434-025-00540-x

Liang Liu, Liying Song, Tianyan Liu, Kaiyuan Hui, Chenxi Hu, Jiarui Yang, Xuelei Pi, Yuanyuan Yan, Shishi Liu, Yating Zhang, Hongna Chen, Yukai Cao, Lihua Zhou, Yun Qiao, Dan Yu, Chengkai Yin, Xu Li, Chenfeng Zhang, Deshan Li, Zhenzhong Wang, Zhihang Liu, Xiaodong Jiang

{"title":"Recombinant oncolytic virus NDV-anti-VEGFR2 enhances radiotherapy sensitivity in NSCLC by targeting VEGF signaling and impairing DNA repair.","authors":"Liang Liu, Liying Song, Tianyan Liu, Kaiyuan Hui, Chenxi Hu, Jiarui Yang, Xuelei Pi, Yuanyuan Yan, Shishi Liu, Yating Zhang, Hongna Chen, Yukai Cao, Lihua Zhou, Yun Qiao, Dan Yu, Chengkai Yin, Xu Li, Chenfeng Zhang, Deshan Li, Zhenzhong Wang, Zhihang Liu, Xiaodong Jiang","doi":"10.1038/s41434-025-00540-x","DOIUrl":"https://doi.org/10.1038/s41434-025-00540-x","url":null,"abstract":"Resistance to radiotherapy is a significant challenge in the clinical management of non-small cell lung cancer (NSCLC). This study investigates a novel multimodal therapeutic strategy that combines oncolytic Newcastle disease virus (NDV) with an anti-VEGFR2 single-chain variable fragment (NDV-anti-VEGFR2) to enhance radiosensitivity in NSCLC. We engineered NDV-anti-VEGFR2 and assessed its efficacy in sensitizing Calu-1 cells to radiation. In vitro results demonstrated that NDV-anti-VEGFR2 significantly inhibited tumor cell proliferation when combined with radiotherapy. In vivo experiments revealed that NDV-anti-VEGFR2, combined with radiation, achieved a tumor growth inhibition rate of 86.48%, surpassing the effects of NDV or radiation alone. Mechanistic investigations indicated that NDV-anti-VEGFR2 mitigated hypoxia by downregulating HIF-1α and impaired DNA repair pathways, as evidenced by reduced levels of RAD51 and γ-H2AX. These findings suggest that NDV-anti-VEGFR2 not only normalizes tumor vasculature but also enhances the cytotoxic effects of radiation by compromising DNA repair mechanisms. Collectively, our results support the clinical potential of NDV-anti-VEGFR2 combined with radiotherapy as a promising strategy to overcome radiotherapy resistance in NSCLC. Future studies in immunocompetent models are warranted to elucidate the immune-mediated effects of this innovative therapeutic approach.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

HDX-MS reveals pH and temperature-responsive regions on AAV capsids and the structural basis for DNA release. HDX-MS揭示了AAV衣壳上的pH和温度响应区域以及DNA释放的结构基础。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-05-09 DOI: 10.1038/s41434-025-00539-4

Xiang Ye, Mengqi Hu, Yunli Hu, Haibo Qiu, Ning Li

引用次数: 0

Nitrous oxide enhances MR-guided focused ultrasound delivery of gene therapy to the murine hippocampus. 氧化亚氮增强核磁共振引导的聚焦超声基因治疗递送到小鼠海马。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-05-06 DOI: 10.1038/s41434-025-00530-z

Deepshikha Bhardwaj, Ibrahim Youssef, Darren Imphean, Sydni K Holmes, Venugopal Krishnan, Sandi Jo Estill-Terpack, Marc Diamond, Rajiv Chopra, Rachel M Bailey, Bhavya R Shah

{"title":"Nitrous oxide enhances MR-guided focused ultrasound delivery of gene therapy to the murine hippocampus.","authors":"Deepshikha Bhardwaj, Ibrahim Youssef, Darren Imphean, Sydni K Holmes, Venugopal Krishnan, Sandi Jo Estill-Terpack, Marc Diamond, Rajiv Chopra, Rachel M Bailey, Bhavya R Shah","doi":"10.1038/s41434-025-00530-z","DOIUrl":"https://doi.org/10.1038/s41434-025-00530-z","url":null,"abstract":"Transcranial Magnetic Resonance Guided Focused Ultrasound can oscillate intravenously delivered microbubbles and transiently open the blood brain barrier (BBB) in a targeted brain region. However, high microbubble doses or Focused ultrasound pressures (FUS) leads to injury. So, we administered nitrous oxide (N2O), an anesthetic gas to determine reduced need of FUS pressure and microbubble dose for opening BBB. Swiss Webster mice were treated with N2O or medical air (MA) at varying FUS pressures, while the microbubble dose was kept constant and the vice-versa. Consequently, BBB opening was quantified by acoustic emissions and enhancement rate on T1-weighted MR. To compare the effect of N2O on gene delivery, following BBB opening with either MA or N2O, a viral vector expressing GFP was subsequently delivered. Additionally, Immunohistochemical studies quantified viral transfection efficacy and assessed acute cell injury. We observed that N2O significantly potentiates acoustic emissions and enhancement rate on post-contrast MRI images, compared to MA at all measured pressures (0.39, 0.45, 0.67 MPa). Furthermore, N2O reduces the microbubble dose to 0.02μl/kg and FUS pressures to 0.28 and 0.39 MPa for BBB disruption and enhanced viral gene delivery, respectively. Hence, N2O potentiates microbubble oscillations, allowing reduced microbubble dose and FUS pressures and improved viral gene delivery.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144007622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Unveiling the sex bias: higher preexisting and neutralizing titers against AAV in females and implications for gene therapy. 揭示性别偏见：女性对AAV的先前存在和中和滴度较高，及其对基因治疗的影响。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-05-05 DOI: 10.1038/s41434-025-00528-7

Stephanee Warrington, Trish T Hoang, Morten Seirup, Leila Abdelhamid, Hrittal Saha, Sojin Bing, Sima Saleh, Je-Nie Phue, Ronit Mazor

{"title":"Unveiling the sex bias: higher preexisting and neutralizing titers against AAV in females and implications for gene therapy.","authors":"Stephanee Warrington, Trish T Hoang, Morten Seirup, Leila Abdelhamid, Hrittal Saha, Sojin Bing, Sima Saleh, Je-Nie Phue, Ronit Mazor","doi":"10.1038/s41434-025-00528-7","DOIUrl":"https://doi.org/10.1038/s41434-025-00528-7","url":null,"abstract":"Gene therapy with AAV vectors is a promising approach for treating numerous genetic disorders but is often hindered by preexisting antibodies that neutralize the vectors. Given that females may exhibit stronger immune responses than males, this study hypothesizes that females may have higher preexisting antibody titers against AAV. Serum samples from two U.S. cohorts were analyzed for antibody titers, antibody subtypes, and transduction inhibition activity against AAV serotypes AAV1, AAV2, AAV5, AAV8, and AAV9. We found that among seropositive samples, females had higher preexisting antibody levels and neutralizing activities against AAV9 and other serotypes. Immunoglobulin subclass analysis showed IgG1 dominance in both sexes, but females had higher IgA levels, whereas males had higher levels of IgG2. We further evaluated the cellular level of this differential immune response to AAV by stimulation of male and female human PBMCs. We observed dose-dependent increase in cytokines and chemokines in female PBMCs which suggests a differential inflammatory response. Altogether, our findings suggest that the enhanced immune response in females could lead to neutralization and faster clearance of AAV vectors with potential to impact the efficacy of gene therapy.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Focused ultrasound widely broadens AAV-delivered Cas9 distribution and activity. 聚焦超声广泛拓宽了aav递送的Cas9分布和活性。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-05-01 Epub Date: 2025-02-01 DOI: 10.1038/s41434-025-00517-w

Emrah Gumusgoz, Sahba Kasiri, Ibrahim Youssef, Mayank Verma, Rajiv Chopra, Daniel Villarreal Acha, Jun Wu, Ummay Marriam, Esther Alao, Xin Chen, Dikran R Guisso, Steven J Gray, Bhavya R Shah, Berge A Minassian

{"title":"Focused ultrasound widely broadens AAV-delivered Cas9 distribution and activity.","authors":"Emrah Gumusgoz, Sahba Kasiri, Ibrahim Youssef, Mayank Verma, Rajiv Chopra, Daniel Villarreal Acha, Jun Wu, Ummay Marriam, Esther Alao, Xin Chen, Dikran R Guisso, Steven J Gray, Bhavya R Shah, Berge A Minassian","doi":"10.1038/s41434-025-00517-w","DOIUrl":"10.1038/s41434-025-00517-w","url":null,"abstract":"Because children have little temporal exposure to environment and aging, most pediatric neurological diseases are inherent, i.e. genetic. Since postnatal neurons and astrocytes are mostly non-replicating, gene therapy and genome editing present enormous promise in child neurology. Unlike in other organs, which are highly permissive to adeno-associated viruses (AAV), the mature blood-brain barrier (BBB) greatly limits circulating AAV distribution to the brain. Intrathecal administration improves distribution but to no more than 20% of brain cells. Focused ultrasound (FUS) opens the BBB transiently and safely. In the present work we opened the hippocampal BBB and delivered a Cas9 gene via AAV9 intrathecally. This allowed brain first-pass, and subsequent vascular circulation and re-entry through the opened BBB. The mouse model used was of Lafora disease, a neuroinflammatory disease due to accumulations of misshapen overlong-branched glycogen. Cas9 was targeted to the gene of the glycogen branch-elongating enzyme glycogen synthase. We show that FUS dramatically (2000-fold) improved hippocampal Cas9 distribution and greatly reduced the pathogenic glycogen accumulations and hippocampal inflammation. FUS is in regular clinical use for other indications. Our work shows that it has the potential to vastly broaden gene delivery or editing along with clearance of corresponding pathologic basis of brain disease.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":"237-245"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

AAV-based gene replacement therapy prevents and halts manifestation of abnormal neurological phenotypes in a novel mouse model of PMM2-CDG. 在一种新型PMM2-CDG小鼠模型中，基于aav的基因替代疗法可以预防和停止异常神经表型的表现。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-05-01 Epub Date: 2025-03-17 DOI: 10.1038/s41434-025-00525-w

Mian-Ling Zhong, Kent Lai

{"title":"AAV-based gene replacement therapy prevents and halts manifestation of abnormal neurological phenotypes in a novel mouse model of PMM2-CDG.","authors":"Mian-Ling Zhong, Kent Lai","doi":"10.1038/s41434-025-00525-w","DOIUrl":"10.1038/s41434-025-00525-w","url":null,"abstract":"Inherited Phosphomannomutase 2 (PMM2) deficiency, also known as PMM2-CDG, is the most prevalent N-linked congenital disorder of glycosylation (CDG), occurring in approximately 1 in 20,000 individuals in certain populations. Patients exhibit a spectrum of symptoms, with neurological involvement being a prominent feature, often manifesting as the initial clinical sign, and can range from isolated neurological deficits to severe multi-organ dysfunction. Given the absence of curative treatments and a high mortality rate before the age of two, alongside considerable lifelong morbidity, there is an urgent need for innovative therapeutic approaches. To address this unmet need, we developed a tamoxifen-inducible Pmm2 knockout (KO) mouse model with widespread tissue deficiency of Pmm2 expression. Characterization of the mouse model to-date revealed distinct neurological phenotypes relevant to PMM2-CDG, as assessed by the Composite Phenotype Scoring System and Open Field Test. Notably, PMM2 augmentation through AAV9-PMM2 gene replacement therapy prevented and halted the disease-relevant neurological phenotypes induced by Pmm2 KO in the animals. These findings underscored the promise of AAV9-PMM2 gene replacement in managing PMM2-CDG.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":"246-254"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Non-replicative herpes simplex virus genomic and amplicon vectors for gene therapy - an update. 用于基因治疗的非复制性单纯疱疹病毒基因组和扩增子载体--最新进展。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-05-01 Epub Date: 2024-11-12 DOI: 10.1038/s41434-024-00500-x

Matthieu Le Hars, Charles Joussain, Teddy Jégu, Alberto L Epstein

{"title":"Non-replicative herpes simplex virus genomic and amplicon vectors for gene therapy - an update.","authors":"Matthieu Le Hars, Charles Joussain, Teddy Jégu, Alberto L Epstein","doi":"10.1038/s41434-024-00500-x","DOIUrl":"10.1038/s41434-024-00500-x","url":null,"abstract":"Two major types of defective vectors have been derived from herpes simplex virus type 1 (HSV-1), non-replicative genomic vectors (nrHSV-1), and amplicon vectors. This review recapitulates the main features of both vector types and summarizes recent improvements in our understanding of virus/vector biology, particularly with regard to the critical role played by the overpowering of antiviral cellular defenses and the epigenetic control of viral gene expression. Over the past years, significant breakthroughs in vector design, genetic engineering, and HSV-1 biology have accelerated the development of nrHSV-1 vectors. The low immunogenicity and enhanced safety profiles allowed the successful translation of these vectors into several clinical trials, with some being approved by the FDA. Regarding amplicons, despite their advantage in carrying very large or multiple transgenes, and their potential to avoid genome dilution in dividing cells, the absence of production procedures capable of generating large amounts of helper-free amplicons at reasonable cost with GMP compliance, still limits the translation of these outstanding vectors to clinical trials.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":"173-183"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Safety, efficacy, and immunogenicity of a novel IgG degrading enzyme (KJ103): results from two randomised, blinded, phase 1 clinical trials. 一种新型IgG降解酶（KJ103）的安全性、有效性和免疫原性：来自两项随机、盲法1期临床试验的结果

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-05-01 Epub Date: 2025-01-18 DOI: 10.1038/s41434-025-00512-1

Mengdie Cao, Rohit Katial, Yanjun Liu, Xiaoyu Lu, Qin Gu, Chen Chen, Katie Liu, Zhen Zhu, Mark R Marshall, Yanxia Yu, Zheng Wang

{"title":"Safety, efficacy, and immunogenicity of a novel IgG degrading enzyme (KJ103): results from two randomised, blinded, phase 1 clinical trials.","authors":"Mengdie Cao, Rohit Katial, Yanjun Liu, Xiaoyu Lu, Qin Gu, Chen Chen, Katie Liu, Zhen Zhu, Mark R Marshall, Yanxia Yu, Zheng Wang","doi":"10.1038/s41434-025-00512-1","DOIUrl":"10.1038/s41434-025-00512-1","url":null,"abstract":"The approved intravenous adeno-associated virus (AAV) therapies are limited by the widespread prevalence of pre-existing anti-AAV antibodies in the general population, which are known to restrict patients' ability to receive gene therapy and limit transfection efficacy in vivo. To address this challenge, we have developed a novel recombinant human immunoglobulin G degrading enzyme KJ103, characterized by low immunogenicity and clinical value for the elimination of anti-AAV antibodies in gene transfer. Herein, we conducted two randomized, blinded, placebo-controlled, single ascending dose Phase I studies in China and New Zealand, to evaluate the pharmacokinetics, pharmacodynamics, safety and immunogenicity of KJ103 in healthy volunteers. The results confirmed that KJ103 rapidly reduced IgG and maintained plasma IgG at low levels for one week. Dose of KJ103 ranging from 0.01 to 0.40 mg/kg had a favorable safety and tolerability profile across diverse ethnic and gender groups. KJ103 demonstrated a lower incidence of pre-existing anti-drug antibodies (ADAs) compared to currently approved human IgG degrading enzyme Imlifidase, with most induced ADAs predominantly reverting to baseline six months after administration. These properties are ideal for the management of immune disorders, rejection responses, and immunotherapies where pre-existing antibodies can reduce efficacy. Furthermore, we tested AAV2 neutralizing antibodies to confirm the potential utility of KJ103 in enhancing gene therapy.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":"223-236"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Unveiling molecular secrets: Analysis of stable lentiviral packaging cell lines enables identification of novel viral gene functions. 揭开分子的秘密：分析稳定的慢病毒包装细胞系可以识别新的病毒基因功能。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-05-01 Epub Date: 2025-04-15 DOI: 10.1038/s41434-025-00533-w

Jona Röscheise, Maximilian Klimpel, Parameswari Govindarajan, Kerstin Otte, Holger Laux

{"title":"Unveiling molecular secrets: Analysis of stable lentiviral packaging cell lines enables identification of novel viral gene functions.","authors":"Jona Röscheise, Maximilian Klimpel, Parameswari Govindarajan, Kerstin Otte, Holger Laux","doi":"10.1038/s41434-025-00533-w","DOIUrl":"10.1038/s41434-025-00533-w","url":null,"abstract":"Lentiviral vectors (LVVs) are widely used in gene therapy due to their ability to infect both dividing and non-dividing cells. For LVV production, the creation of stable packaging cell lines with integrated genes necessary for viral replication offer a more consistent and scalable alternative to transient plasmid transfection approach. Although the development of such stable LVV packaging cell lines has been reported, the molecular changes induced by stable and inducible viral gene expression and the impact of genome integrated viral genes on cellular pathways remain poorly characterized. For better insight, we investigated the molecular characteristics of a stable LVV packaging cell line and its host cell line (HEK293T/17) by comparing differential expressed genes. This pathway analysis revealed significant changes in pathway usage between packaging and host cell lines, influenced by different viral transgenes. Gag-pol expression was found to suppress host translational machinery, while rev and VSV-G expression modulated mitochondrial pathways, including oxidative phosphorylation. HIV-1 tat expression, on the other hand, activated histone-related genes. These regulatory shifts suggest a strategic reprogramming of host cellular states to favor viral replication, curbing protein synthesis and energy production to levels that support viral assembly but impair the host's immune defense and the production of immune-related proteins. Our findings provide a deeper understanding of the molecular changes associated with stable viral gene expression, which can inform the optimization of LVV production in gene therapy applications.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":"266-276"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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