Gene Therapy最新文献

Characteristics of long-term follow-up studies for gene therapies registered on ClinicalTrials.gov. 在ClinicalTrials.gov上注册的基因疗法的长期随访研究的特点。

IF 4.5 3区医学

Gene Therapy Pub Date : 2025-10-22 DOI: 10.1038/s41434-025-00571-4

Carolyn Riley Chapman, Ava Glazier, Emina Berbić, Barbara E Bierer

{"title":"Characteristics of long-term follow-up studies for gene therapies registered on ClinicalTrials.gov.","authors":"Carolyn Riley Chapman, Ava Glazier, Emina Berbić, Barbara E Bierer","doi":"10.1038/s41434-025-00571-4","DOIUrl":"https://doi.org/10.1038/s41434-025-00571-4","url":null,"abstract":"Guidance from the U.S. Food and Drug Administration and other regulatory agencies recommends long-term follow-up (LTFU) studies of gene therapy recipients. The primary objective of LTFU studies is to understand the long-term safety of gene therapy products; evaluation of efficacy outcomes may be a secondary goal. To learn more about LTFU study design and conduct, we conducted a descriptive study of key characteristics of LTFU gene therapy study protocols registered in ClinicalTrials.gov, including data about status and duration, funding source, enrollment, number of clinical trial sites per study, eligibility criteria, geographic location, and intent to monitor and report adverse events. This analysis enabled a better understanding of how registered LTFU studies are currently designed and stimulated ideas for improvement, which are discussed. Most notably, our results suggest that there is a lack of harmonization in how safety outcomes are monitored and reported across LTFU studies. Standardization and/or harmonization of outcome reporting for LTFU studies of GTs may increase their scientific value. The development of better guidance and innovative approaches for LTFU study design and conduct would help support best practices and the fulfillment of LTFU commitments to understand the overall long-term benefit-risk profile of GT products.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344977","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

Codon changes challenge PCR-based gene doping detection. 密码子变化挑战基于pcr的基因兴奋剂检测。

IF 4.5 3区医学

Gene Therapy Pub Date : 2025-10-07 DOI: 10.1038/s41434-025-00569-y

Die Wu, Shengqian Ding, Nian Liu, Yi Shi, Peipei Su, Hui Shi, Yue Shi, Bo Han, Sheng Cheng, Xinyuan Ren, Futong Tian, Peijie Chen, Jiaoxiang Wu, Xianbin Su, Ruihong Li

{"title":"Codon changes challenge PCR-based gene doping detection.","authors":"Die Wu, Shengqian Ding, Nian Liu, Yi Shi, Peipei Su, Hui Shi, Yue Shi, Bo Han, Sheng Cheng, Xinyuan Ren, Futong Tian, Peijie Chen, Jiaoxiang Wu, Xianbin Su, Ruihong Li","doi":"10.1038/s41434-025-00569-y","DOIUrl":"https://doi.org/10.1038/s41434-025-00569-y","url":null,"abstract":"Genetic/genomic manipulation techniques (gene transfer/delivery, gene editing, etc.) have become more and more mature, and the illegal use as gene doping in sports has drawn attentions. World Anti-Doping Agency (WADA) strictly prohibits gene doping, and has issued guideline on quantitative real-time PCR (qPCR) detections. However, the technical feature of qPCR makes it difficult to detect new doping targets, and codon changes on targets may also affect detection efficiency. Here, we prepare standard materials for genomic and transgenic versions of human EPO (hEPO) gene, and design qPCR primers to check the consequences of codon changes on gene doping detection. We confirm that carefully designed qPCR assays could indeed capture transgene signal, but codon changes on the transgene could severely undermine detection efficiency. We have also mimicked real world gene doping scenario by mixing genomic and transgenic versions of hEPO, and qPCR could detect wild-type but not codon-changed transgenes. As a method validation for such a challenge, we also use Sanger sequencing to confirm that sequencing could easily capture gene doping even for codon-changed transgenes. Our study confirms that codon changes will challenge qPCR-based gene doping detection, and calls for un-biased detection tools based on high-throughput sequencing in the future.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244376","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

Genetic mutations in HSV-1 replication-defective vectors: Implications for their safety in gene therapy applications. HSV-1复制缺陷载体的基因突变：对其在基因治疗应用中的安全性的影响。

IF 4.5 3区医学

Gene Therapy Pub Date : 2025-09-28 DOI: 10.1038/s41434-025-00566-1

Stefano Cattaneo, Barbara Bettegazzi, Selene Ingusci, Gianluca Verlengia, Tascini Anna Sofia, Zucchini Silvia, Franca Codazzi, Marco J Morelli, Marco Marzulli, Joseph C Glorioso, Michele Simonato

{"title":"Genetic mutations in HSV-1 replication-defective vectors: Implications for their safety in gene therapy applications.","authors":"Stefano Cattaneo, Barbara Bettegazzi, Selene Ingusci, Gianluca Verlengia, Tascini Anna Sofia, Zucchini Silvia, Franca Codazzi, Marco J Morelli, Marco Marzulli, Joseph C Glorioso, Michele Simonato","doi":"10.1038/s41434-025-00566-1","DOIUrl":"https://doi.org/10.1038/s41434-025-00566-1","url":null,"abstract":"Beyond its well-known role in orofacial recurrent infections, HSV-1 has garnered significant attention in neuroscience for contrasting reasons. On one hand, it has been found to be involved in neurodegenerative processes; on the other, it may represent a versatile platform for gene therapy of brain diseases, due to its large genome that enables the delivery of sizable or multiple genes. These opposite features underscore the importance of understanding HSV-1 interactions with neural tissues in view of its employment as a gene therapy platform. We recently developed a new generation of highly defective backbones that proved very efficient and safe after direct injection in the brain parenchyma. Here we aimed at probing in depth the safety of viral batches that lack obvious unwanted (specifically, fusogenic) activities during production and, therefore, may escape negative selection. We employed whole-genome sequencing, electrophysiology, and viral engineering to compare different viral batches. We identified mutations (in particular A to I at position 549 in the UL27 gene) that confer fusogenic capacity to the envelop glycoprotein gB, inducing a hyperexcitable phenotype in transduced neurons. Such syncytial variants should be identified and avoided for any application of HSV-1 vectors implicating their direct injection in the nervous system.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185499","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

Overcoming matrix effects in AAV neutralization assays with a constant serum concentration approach. 用恒血清浓度法克服AAV中和试验中的基质效应。

IF 4.5 3区医学

Gene Therapy Pub Date : 2025-09-26 DOI: 10.1038/s41434-025-00567-0

Beatrix Kovács, Viktória Szabó, Domonkos Horváth, Attila Balázs Dobos, Zoltán Zsolt Nagy, Wim Vanduffel, Zsuzsanna Szemlaky, Áron Szepesi, István Ulbert, Balázs Rózsa, Dániel Hillier

{"title":"Overcoming matrix effects in AAV neutralization assays with a constant serum concentration approach.","authors":"Beatrix Kovács, Viktória Szabó, Domonkos Horváth, Attila Balázs Dobos, Zoltán Zsolt Nagy, Wim Vanduffel, Zsuzsanna Szemlaky, Áron Szepesi, István Ulbert, Balázs Rózsa, Dániel Hillier","doi":"10.1038/s41434-025-00567-0","DOIUrl":"https://doi.org/10.1038/s41434-025-00567-0","url":null,"abstract":"Sensitive quantification of adeno-associated virus (AAV) neutralizing antibodies (NAbs) is essential for gene therapy success. Conventional cell-based transduction inhibition assays often encounter matrix-induced artifacts resulting from variable serum content across dilutions, which artificially inflate transduction baselines and mask partial neutralization. To address this challenge, we developed the constant serum concentration (CSC) assay, which maintains constant serum levels across dilutions to stabilize assay baselines and enhance NAb detection sensitivity. Using human sera across multiple AAV serotypes, we demonstrated that CSC reclassified up to 21.7% of samples classified as non-neutralizing by a conventional variable serum concentration (VSC) assay format. This improved sensitivity was validated using monoclonal antibody and multi-species serum test benchmarks and enhanced the reliability of seronegative control pool selection. Importantly, CSC detected persistent seropositivity in preclinical seroreversion models up to one year longer than a conventional VSC assay. Since even low-level neutralizing antibodies can significantly impact gene therapy efficacy, these findings have direct implications for optimizing AAV redosing strategies and refining patient stratification. By addressing fundamental limitations in NAb quantification while maintaining procedural simplicity, the CSC assay provides crucial insights into antibody persistence with translational relevance across species and clinical settings.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174670","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

Correction: PPARγ is essential for protection against nonalcoholic steatohepatitis. 更正：PPARγ对预防非酒精性脂肪性肝炎至关重要。

IF 4.5 3区医学

Gene Therapy Pub Date : 2025-09-26 DOI: 10.1038/s41434-025-00568-z

C W Wu, E S H Chu, C N Y Lam, A S L Cheng, C W Lee, V W S Wong, J J Y Sung, J Yu

引用次数: 0

Correction: Identification of AAV variants with improved transduction of human vascular endothelial cells by screening AAV capsid libraries in non-human primates. 更正：通过筛选非人灵长类动物的AAV衣壳文库，鉴定具有改进的人血管内皮细胞转导的AAV变体。

IF 4.5 3区医学

Gene Therapy Pub Date : 2025-09-05 DOI: 10.1038/s41434-025-00565-2

Maria Stamataki, Julia Lüschow, Christina Schlumbohm, Malik Alawi, Lars Lunding, Eberhard Fuchs, Martin Trepel, Markus Schwaninger, Jakob Körbelin

引用次数: 0

AAV-mediated MUC5AC siRNA delivery to prevent mucociliary dysfunction in asthma aav介导的MUC5AC siRNA递送预防哮喘患者粘膜纤毛功能障碍。

IF 4.5 3区医学

Gene Therapy Pub Date : 2025-08-23 DOI: 10.1038/s41434-025-00564-3

Sahana Kumar, Maria Corkran, Yahya Cheema, Margaret A. Scull, Gregg A. Duncan

{"title":"AAV-mediated MUC5AC siRNA delivery to prevent mucociliary dysfunction in asthma","authors":"Sahana Kumar, Maria Corkran, Yahya Cheema, Margaret A. Scull, Gregg A. Duncan","doi":"10.1038/s41434-025-00564-3","DOIUrl":"10.1038/s41434-025-00564-3","url":null,"abstract":"The main structural components of mucus produced in the lung are mucin 5B (MUC5B) and mucin 5AC (MUC5AC) where a relatively higher expression of MUC5B is typical in health. In the lungs of individuals with asthma, there is a shift from MUC5B to MUC5AC as the predominantly secreted mucin which has been shown to impair mucociliary clearance (MCC) and increase airway mucus plug formation. Given its role in asthmatic lung disease, MUC5AC represents a potential therapeutic target where a gene delivery approach could be leveraged to modulate its expression. For these purposes, we explored adeno-associated virus serotype 6 (AAV6), as a viral gene vector to transduce airway epithelial cells and reduce MUC5AC expression via siRNA delivery. We confirmed that AAV6 was able to transduce epithelial cells in vitro as well as in the airways of healthy mice in vivo with high transgene expression in mucus-secreting goblet cells. Using multiple particle tracking analysis, we observed that AAV6 was capable of penetrating both normal and MUC5AC-enriched mucus barriers. AAV6 carrying MUC5AC-targeting siRNA was evaluated as a prophylactic treatment in HAE cell cultures before IL-13 challenge. IL-13 stimulated HAE cultures treated with AAV6-MUC5AC siRNA had significantly reduced MUC5AC mRNA and protein expression compared to untreated controls. Mucociliary transport in IL-13 stimulated HAE cultures was also maintained and comparable to healthy controls following AAV6-MUC5AC siRNA treatment. Together, these findings support that AAV6 may be used as an inhaled gene therapy to suppress MUC5AC overexpression and restore normal airway clearance function in asthma.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 5","pages":"508-516"},"PeriodicalIF":4.5,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41434-025-00564-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Identification of AAV variants with improved transduction of human vascular endothelial cells by screening AAV capsid libraries in non-human primates 通过筛选非人灵长类动物AAV衣壳文库，鉴定具有改善人血管内皮细胞转导的AAV变体。

IF 4.5 3区医学

Gene Therapy Pub Date : 2025-08-22 DOI: 10.1038/s41434-025-00563-4

Maria Stamataki, Julia Lüschow, Christina Schlumbohm, Malik Alawi, Lars Lunding, Eberhard Fuchs, Martin Trepel, Markus Schwaninger, Jakob Körbelin

{"title":"Identification of AAV variants with improved transduction of human vascular endothelial cells by screening AAV capsid libraries in non-human primates","authors":"Maria Stamataki, Julia Lüschow, Christina Schlumbohm, Malik Alawi, Lars Lunding, Eberhard Fuchs, Martin Trepel, Markus Schwaninger, Jakob Körbelin","doi":"10.1038/s41434-025-00563-4","DOIUrl":"10.1038/s41434-025-00563-4","url":null,"abstract":"The development of targeted vector systems for gene therapy has made impressive progress during the last decade. Promising vector candidates were identified by screening large pools of adeno-associated virus (AAV) mutants in small animal models. However, it became apparent that targeted AAV mutants isolated from rodents may not function in humans as the tropism of individual AAV mutants can differ between species. To identify novel vascular-targeted AAV capsid mutants suitable for treating human patients, we generated a set of AAV2 display peptide libraries and screened them in the common marmoset, a non-human primate. To evaluate the impact of different AAV library production methods, progress of the screening process was monitored by next generation sequencing. Particle distribution and enrichment was compared between different AAV libraries and selection rounds. We observed enrichment of AAV variants in the brain and other well-perfused organs (lung, heart, kidney) potentially mediated by high capsid affinity for the vascular endothelium in general. In vitro experiments on primary human microvascular endothelial cells isolated from a set of different organs (brain, heart, lung, liver, kidney and spleen) confirmed superior transduction of a selected AAV variant displaying the “DWP” amino acid sequence motif compared to natural AAV serotypes 1–9.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 5","pages":"529-541"},"PeriodicalIF":4.5,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41434-025-00563-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Rapid detection of AAV8 binding antibodies in gene therapy candidates: development of a point-of-care approach. 基因治疗候选药物中AAV8结合抗体的快速检测：一种即时护理方法的发展。

IF 4.5 3区医学

Gene Therapy Pub Date : 2025-08-21 DOI: 10.1038/s41434-025-00559-0

Alexander Kozikowski, Qing Wang, Cheng Yang, Neil Gordon, Kristina M Ciociola, Asanka Yapa, Claudia Villa, Paul Lambotte, Thomas Pisani, Javan Esfandiari, Angelo H Gunasekera

{"title":"Rapid detection of AAV8 binding antibodies in gene therapy candidates: development of a point-of-care approach.","authors":"Alexander Kozikowski, Qing Wang, Cheng Yang, Neil Gordon, Kristina M Ciociola, Asanka Yapa, Claudia Villa, Paul Lambotte, Thomas Pisani, Javan Esfandiari, Angelo H Gunasekera","doi":"10.1038/s41434-025-00559-0","DOIUrl":"https://doi.org/10.1038/s41434-025-00559-0","url":null,"abstract":"Preexisting anti-AAV antibodies pose a significant challenge to the success of Adeno-associated Virus (AAV) mediated gene therapies, as they can diminish therapeutic effectiveness, restrict patient eligibility for treatment, and cause serious health issues during treatment. This study introduces the first point-of-care (POC) test for the rapid, quantitative detection of AAV8 binding antibodies in patients' plasma, serum, and blood, leveraging Chembio's Dual Path Platform (DPP) technology. The DPP AAV8 Total Antibody (TAb) assay delivers results within 20 min from sample addition, with a dynamic range of 0-32 µg/ml when evaluated with purified human polyclonal antibodies that bind to AAV8, with reasonable specificity and sensitivity relative to Chembio's AAV8 TAb ELISA (R² = 0.90). Moreover, the assay demonstrated strong correlations with Chembio's AAV8 neutralizing antibody (NAb) ELISA and cell-based NAb assays (R² = 0.97 in plasma) (Cell-based assay adapted from BioAgilytix EU protocol). This rapid and reliable test can facilitate the screening of potential gene therapy patients for pre-existing antibodies that bind to AAV8 and assess their suitability for AAV8-mediated gene therapy.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951525","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

Gene therapy restores auditory function and rescues damaged inner hair cells in an aged Vglut3 knockout mouse model 在Vglut3基因敲除小鼠模型中，基因治疗可恢复听觉功能并挽救受损的内毛细胞。

IF 4.5 3区医学

Gene Therapy Pub Date : 2025-08-21 DOI: 10.1038/s41434-025-00558-1

Xingle Zhao, Hongen Xu, Chengyu Lian, Shousen Hu, Yue Zhao, Jia Wang, Rongqun Zhai, Mihuan Yang, Yuanjing Zhang, Wei Lu, Wenxue Tang, Liang Wang

{"title":"Gene therapy restores auditory function and rescues damaged inner hair cells in an aged Vglut3 knockout mouse model","authors":"Xingle Zhao, Hongen Xu, Chengyu Lian, Shousen Hu, Yue Zhao, Jia Wang, Rongqun Zhai, Mihuan Yang, Yuanjing Zhang, Wei Lu, Wenxue Tang, Liang Wang","doi":"10.1038/s41434-025-00558-1","DOIUrl":"10.1038/s41434-025-00558-1","url":null,"abstract":"Vesicular glutamate transporter 3 (VGLUT3) is prominently expressed in the inner hair cells of the cochlea, playing a vital role in auditory signal transmission to the brain. Previous studies have shown that Vglut3 gene knockout in mice causes severe sensorineural hearing loss without affecting hair cell integrity. However, the cochlear structure of the aged Vglut3KO remains inadequately explored. In this study, we analyzed the cochlear structure of aged Vglut3KO mice, revealing significant degeneration of inner hair cells, synapses, and stereocilia. To explore the potential of gene therapy to restore cochlear structure, we employed AAV8 vectors to express Vglut3 in the cochleae of 5-week-old Vglut3KO mice. Twenty-seven weeks post-injection, we conducted a series of experiments to evaluate the efficacy of our gene therapy approach. Auditory brainstem response (ABR) testing demonstrated restoration of auditory function following gene therapy. Immunohistochemical staining and scanning electron microscopy (SEM) analysis revealed substantial recovery of inner hair cells and stereocilia post-injection. Our findings provide important insights into the development of novel therapeutic strategies for age-related hearing loss.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 5","pages":"542-552"},"PeriodicalIF":4.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951497","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