Human gene therapy最新文献

Adeno-Associated Virus Gene Delivery to Hard-to-Transduce Tissues: Biological Barriers, Engineering Strategies, and Clinical Challenges. 腺相关病毒基因传递到难以转导的组织：生物障碍、工程策略和临床挑战。

IF 4 3区医学

Human gene therapy Pub Date : 2026-06-01 Epub Date: 2026-04-03 DOI: 10.1177/10430342261432669

Xiaoyu Nan, Jiawen Sun, Yunuo Jiao, Wangan Li, Yujuan Chen, Yurong Liu, Bo Xu, Li Yu, Wenyan Guo, Yang Wu

{"title":"Adeno-Associated Virus Gene Delivery to Hard-to-Transduce Tissues: Biological Barriers, Engineering Strategies, and Clinical Challenges.","authors":"Xiaoyu Nan, Jiawen Sun, Yunuo Jiao, Wangan Li, Yujuan Chen, Yurong Liu, Bo Xu, Li Yu, Wenyan Guo, Yang Wu","doi":"10.1177/10430342261432669","DOIUrl":"10.1177/10430342261432669","url":null,"abstract":"Adeno-associated virus (AAV) is widely regarded as a leading vector for gene therapy, underscored by clinical successes such as Luxturna and Zolgensma. However, efficient gene delivery to hard-to-transduce tissues-including the retina, deep skeletal muscle, and the central nervous system-remains a significant challenge, limited by structural barriers, preexisting immunity, and dose-dependent toxicities. This review systematically outlines recent advances in overcoming these delivery bottlenecks. We delve into four key strategic areas: (i) capsid engineering (e.g., rational design, directed evolution, and computational approaches) to enhance tropism and evade immune detection; (ii) innovative delivery routes (local, systemic, and physical/chemical methods) to improve vector bioavailability; (iii) modulation of intracellular trafficking to boost nuclear delivery; and (iv) immunomodulatory strategies to mitigate both innate and adaptive immune responses. We further highlight translational progress in neuromuscular and retinal diseases and discuss persistent challenges. Looking forward, we envision that the convergence of next-generation capsids, smart vector systems, and integrated delivery platforms will be critical to expand the therapeutic landscape of AAVs from rare monogenic disorders to broader clinical applications.","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"463-481"},"PeriodicalIF":4.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147615747","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

AVLAYAH and KRESLADI Win FDA Accelerated Approvals. AVLAYAH和KRESLADI获得FDA加速批准

IF 4 3区医学

Human gene therapy Pub Date : 2026-06-01 Epub Date: 2026-04-20 DOI: 10.1177/10430342261445261

Alex Philippidis

引用次数: 0

A Review of the Challenge of Pre-Existing Humoral Immunity in Adeno-Associated Virus Gene Therapy and Potential Solutions. 腺相关病毒基因治疗中预先存在的体液免疫挑战及其潜在解决方案综述

IF 4 3区医学

Human gene therapy Pub Date : 2026-06-01 Epub Date: 2026-03-18 DOI: 10.1177/10430342261430244

Monica Alvisi, Luke Roberts, Lothar Roessig, Diane Balderson, Santosh Sanganalmath, Manuela Braun, Shari Gordon, Simon Lacey, Purva Pandya, Roger J Hajjar

{"title":"A Review of the Challenge of Pre-Existing Humoral Immunity in Adeno-Associated Virus Gene Therapy and Potential Solutions.","authors":"Monica Alvisi, Luke Roberts, Lothar Roessig, Diane Balderson, Santosh Sanganalmath, Manuela Braun, Shari Gordon, Simon Lacey, Purva Pandya, Roger J Hajjar","doi":"10.1177/10430342261430244","DOIUrl":"10.1177/10430342261430244","url":null,"abstract":"Adeno-associated virus (AAV) vectors are promising platforms used in a growing number of approved gene therapy (GT) products across diverse therapeutic areas. Due to the potential safety and efficacy concerns associated with AAV-based immune responses, patients with pre-existing anti-AAV antibodies (Abs) are routinely excluded from GT trials to prevent treatment of patients who are hypothesized to have potentially higher risk and/or little or no benefit. However, the exclusion of seropositive patients without prior GT exposure is not based on data-driven Ab titer cut-offs, and diagnostics to identify levels of pre-existing immunity have not been standardized, precluding data generation that would substantiate or reject this hypothesis. There are also significant gaps in clinical data comparing the impact of pre-existing immunity with treatment-induced immune responses for a variety of disease states. This review aims to address these gaps by examining the impact of pre-existing anti-AAV Abs on the safety and efficacy of approved and failed GT products and ongoing clinical trials. Together, these data suggest that pre-existing immunity may not be the principal determinant of GT success. Therefore, to expand the number of patients eligible for treatment, novel AAV GTs should be optimized to mitigate against the effects of anti-AAV Abs and avoid the need for exclusionary screening; in turn, including both seronegative and seropositive patients in clinical trials will enable characterization of the clinical relevance of anti-AAV Abs. Strategies to prevent an undesirable immune response to GT, including immunosuppressive regimens and modifications to GT manufacturing, design and delivery, are presented for consideration in future GT trials.","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"482-499"},"PeriodicalIF":4.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147473506","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

SG33, a Vaccine Strain of Myxoma Virus with Oncolytic Potential, Exploits Macropinocytosis and Clathrin-Mediated Endocytosis for Entry into Pancreatic Cancer Cells. 具有溶瘤潜能的黏液瘤病毒疫苗株SG33利用巨噬细胞和网格蛋白介导的内吞作用进入胰腺癌细胞

IF 4 3区医学

Human gene therapy Pub Date : 2026-06-01 Epub Date: 2026-04-10 DOI: 10.1177/10430342261441043

Nikolaos Kontopoulos, Noémie Delenclos, Laetitia Ligat, Sokunthea Top, Franck Gallardo, Stephane Bertagnoli, Nelson Dusetti, Louis Buscail, Pierre Cordelier

{"title":"SG33, a Vaccine Strain of Myxoma Virus with Oncolytic Potential, Exploits Macropinocytosis and Clathrin-Mediated Endocytosis for Entry into Pancreatic Cancer Cells.","authors":"Nikolaos Kontopoulos, Noémie Delenclos, Laetitia Ligat, Sokunthea Top, Franck Gallardo, Stephane Bertagnoli, Nelson Dusetti, Louis Buscail, Pierre Cordelier","doi":"10.1177/10430342261441043","DOIUrl":"10.1177/10430342261441043","url":null,"abstract":"Oncolytic viruses are being investigated as therapeutic agents in cancer, yet their mechanisms of entry into tumor cells remain incompletely understood. We previously showed that SG33, a veterinary vaccinal strain derived from a pathogenic myxoma virus, displays oncolytic activity in preclinical models of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated the entry pathways of SG33 into primary PDAC-derived cultures. We found that macropinocytosis, an endocytic process frequently upregulated in PDAC, contributes to SG33 uptake. Moreover, SG33 infection itself induced macropinocytosis in a subset of primary PDAC cultures. Mechanistic studies revealed that phosphatidylserine exposed on the viral envelope promotes SG33 internalization through apoptotic mimicry. In PDAC cultures lacking detectable macropinocytosis, SG33 employed clathrin-mediated endocytosis as an alternative entry route. These findings provide the first insights into the entry mechanisms of SG33 into PDAC-derived cells and indicate that this virus can utilize distinct endocytic pathways depending on the cellular context.","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"500-514"},"PeriodicalIF":4.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645121","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

Quantification of Lentiviral Vectors with Nucleic Acid Dyes. 慢病毒载体核酸染色定量研究。

IF 4 3区医学

Human gene therapy Pub Date : 2026-06-01 Epub Date: 2026-03-16 DOI: 10.1177/10430342261431313

Jian Xu, Nancy Zhao, Morgane Chiesa, Anis Contractor, Yongling Zhu

{"title":"Quantification of Lentiviral Vectors with Nucleic Acid Dyes.","authors":"Jian Xu, Nancy Zhao, Morgane Chiesa, Anis Contractor, Yongling Zhu","doi":"10.1177/10430342261431313","DOIUrl":"10.1177/10430342261431313","url":null,"abstract":"Lentiviral vectors are widely used in both biological research and therapeutic applications. Accurate and reliable quantification is essential for their effective use, yet existing methods are often technically demanding and time-consuming. Here, we describe a simple and robust approach to measure lentiviral titers by quantifying viral genomic RNA with nucleic acid-binding dyes. We first evaluated several newly developed commercially available fluorescent dyes for their ability to detect RNA and DNA, identifying SYBR Green II and SYBR Gold as the most sensitive for RNA, with detection limits in the low-nanogram range. We further observed that SYBR Green II readily stained nucleic acids in live cells, whereas SYBR Gold was only partially membrane-permeable. Based on these findings, we developed a quantification method combining SYBR Green II with benzonase to selectively detect encapsidated lentiviral RNA. This assay yielded results consistent with those obtained by enzyme-linked immunosorbent assays. Importantly, this SYBR Green II-based method is rapid (<60 min), reliable, and cost-effective, making it a practical tool for titering lentiviral vectors.","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"515-528"},"PeriodicalIF":4.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147467870","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

Retroviral Transduction of Human CD4⁺ T Cells with Membrane-Attached IL-10 Generates Type 1-Like Regulatory T Cells. 人CD4+ T细胞与膜附着IL-10的逆转录病毒转导产生1型样调节性T细胞

IF 4 3区医学

Human gene therapy Pub Date : 2026-06-01 Epub Date: 2026-04-02 DOI: 10.1177/10430342261437963

Dayana Blokon-Kogan, Shaul Davidson, Maya Levi-Mann, Gideon Gross, Hadas Weinstein-Marom

引用次数: 0

An Engineered Adeno-Associated Virus Variant Enables Efficient Gene Editing in Human T Cells. 一种工程化的腺相关病毒变体能够在人类T细胞中进行有效的基因编辑。

IF 4 3区医学

Human gene therapy Pub Date : 2026-05-01 Epub Date: 2026-02-26 DOI: 10.1177/10430342261424779

Mi Leng, Chunmei Gan, Zhaoyue Zheng, Siwu He, Yu Liu, Lixing Zhou, Rui Cheng, Jiao Zhou, Lin Xiao, Jingya Ye, Zhian Chen, Liangting Xu, C Alexander Valencia, Hoi Yee Chow, Yan Zhang, Biao Dong

{"title":"An Engineered Adeno-Associated Virus Variant Enables Efficient Gene Editing in Human T Cells.","authors":"Mi Leng, Chunmei Gan, Zhaoyue Zheng, Siwu He, Yu Liu, Lixing Zhou, Rui Cheng, Jiao Zhou, Lin Xiao, Jingya Ye, Zhian Chen, Liangting Xu, C Alexander Valencia, Hoi Yee Chow, Yan Zhang, Biao Dong","doi":"10.1177/10430342261424779","DOIUrl":"10.1177/10430342261424779","url":null,"abstract":"Chimeric antigen receptor T (CAR-T) cells, created by gene editing systems along with recombinant adeno-associated virus (rAAV), provide a promising strategy for treating leukemia. rAAVs serve as a safe and effective donor template for homology-directed repair because they can avoid integrating into the host genome. However, only a few AAV serotypes can efficiently transduce human primary T cells at low multiplicities of infection (MOIs) with high packaging efficiency. To address this problem, variants derived from an AAV2 peptide library were screened in Jurkat cells and later validated in primary T cells. A high-ranking sequence identified outside the VR-VIII region, NNSKLTV, was discovered after three rounds of selection and was named Tot3. Tot3 demonstrated transduction efficiency similar to AAV2, but at a 27-fold lower MOI. In addition, Tot3 exhibited greater packaging efficiency and reduced thermal stability. Simultaneously, programmed cell death protein 1 (PD-1) knockout and CAR overexpression were achieved in human primary T cells using Tot3, with knockout and knock-in efficiencies reaching up to 70% and 55%, respectively. These CAR-T cells demonstrated significantly enhanced antitumor activity and increased survival times in a mouse model of diffuse B cell lymphoma.","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"425-441"},"PeriodicalIF":4.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147305252","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

Construct Optimization Enables Oncolytic Virus-Mediated Functional Membrane Localization of Calreticulin and Macrophage Reprogramming. 结构优化实现溶瘤病毒介导的钙网蛋白功能膜定位和巨噬细胞重编程。

IF 4 3区医学

Human gene therapy Pub Date : 2026-05-01 Epub Date: 2026-02-19 DOI: 10.1177/10430342261423100

Xinyuan Zhang, Shengfeng Xiong, Song Zhang, Yao Si, Zhoutong Dai, Teng Ji, Xiaoyuan Huang, Dong Chen, Fei Li, Fayong Hu, Xi Li

{"title":"Construct Optimization Enables Oncolytic Virus-Mediated Functional Membrane Localization of Calreticulin and Macrophage Reprogramming.","authors":"Xinyuan Zhang, Shengfeng Xiong, Song Zhang, Yao Si, Zhoutong Dai, Teng Ji, Xiaoyuan Huang, Dong Chen, Fei Li, Fayong Hu, Xi Li","doi":"10.1177/10430342261423100","DOIUrl":"10.1177/10430342261423100","url":null,"abstract":"The recent evolution of oncolytic virotherapy has yielded viral platforms with enhanced tumor tropism and expanded engineering flexibility, thereby enabling not only direct oncolysis but also deliberate promotion of antitumor immune responses. Here, we systematically explore multiple insertion sites for calreticulin (CALR) within an oncolytic adenovirus, identifying the most optimal variant that exposes robust CALR on tumor cell membrane and functionally motivates macrophages in addition to directly mediating tumor cell lysis. Mechanistically, this variant incorporates a precise deletion within the E1A CR2 domain (920-946 bp), enabling selective replication in retinoblastoma-deficient tumor cells. Furthermore, the E3-gp19k region has been replaced with an exogenous Cytomegalovirus (CMV) promoter to achieve precise regulation of CALR overexpression and diminish systemic toxicity. Functionally, by bulk-RNA-Seq, we demonstrate that oncolytic adenovirus (oAd)-CMV-CALR transfection induces endoplasmic reticulum stress, as evidenced by upregulation of phosphorylated eIF2α, which facilitates the translocation of CALR to the plasma membrane. Via ex vivo coculture assays, we validate that oAd-CMV-CALR transfection enhances the phagocytic capacity of M2 macrophages and promotes their repolarization toward an M1-like phenotype. These findings are further validated in patient-derived ovarian cancer spheroids, underscoring the translational potential of our approach. In vivo, oAd-CMV-CALR suppresses Hepa1-6 xenograft growth, boosts CD8+ T-cell infiltration, and exhibits favorable safety. Collectively, our findings highlight oAd-CMV-CALR as a potential therapeutic approach to modulate the tumor microenvironment and improve cancer immunotherapy outcomes.","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"412-424"},"PeriodicalIF":4.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146226633","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

Ethical and Regulatory Considerations for Developing Gene Therapies Involving Genome Editing. 开发涉及基因组编辑的基因疗法的伦理和监管考虑。

IF 4 3区医学

Human gene therapy Pub Date : 2026-05-01 Epub Date: 2026-03-28 DOI: 10.1177/10430342261430765

Pishoy Gouda, Lauren Cohen, Keith Berelowitz, Juli Bollinger, Julianne Bruno, Jeffrey Cehelsky, R Alta Charo, Jamie Harrop, Jeffrey Kahn, Amy L McGuire, Pearl O'Rourke, Naimish Patel, Eugene Patin, Tammy L Reece, Alan Regenberg, Ricardo Rocha, Hannah Webster, Kevin Weinfurt, Jeremy Sugarman, Adrian F Hernandez

{"title":"Ethical and Regulatory Considerations for Developing Gene Therapies Involving Genome Editing.","authors":"Pishoy Gouda, Lauren Cohen, Keith Berelowitz, Juli Bollinger, Julianne Bruno, Jeffrey Cehelsky, R Alta Charo, Jamie Harrop, Jeffrey Kahn, Amy L McGuire, Pearl O'Rourke, Naimish Patel, Eugene Patin, Tammy L Reece, Alan Regenberg, Ricardo Rocha, Hannah Webster, Kevin Weinfurt, Jeremy Sugarman, Adrian F Hernandez","doi":"10.1177/10430342261430765","DOIUrl":"10.1177/10430342261430765","url":null,"abstract":"Developing gene therapies involving gene editing is a rapidly evolving field with large potential implications for improving health for both rare and common diseases. Ensuring that these technologies are developed safely, efficiently, and fairly is essential. To better understand the ethical considerations and regulatory requirements and challenges with gene therapies involving gene editing that may advance precision health. Through a multistakeholder workshop and subsequent engagements, multiple ethical and regulatory barriers to developing and implementing gene therapies involving gene editing were identified. Eight major themes emerged that warrant careful consideration, including (1) objectives (treatment, risk reduction, and enhancement) for the intervention; (2) competing interests of safety, equity, and desire for research efficiencies; (3) unique aspects of gene editing related to rare and ultrarare genetic conditions; (4) considerations in the pediatric population; (5) regulatory requirements and ethics oversight; (6) challenges with long-term follow-up and data sharing; and (7) communication. To promote the safe, efficient development of gene therapies involving gene editing that will reach their full potential, all stakeholders will have to undertake an unprecedented degree of collaboration. However, this will be essential to ensure that these interventions are effective, ethically sound, and patient-centered.","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"392-402"},"PeriodicalIF":4.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147573668","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

A Tripartite AAV System with Engineered Lox Sites Enables Efficient Delivery of the EYS Gene for Retinal Gene Therapy. 一个具有工程Lox位点的三方AAV系统能够有效地传递EYS基因用于视网膜基因治疗。

IF 4 3区医学

Human gene therapy Pub Date : 2026-05-01 Epub Date: 2026-02-19 DOI: 10.1177/10430342261426597

Kun-Do Rhee, Poppy Datta, Clairissa Baccam, Seongjin Seo

{"title":"A Tripartite AAV System with Engineered Lox Sites Enables Efficient Delivery of the EYS Gene for Retinal Gene Therapy.","authors":"Kun-Do Rhee, Poppy Datta, Clairissa Baccam, Seongjin Seo","doi":"10.1177/10430342261426597","DOIUrl":"10.1177/10430342261426597","url":null,"abstract":"Mutations in the Eyes Shut Homolog (EYS) gene are one of the leading causes of autosomal recessive retinitis pigmentosa, a progressive retinal degenerative disease for which no effective treatment currently exists. However, the large size of the EYS coding sequence (∼9.4 kb) exceeds the packaging limit of adeno-associated virus (AAV) vectors, posing a major barrier to gene replacement therapy. To address this challenge, we developed a tripartite AAV vector system that enables delivery and reconstitution of the full-length EYS gene using a Cre-lox-based unidirectional DNA recombination strategy, Uni-directional and Site-specific Transgene Assembly by Recombination (Uni-STAR). The system consists of three AAV constructs carrying discrete EYS segments flanked by engineered, noncompatible lox sites that drive ordered and unidirectional recombination in target cells. We validated this system in vitro by demonstrating successful reconstitution and expression of full-length EYS protein in HEK293T cells. In vivo, subretinal co-injection of the three AAV vectors into mouse eyes led to precise reconstitution and expression of full-length EYS protein in the retina. These findings establish the feasibility of using a tripartite AAV system to deliver the complete EYS gene and provide a foundation for future therapeutic development targeting EYS-associated retinal degenerations.","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"442-452"},"PeriodicalIF":4.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146226625","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