Human gene therapy最新文献

{"title":"Celyvir: Oncolytic Virotherapy with Mesenchymal Stromal Cells. From Concept to Clinical Translation.","authors":"Alvaro Morales-Molina, Javier García-Castro","doi":"10.1177/10430342261437962","DOIUrl":"10.1177/10430342261437962","url":null,"abstract":"<p><p>Oncolytic virotherapy harnesses genetically engineered viruses to selectively infect and lyse tumor cells while stimulating antitumor immunity through pro-inflammatory microenvironment activation. Celyvir represents a pioneering cell-based oncolytic therapy combining mesenchymal stromal cells (MSCs) as carriers of the human oncolytic adenovirus ICOVIR-5. Developed over two decades through collaborative efforts, Celyvir leverages the tumor-homing capacity of MSCs to enhance systemic delivery and therapeutic efficacy of oncolytic virotherapy against solid tumors. Preclinical and clinical studies, including compassionate use programs and phase I trials, have demonstrated Celyvir's safety, feasibility, and potential efficacy. Mechanistic insights reveal that MSCs with a low pro-inflammatory profile and patients' baseline immune competence correlate with improved responses. The evolution from autologous (Celyvir) to allogeneic MSC-based delivery (AloCelyvir) aims to overcome manufacturing delays and optimize clinical outcomes. This review summarizes the conceptual foundations, preclinical models, translational milestones, and ongoing clinical trials of Celyvir, illustrating its trajectory from bench to bedside as an improved oncolytic virotherapy modality.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"641-662"},"PeriodicalIF":4.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148455669","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}

{"title":"Real-World Data from a Single-Center, Large Academic Centralized Manufacturing of CD19 CAR T Cells in an Industry Partnership.","authors":"Kati Kebbel, Gerno Schmiedeknecht, Andrea Quaiser, Susann Schumann, Carolin Poch, Manuela Haß, Andreas Grahnert, Margarida Rodrigues, Kristin Reiche, Markus Kreuz, Ulrike Koehl","doi":"10.1177/10430342261472597","DOIUrl":"https://doi.org/10.1177/10430342261472597","url":null,"abstract":"<p><p>To date, prediction of manufacturing failure for CAR T cells is still lacking. In a retrospective multivariate analysis of our 368 manufactured CAR-T cell batches (tisagenlecleucel), we investigated potential factors that might be associated with manufacturing failure. In this letter to the editor, we provide a summary of our findings and outline recommendations for future advanced quality control strategies.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":"37 15-16","pages":"802-804"},"PeriodicalIF":4.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148712230","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}

{"title":"The German National Strategy for Gene- and Cell-Based Therapies: Generating Impact by Employing a Novel Multi-Stakeholder Approach.","authors":"Christian Gallus, Francis Ayuk, Philipp Beckhove, Daniel Besser, Martin Bornhäuser, Hildegard Büning, Tobias Cantz, Christoph Conrad, Stefan Eichmüller, Thomas Gazlig, Holm Graessner, Annette Grüters-Kieslich, Nathalie Huber, Michael Hudecek, Thekla Kurz, Björn Lamprecht, Elke Luger, Ulrike Protzer, Axel Schambach, Richard Schäfer, Pablo Serrano, Sven Stegemann, Isabelle Stöckert, Christof von Kalle, Joachim Weber, Christopher Baum","doi":"10.1177/10430342261464845","DOIUrl":"10.1177/10430342261464845","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Gene- and cell-based therapies (GCTs) represent a disruptive and transformative class of biomedical innovations. They address diseases by adding, removing, repairing, or replacing genes and/or by endowing distinct living cells with additional biological functions. Through this plethora of options, numerous conditions-including genetic disorders, cancers, and degenerative diseases-have become potential targets for a curative therapy. Thus, GCTs are considered the \"Future of Medicine\" as they (i) offer a potential cure, particularly for rare and severe disorders previously considered untreatable, (ii) expand the treatment options for common diseases, and (iii) possess the possibility to complement currently applied conventional treatment options. Recognizing both the scientific promise and translational challenges of GCTs, Germany has launched a coordinated national initiative-the National Strategy for Gene- and Cell-Based Therapies. The Strategy was commissioned by the German Federal Ministry of Research, Technology and Space (BMFTR, formerly the German Federal Ministry of Education and Research [BMBF]) and developed through a multi-stakeholder process. The latter involved more than 150 experts from academia, industry, health care sector, professional associations, and patient organizations, who were nominated by the community and assembled into eight working groups to identify current roadblocks and propose possible solutions. Summarized in the Strategy Paper, which was submitted to the BMFTR and published on June 12, 2024, a comprehensive roadmap was developed in this bottom-up process to accelerate the development and clinical implementation of GCTs in Germany. Although it initially had a national focus, the resulting framework is increasingly contributing to the international GCT landscape through growing exchange with GCT initiatives launched in other European member states and with the European Society of Gene and Cell Therapy (ESGCT).In brief, the initiative is focusing on translation starting from research through all steps to clinical application and beyond. This includes workforce development, regulatory frameworks, manufacturing capacity, patient access, and communication with the general public. Numerous targeted measures have been developed by the participating experts in the working groups and are currently being implemented in this broad, collaborative, and bottom-up multi-stakeholder approach. They encompass, for example, the establishment of a website as central information platform, including the GCT-Atlas, a web-based networking and information tool for stakeholders and actors in the GCT field, tailored communication and outreach formats, a Regulatory Support Unit providing independent regulatory guidance for publicly funded early-stage, nonclinical product development, different funding and entrepreneurship programs offering researchers and clinicians financial, educational, and mentoring support, as well as the establish","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"623-629"},"PeriodicalIF":4.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396687","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}

{"title":"Nonhuman Primate Genomes Have Limited Relevance for Evaluating Human CRISPR Off-Target Effects.","authors":"Laura Blaha, Mia Bosinger, Dale L Bodian, Victoria Qu, Jason B Warner, Christopher M Borges, Christian Mueller","doi":"10.1177/10430342261466427","DOIUrl":"https://doi.org/10.1177/10430342261466427","url":null,"abstract":"<p><p>Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology has revolutionized genetic medicine by enabling precise genome editing for therapeutic benefit. CRISPR nucleases are programmed to target genomic sites with sequence complementarity to the spacer region of an associated guide RNA. However, these nucleases may target genomic loci with sequences similar to the target site, which can lead to unintended disruption of off-target genes. The risks associated with these off-target editing events are critical to assess as CRISPR-based <i>in vivo</i> editing systems advance to clinical development. Nonhuman primates (NHPs) are common model species for evaluating the human safety of many therapeutic modalities, but their relevance for evaluating human CRISPR off-target activity has yet to be determined. In this study, 1,220,908 Cas12a and 6,159,066 Cas9 spacer sequences targeting human genes were designed, and off-target editing sites were computationally predicted in humans and five common NHP species. Of the 7,413 Cas12a and 570,754 Cas9 spacers meeting defined on- and off-target inclusion criteria, only 14-21% of Cas12a and 7-15% of Cas9 human off-targets per spacer are recapitulated in the genomes of NHPs commonly used in preclinical studies. These results highlight the limitations of NHPs for the study of human CRISPR spacer specificity and contextualize human risk informed by these studies.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"10430342261466427"},"PeriodicalIF":4.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148653506","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}

{"title":"Restoring Cancer Genomes: Functional Mutation Correction as a Platform for Precision Oncology.","authors":"Pascal Wang, Shady Sayed, Frank Buchholz","doi":"10.1177/10430342261468973","DOIUrl":"10.1177/10430342261468973","url":null,"abstract":"<p><p>Cancer genome sequencing has uncovered an extensive landscape of somatic mutations. However, determining which of these alterations are biologically consequential and therapeutically actionable remains a central challenge in oncology. CRISPR-based genome editing now enables precise correction of oncogenic mutations within their endogenous genomic context. Recent work demonstrates that repairing cancer hotspot mutations restores conserved tumor-relevant transcriptional programs across diverse tumor types, revealing tumor-agnostic dependencies. Beyond therapeutic implications, this mutation-correction framework provides a scalable functional platform to stratify drivers, interrogate variants of uncertain significance, and refine precision diagnostics. This perspective discusses how programmable mutation correction advances (i) mechanistic cancer biology, (ii) personalized cancer diagnostics, and (iii) next-generation precision gene therapies. We propose that systematic reversal of cancer mutations represents a conceptual shift from observing mutational landscapes to actively testing their biological necessity.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"663-669"},"PeriodicalIF":4.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148591106","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}

{"title":"Novel, Stable, and Well-Secreted Single-Chain Fc Forms of Programmed Death-1 Immune Checkpoint Inhibitor Efficiently Block PD-1/PD-L1 Interaction.","authors":"Piia Käyhty, Tiina Nieminen, Amira Hyvönen, Justin Albers-Skirdenko, Tomi T Airenne, Mark S Johnson, Hanna P Lesch, Seppo Ylä-Herttuala, Kari J Airenne","doi":"10.1177/10430342261422764","DOIUrl":"10.1177/10430342261422764","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICI), such as antibodies against Programmed Death 1 (PD-1), are widely used to treat different types of cancer. Unfortunately, only a small subset of patients benefits from such treatments, and the systemic administration of ICIs can cause severe immune-related adverse events. To overcome these hurdles, we performed an <i>in vitro</i> proof-of-concept investigation of recombinant adenoviral vectors encoding different variants of secreted PD-1 (sPD-1), differing in size, cysteine mutations, oligomerization, and effector functions. First, eight sPD-1 variants were screened, followed by the generation of recombinant adenoviruses with four of the highest-performing sPD-1 constructs based on qualitative analysis of sPD-1 secretion and ligand binding. The secretion of sPD-1 was analyzed using immunoblotting, while binding to PD-L1 and PD-L2 ligands was assessed using a pull-down assay and ELISA. In addition, the inhibition of PD-1:PD-L1 interaction was studied using cell-based signaling bioassays. It was demonstrated that the Fc-fusion sPD-1 variants resulted in the highest sPD-1 yields and were the most efficient in ligand binding. In particular, the single-chain Fc-fusion sPD-1 constructs were the most potent variants, as they effectively blocked PD-1-mediated signaling in T cells in two different coculture assays. The results of this <i>in vitro</i> proof-of-concept study indicate that stable and well-secreted sPD-1 constructs have significant potential for site-specific immune gene therapy.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"733-743"},"PeriodicalIF":4.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165214","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}

{"title":"Accelerating Translation of NK Cell Therapies to the Clinic: A European Perspective.","authors":"Lea Rebecca Knapp, Katharina Sophie Fischer, Janika Sosat, Jose Francisco Villena-Ossa, Pia Kluge, Dominik Schmiedel, Jürgen Kuball, Harry Dolstra, Susana Minguet, Tatjana I Cornu, Toni Cathomen, Evren Alici, Michael O'Dwyer, Winfried Stephan Wels, Karl-Johan Malmberg, Rizwan Romee, Eric Vivier, Ulrike Köhl, Adelheid Cerwenka, Evelyn Ullrich","doi":"10.1177/10430342261468974","DOIUrl":"10.1177/10430342261468974","url":null,"abstract":"<p><p>Adoptive immunotherapies have emerged as a promising strategy in the treatment of hematological malignancies. To date, seven chimeric antigen receptor (CAR)-T cell products have obtained market authorization in Europe for B-cell malignancies, where they have revolutionized treatment for eligible patients. In addition, natural killer (NK) cells and γδ T cells are of particular interest for cell-based therapies due to their strong intrinsic cytotoxicity and favorable safety profile. Addressing challenges facing the clinical translation of NK cell therapies was one of the issues discussed in the NK & ILC Symposium that took place in Freiburg, Germany from March 11 to 13, 2026, as the annual meeting of the NK & ILC study group of the German Society for Immunology (DGfI). Topics ranging from basic immunological research to technological innovations and clinical trial results were discussed during the 3-day conference, spanning over 40 presentations and 100 posters. A highlight of the conference was a workshop featuring short presentations and a panel discussion that focused specifically on the current challenges and future prospects of the clinical implementation of NK cell therapies; the findings of this workshop are summarized in this opinion paper.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"691-701"},"PeriodicalIF":4.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148663810","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}

{"title":"A Modular Polymer Enhancer Promotes AAV Transduction and Circumvents Preexisting Immunity in Nonhuman Primates.","authors":"Lauren E Switala, Afsana Mim Khandaker, Sumita Dutta, Matthew J Jorgensen, Andrei Maiseyeu","doi":"10.1177/10430342261471124","DOIUrl":"https://doi.org/10.1177/10430342261471124","url":null,"abstract":"<p><p>Adeno-associated virus (AAV) gene therapy is frequently hindered by dose-limiting toxicities and preexisting neutralizing antibodies (nAbs). Here, we evaluate enhancer polymer (ePL), a cargo-less poly(L-lactic-co-glycolic acid) nanoparticle, the systemic administration of which demonstrated biocompatibility in nonhuman primates (NHPs) and generated a protransduction serum secretome that significantly enhanced AAV uptake in human iPSC-derived cardiomyocytes. Proteomic analysis of human peripheral blood mononuclear cell-derived secretomes identified a transient upregulation of AAV-entry factors, including ITGB3, alongside a downregulation of inflammatory cytokine pathways. Mechanistically, ePL-stimulated macrophages release a paracrine secretome that triggers the rapid, transient degradation of hepatic insulin receptor substrate 2 and subsequent AKT inhibition in liver and isolated primary mouse hepatocytes. Additionally, ePL attenuated the levels of NHP-derived nAbs <i>in vitro</i> and in a mouse-NHP xenotransfusion model without depleting total systemic immunoglobulins. Finally, ePL reduced Immunoglobulin G (IgG) secretory capacity of splenic B cells, suggesting a mechanistic link by which levels of nAbs are likely attenuated. Together, these findings highlight ePL as a promising supporting agent to improve AAV gene transfer, warranting its further optimization for clinical translation.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"10430342261471124"},"PeriodicalIF":4.6,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148619577","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}

{"title":"Systematic Benchmarking of CRISPR-Cas9 Off-Target Prediction Tools Reveals Limitations and Implications for Preclinical Assessment.","authors":"Masako M Kaufmann, Maren Hackenberg, William Jobson Pargeter, Rolf Backofen, Harald Binder, Toni Cathomen","doi":"10.1177/10430342261466407","DOIUrl":"https://doi.org/10.1177/10430342261466407","url":null,"abstract":"<p><p>Accurate identification of CRISPR-Cas9 off-target sites is essential for the safety assessment of genome-editing-based therapies. While numerous <i>in silico</i> prediction tools have been developed, their comparative performance and practical utility in preclinical workflows remain incompletely defined. We performed a systematic benchmarking of 14 <i>in silico</i> CRISPR-Cas9 off-target prediction tools, including both standard approaches and machine learning-based models. The analysis was based on a curated dataset derived from the CRISPRoffT database, comprising 3,827 deep-sequenced genomic sites across 26 guide RNA/Cas9 combinations in human cells. Sites with indel frequencies ≥0.1% were operationally defined as true off-targets. We evaluated tool performance using score distributions, correlation with indel frequencies, precision-recall characteristics, recall among top-ranked candidate sites, and the effect of combining tools. All tools assigned higher scores to true off-target sites compared with nontarget sites, although substantial overlap between classes was observed. Correlation between prediction scores and indel frequencies was weak to moderate, indicating limited ability to predict editing magnitude. Precision-recall performance was moderate across all tools, reflecting inherent trade-offs between sensitivity and specificity. Recall increased with the number of predicted sites considered, reaching approximately 77% among the top 500 and up to 83% among the top 1,250 sites, but leaving a substantial fraction of true off-targets undetected. Combining tools yielded only modest improvements. Current <i>in silico</i> tools enable prioritization of CRISPR-Cas9 off-target candidates but remain limited in their ability to comprehensively identify and quantitatively predict off-target activity. Our findings highlight the importance of considering both ranking performance and candidate site coverage and support the use of combined computational and experimental strategies for robust off-target assessment in preclinical gene editing workflows.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"10430342261466407"},"PeriodicalIF":4.6,"publicationDate":"2026-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148591145","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}

{"title":"The 2026 ESGCT Spring School.","authors":"Thomas Gallagher","doi":"10.1177/10430342261471871","DOIUrl":"https://doi.org/10.1177/10430342261471871","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"10430342261471871"},"PeriodicalIF":4.6,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148470382","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}