Human gene therapy最新文献

{"title":"Ocular Gene Therapy in China: Technological Framework, Clinical Translation, and Future Perspectives.","authors":"Di Zhang, Ziyan He, Fang Lu, Yang Yang","doi":"10.1177/10430342261495300","DOIUrl":"https://doi.org/10.1177/10430342261495300","url":null,"abstract":"<p><p>The eye is well suited to gene therapy because of its compartmentalized anatomy, accessibility for local delivery, and capacity for longitudinal assessment. In China, ocular gene therapy is undergoing rapid clinical translation, with expanding innovation in vector engineering, delivery technologies, genome editing, and therapeutic modalities. Clinical development has progressed from inherited optic neuropathies and retinal diseases to complex acquired ocular disorders, anterior-segment genome editing, and optogenetic vision restoration. This review summarizes the technological landscape and representative clinical advances of ocular gene therapy in China, highlighting the evolution from established gene-replacement approaches toward increasingly differentiated therapeutic strategies. We further discuss key challenges in interpreting clinical benefit and translating early clinical signals into durable, reproducible outcomes. Future progress will depend on clinically driven innovation, rigorous evidence of meaningful patient benefit, and standardized pathways for sustainable clinical translation.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"10430342261495300"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149193260","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":"Beyond Viruses: Transposons and CRISPR-Programmable Nonviral Systems for Genome Engineering.","authors":"Satnam Singh, Omkar Vikram Panchal, Zoltán Ivics","doi":"10.1177/10430342261493722","DOIUrl":"https://doi.org/10.1177/10430342261493722","url":null,"abstract":"<p><p>Human gene therapy has been transformed by repurposing mobile genetic elements as tools for efficient gene delivery and precise genome modification. Viruses, transposons, and retrotransposons mobilize genetic material through distinct mechanisms with distinct advantages for genome engineering platforms with therapeutic potential. This review describes the mechanisms, performance characteristics, and translational relevance of nonviral methods of gene transfer and genome engineering, with emphasis on engineered systems such as the <i>Sleeping Beauty</i> (SB) and <i>piggyBac</i> (PB) DNA transposons, R2 retrotransposon-based platforms, CRISPR-associated transposons (CASTs), and prime editing (PE). Clinical trials using both SB- and PB-engineered cells have shown feasibility by demonstrating sustained therapeutic effect through stable transgene integration, such as CD19-directed CAR-T cell therapy for hematological malignancies. These transposon-based vectors enable robust gene transfer for cell engineering, but are fairly promiscuous with respect to where in the genome they insert their genetic cargo. On the contrary, R2-derived systems and CASTs represent promising technologies for programmable insertion, but are still under preclinical development. CRISPR-based PE provides a distinct route to precise sequence correction without double-strand breaks and is particularly attractive for the correction of monogenic disorders. Taken together, these technologies define a continuum from natural genome mobility to clinically relevant genome engineering. Continued optimization of delivery, targeting, and editing fidelity will determine how rapidly these approaches move from experimental innovation into routine clinical use.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"10430342261493722"},"PeriodicalIF":4.6,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181580","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":"Automated Production of Gene-Edited CAR-T Cells for People Living with HIV.","authors":"Lea Isabell Schwarze, Niklas Nuppenau, Jan Hendrik Müller, Almut Uhde, Nahla Al Ashkar, Tanja Schröder, Kristoffer Riecken, Boris Fehse","doi":"10.1177/10430342261492461","DOIUrl":"https://doi.org/10.1177/10430342261492461","url":null,"abstract":"<p><p>Adoptive transfer of gene-modified autologous T cells, for example, expressing chimeric antigen receptors (CARs), is a promising therapy option for a variety of malignant and nonmalignant diseases. Given their increased risk to develop certain cancer types, namely lymphoma, and the current progress with HIVenv-directed CARs, people living with HIV (PLWH) might particularly profit from CAR-T therapies. At the same time, clinical translation of novel advanced therapy medicinal products remains challenging, partly due to the elaborate <i>ex vivo</i> production under good manufacturing practice (GMP) conditions. This holds especially true for T-cell products from PLWH, which require special manufacturing conditions to suppress HIV replication. We aimed to exemplarily address this limitation in the context of CD19-CAR-T cells for HIV-positive cancer patients. To this end, we developed an integrated, GMP-compliant process for lentiviral CAR transfer and simultaneous knockout of the HIV coreceptor C-C chemokine receptor 5 (CCR5) by mRNA electroporation of our transcription activator-like effector nuclease (CCR5-Uco-hetTALEN) based on the CliniMACS Prodigy. We successfully performed three manufacturing runs to produce CCR5-edited CD19-CAR-T cells on a clinical scale, generating up to 3.9 × 10⁹ viable T cells. Thirty-seven percent to 55% of the T cells in the final product expressed functional CD19-CARs, the overall CCR5 editing rates ranged from 42% to 54%. The third large-scale process was performed in the presence of the antiretroviral drug saquinavir to suppress potential viral replication during manufacturing of cells from HIV-positive patients. In summary, we have developed a GMP-compliant manufacturing process for gene-edited CAR-T cells under antiretroviral suppression, which might help to accelerate the translation of cellular immunotherapies, namely CAR-T cells for patients living with HIV in the future.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"10430342261492461"},"PeriodicalIF":4.6,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136504","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":"Adeno-Associated Virus Gene Therapy Translation: Lessons from Early Regulatory Meetings.","authors":"Rodica Stan, Richa Madan Lomash, Oleg A Shchelochkov, Irini Manoli, Carolina I Galarreta Aima, Venkata Mangalampalli, Eun-Young Choi, Randy J Chandler, Lina Li, Jennifer L Sloan, Pramod Terse, Xin Xu, Jean Dehdashti, Philip J Brooks, Carsten G Bönnemann, Charles P Venditti, Elizabeth A Ottinger","doi":"10.1177/10430342261452217","DOIUrl":"10.1177/10430342261452217","url":null,"abstract":"<p><p>The Platform Vector-Gene Therapy (PaVe-GT) program is a National Institutes of Health (NIH) initiative that aims to develop adeno-associated virus (AAV) gene therapies for four monogenic rare diseases, two organic acidemias and two congenital myasthenic syndromes. PaVe-GT's platform-based approach identifies and diminishes redundancies and applies efficiencies in preclinical, clinical, and regulatory activities. The program's hypothesis is that implementing these efficiencies can accelerate clinical trial initiation. Based on its platform-centric experience and public-serving mission, the PaVe-GT program actively shares its scientific and regulatory learnings with the public to benefit the development of similar gene therapy products for rare diseases. PaVe-GT's first investigational AAV gene therapy candidate is AAV serotype 9 human propionyl-CoA carboxylase alpha subunit (AAV9-hPCCA) for propionic acidemia caused by PCCA deficiency, which received initial feedback from the Food and Drug Administration (FDA) in an <b>IN</b>itial <b>T</b>argeted <b>E</b>ngagement for <b>R</b>egulatory <b>A</b>dvice on <b>C</b>BER/Center for Drug Evaluation and Research (CDER) Produc<b>T</b>s (INTERACT) meeting. Upon further product development that took into consideration the FDA's initial advice, the program obtained the Agency's feedback in pre-investigational new drug (IND) (Type B) and Type C meetings. Here, we share our experience from these meetings, including strategy, preparation, pre- and post-meeting feedback from the FDA, and lessons learned during the AAV9-hPCCA regulatory process, which the program plans to apply across the PaVe-GT platform. Topics discussed in the regulatory meetings included animal model and efficacy studies, toxicology study plans, manufacturing of the investigational AAV product, and clinical trial design. The main lessons learned from the pre-IND and Type C meetings for AAV9-hPCCA are: (1) Pharmacology/Toxicology studies in a single rodent species are sufficient for filing an initial IND; (2) FDA feedback guides product quality improvements and early development of a quantitative potency assay; (3) use of biomarkers as potential surrogate endpoints in a future efficacy trial benefits from collection of data in the natural history study and the first-in-human Phase 1/2 study; and (4) evidence from the Phase 1/2 clinical trial could be leveraged to support a license application. Lightly redacted regulatory documents and comprehensive templates developed by the PaVe-GT team are available on the PaVe-GT website.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"932-947"},"PeriodicalIF":4.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148283646","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":"CAR-T Cell Therapy: Manufacturing Platforms and Clinical Consequences.","authors":"Duc-Hiep Bach, Thanh Liem Nguyen","doi":"10.1177/10430342261467645","DOIUrl":"10.1177/10430342261467645","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T-cell therapy has transformed hematological cancer care, yet variability in efficacy, durability, and safety cannot be explained solely by antigen selection or patient factors. We propose that manufacturing platforms are active biological determinants of outcome. Viral vectors, used in all licensed products, provide stable genomic integration and durable expression but are limited by cost, cargo capacity, and centralized production. Nonviral strategies, including transposons, CRISPR knock-ins, and messenger RNA delivery, enable faster, less-expensive manufacturing with larger payloads, while introducing distinct safety and persistence profiles. This review presents a three-layer mechanistic framework that reframes manufacturing as biology: integration biology determines genomic risk and transgene stability; clonal fitness shapes persistence, dominance, and exhaustion; and epigenomic imprinting, influenced by gene transfer method, cytokines, and culture stress, preconfigures functional trajectories. Clinical observations link platform choice to immune recovery, where prolonged B-cell aplasia and delayed T-cell reconstitution contribute to infection-related nonrelapse mortality, and hematopoietic reserve at apheresis emerges as a practical predictor. Finally, manufacturing is positioned as the key to democratizing cell therapy. Decentralized, nonviral production aligned with regulatory standards may enable equitable access and transition CAR-T therapy from innovation to sustainable global care.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"920-931"},"PeriodicalIF":4.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148420751","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":"Suppression of AAV-Delivered Transgene Expression Using Artificial MicroRNAs Delivered by an Alternative AAV Serotype.","authors":"Miguel de Mulder Rougvie, Mara R Kebret, Youjun Wu, Katie M Stiles, Ronald G Crystal","doi":"10.1177/10430342261457812","DOIUrl":"10.1177/10430342261457812","url":null,"abstract":"<p><p>Adeno-associated virus (AAV) gene transfer vectors mediate long-term expression in nondividing cells, an advantage for treating chronic disorders. However, current platforms lack a way to selectively shut down transgene expression if adverse effects arise. To create an \"off switch,\" we hypothesized that incorporating unique artificial microRNA (amiRNA) target sequences into an AAV expression cassette would allow subsequent suppression of transgene expression using a second AAV vector encoding the cognate amiRNA. We introduced 22-nt sequences absent from human and mouse transcriptomes into the 3' untranslated region (UTR) of a therapeutic AAV cassette. To identify optimal amiRNAs, two tandem copies of each amiRNA were cloned into the 3'UTR of an mCherry reporter gene. <i>In vitro</i> assessment of six amiRNA/target pairs using a dual luciferase assay identified four amiRNAs that efficiently suppressed reporter expression. Cells cotransfected with target site 3 (TS3) and amiRNA-T3B showed the greatest reduction in luciferase activity (80%, <i>p</i> < 0.0001) and were selected for further study. The \"off-switch\" system was then evaluated using an AAV5 therapeutic vector expressing a recombinant humanized anti-IgE monoclonal antibody (AAV5-TBG-anti-IgE-TS3), designed for long-term suppression of allergen-induced reactions. Co-transfection of HEK293T cells with anti-IgE-TS3 and amiRNA-T3B significantly reduced anti-IgE mRNA and protein levels relative to a control amiRNA (<i>p</i> < 0.0001). <i>In vivo</i> testing in Balb/c mice (<i>n</i> = 5) involved intravenous administration of AAV5-anti-IgE-TS3 (3.2 × 10¹⁰ gc), followed 4 weeks later by an AAVrh.10 amiRNA vector (AAVrh.10-TBG-amiRNA-T3B; 1 × 10¹¹ gc). Control mice receiving only the therapeutic vector expressed 18.4 ± 13.8 µg/mL serum anti-IgE at 10 weeks. In contrast, mice receiving the amiRNA \"off\" vector showed marked suppression of anti-IgE (0.3 ± 0.15 µg/mL, <i>p</i> < 0.0001). These findings provide proof-of-concept that AAV-delivered amiRNAs can selectively switch off transgene expression, offering a strategy to improve the safety of AAV-mediated gene therapies.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"948-962"},"PeriodicalIF":4.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148673588","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":"<i>In Vivo</i> Genome Editing Approach to Disrupt Hydroxyacid Oxidase 1 for the Treatment of Primary Hyperoxaluria Type 1.","authors":"Jenny A Greig, Camilo Breton, Melanie K Smith, Thomas Furmanak, Peter Bell, Peter Clark, James M Wilson","doi":"10.1177/10430342261460681","DOIUrl":"10.1177/10430342261460681","url":null,"abstract":"<p><p>Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder that leads to kidney and liver failure. PH1 is caused by a mutation in the alanine glyoxylate aminotransferase (<i>AGXT</i>) gene, which encodes a key metabolic enzyme that converts glyoxylate to glycine in the liver. Inability to metabolize glyoxylate leads to oxalate overproduction, yielding insoluble calcium oxalate crystals; accumulation of these crystals leads to progressive organ failure. Here, we used a novel, minimally disruptive genome-editing approach to disrupt the mechanism of action of hydroxyacid oxidase 1 (HAO1), an upstream enzyme in the glyoxylate metabolic pathway. Successful gene editing and disruption of the <i>HAO1</i> gene is expected to increase levels of glycolate, a harmless intermediate of the glycine metabolic pathway, thereby preventing the formation of calcium oxalate crystals. We intravenously administered an adeno-associated virus (AAV) vector expressing the M1HAO1 meganuclease to both wild-type and <i>Agxt^-/-</i> mice, a mouse model of PH1. We observed >30% editing of <i>HAO1</i> in <i>Agxt^-/-</i> mice, correlating with a dose-dependent increase in serum glycolate levels. At the highest dose tested, urine glycolate levels increased by 79%, with a concomitant 75% decrease in urine oxalate levels. We also evaluated <i>in vivo</i> targeting in rhesus macaques injected with AAV expressing two different versions of the HAO1 meganuclease. Dose-dependent editing of hepatic DNA and RNA was achieved, and serum glycolate levels changed in a manner consistent with successful liver editing; additionally, the treatment was well tolerated. Our results indicate that AAV-delivered meganucleases can effectively target <i>HAO1</i> in mice and nonhuman primates to achieve high levels of <i>HAO1</i> gene editing. Moreover, increased glycolate levels in serum indicate that this intervention significantly impacts the HAO1-mediated glycolate-to-glyoxylate pathway. These data suggest that this approach may represent an effective treatment for PH1.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"963-974"},"PeriodicalIF":4.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148258016","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":"Advances in Precision Editing Therapies for Alpha-1 Antitrypsin Deficiency.","authors":"Jenny Gao, Erik Sontheimer, Terence R Flotte, Wen Xue","doi":"10.1177/10430342261417356","DOIUrl":"10.1177/10430342261417356","url":null,"abstract":"<p><p>Genome and RNA editing modalities have revolutionized precision gene therapy, offering a safer alternative to traditional gene replacement approaches. Alpha-1 antitrypsin deficiency (AATD) is a compelling model for precision medicine because the disease mechanism is well defined-mutations in a single gene are responsible for both liver and lung pathology. In this review, we summarize the current preclinical and clinical efforts for AATD, with an emphasis on genome and RNA editing strategies.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"912-919"},"PeriodicalIF":4.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13372069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146051835","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}

{"title":"High Prevalence of Preexisting Neutralizing Antibodies Against Adeno-Associated Virus Capsids in Mongolian People with Hemophilia.","authors":"Nemekhbayar Baatartsogt, Khongorzul Batchuluun, Yuji Kashiwakura, Munkhuu Amarbayasgalan, Munkhuchral Nordog, Otgonbat Altangerel, Purevjal Otgonbayar, Urangoo Tegshee, Khishigjargal Batjargal, Tomoki Togashi, Morisada Hayakawa, Elberelt Unurbat, Zesemdorj Otgon-Uul, Erdenetuya Ganbaatar, Damdindorj Boldbaatar, Khurelbaatar Nyamdavaa, Battogtokh Chimeddorj, Odgerel Tsogbadrakh, Tsukasa Ohmori","doi":"10.1177/10430342261459805","DOIUrl":"10.1177/10430342261459805","url":null,"abstract":"<p><p>Adeno-associated virus (AAV) vector-mediated gene therapy for hemophilia offers the potential for sustained therapeutic benefit after a single administration and is particularly attractive in regions with limited access to standard therapies. However, the prevalence of anti-AAV neutralizing antibodies (NAbs), which can impair therapeutic efficacy, varies geographically and remains poorly characterized in Mongolia. Here, we evaluated the seroprevalence of NAbs against clinically relevant AAV serotypes in Mongolia. NAbs against AAV3B, AAV5, and AAV8 were assessed in serum samples from 23 healthy volunteers and 52 people with hemophilia (PwH) using a validated cell-based transduction inhibition assay. A high seroprevalence of anti-AAV NAbs was observed across all three serotypes in both healthy volunteers (69.6%-87.0%) and PwH (78.9%-84.6%), with no significant differences between groups. NAbs were detected across all age groups, including early childhood, and frequently exhibited neutralization against multiple AAV serotypes, which was associated with higher NAb titers. Taken together, anti-AAV NAbs are highly prevalent and acquired early in life in the Mongolian population, with multiserotype neutralization patterns. These findings identify a substantial population-specific barrier to AAV-mediated gene therapy and highlight the need for alternative therapeutic strategies beyond AAV-based platforms to overcome immunological constraints in this setting.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"975-982"},"PeriodicalIF":4.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148591062","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":"Gene Editing Therapy Developer Scribe Therapeutics Closes $155.5M IPO.","authors":"Alex Philippidis","doi":"10.1177/10430342261479856","DOIUrl":"10.1177/10430342261479856","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"907-911"},"PeriodicalIF":4.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148818335","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}