Human gene therapy最新文献

{"title":"<i>Corrigendum to:</i> \"Interlaboratory Measurement of Adeno-Associated Virus: Comparative Quantification of Full and Empty Capsids\".","authors":"","doi":"10.1177/10430342261485765","DOIUrl":"https://doi.org/10.1177/10430342261485765","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"10430342261485765"},"PeriodicalIF":4.6,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108627","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":"Regulatory Progress in the Clinical Translation of Gene Therapy in China: Evolution, Challenges, and Future Perspectives.","authors":"Kaizhen Wang, Nvjin Zeng, Hualan Yang, Rui He, Qi Chen, Mingjin Jiang, Ping Liu, Yue Qiu, Zhenhang Yu","doi":"10.1177/10430342261490050","DOIUrl":"https://doi.org/10.1177/10430342261490050","url":null,"abstract":"<p><p>In recent years, gene therapy has emerged as a major frontier in biomedicine, with translation from basic research to clinical application accelerating worldwide. Clinical research in this field has also expanded substantially in China. Prior to the implementation of the new regulatory framework in 2026, investigator-initiated clinical research played an important role in early clinical exploration and technology validation, alongside product-oriented clinical trials conducted under the pharmaceutical regulatory pathway. However, under the previous framework, the pathways for translating research outcomes into clinical use and their interface with product development remained insufficiently defined. Against this background, this review systematically examines the evolution of China's regulatory framework for gene therapy clinical research and translation, with particular attention to the institutional changes introduced by the Regulation on the Administration of Clinical Research and Translational Application of New Biomedical Technology (the \"818 Regulation\"). Relevant regulatory approaches in the United States, the European Union, Japan, and South Korea are also examined for comparative context. The 818 Regulation provides a more clearly defined institutional framework for gene therapy clinical research and translation, while also introducing new practical requirements for research implementation. In particular, initiating institutions and clinical research institutions need to strengthen their professional implementation capacity and cross-departmental coordination. For innovative technologies at an early stage of development, where the ultimate translational direction may not yet be fully determined, greater attention should be given to the assessment of technological characteristics and prospective planning of translational pathways. Differences in data standards, quality-control requirements, and evidentiary expectations across translational pathways also place greater demands on evidence continuity and the future usability of research data. Accordingly, under the new regulatory environment, initiating institutions and clinical research institutions should strengthen internal governance and professional management, prospectively assess technological characteristics and intended translational objectives, appropriately plan research and translational pathways, and adopt high-standard data governance to improve the completeness, reliability, and traceability of research evidence. Such efforts would preserve opportunities for future data linkage and reuse, as well as the potential acceptability of data across different translational pathways. Effective institutional adaptation to the new framework will be critical to realizing the potential benefits of the 818 Regulation and improving the quality and efficiency of gene therapy clinical translation in China.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"10430342261490050"},"PeriodicalIF":4.6,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016665","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":"Practical Considerations for Gene and Cell Therapy Delivery in Temporal Lobe Epilepsy and Other Neurological Disorders.","authors":"Christina Feller, Sarah C Young, Kunal Gupta","doi":"10.1177/10430342261488959","DOIUrl":"https://doi.org/10.1177/10430342261488959","url":null,"abstract":"<p><p>Biological cell and gene approaches have great potential to provide durable, disease-modifying therapies for, as yet, incurable neurological disorders. The central nervous system (CNS), unlike other organ systems, however, poses unique challenges for access for biological therapies. Access challenges include physical barriers such as the blood-brain barrier, technical barriers such as procedural considerations, and variability in response to biological therapies that are dependent on route of delivery. In this review, these challenges are discussed along with the practicalities of therapeutic access for biological therapies to the CNS by systemic intravenous (IV) delivery, intrathecal delivery, and direct intraparenchymal delivery in the context of epilepsy and with relevance to other neurological disorders. In the context of IV delivery, the practicalities of CNS target and off-target systemic effects are discussed. In the context of intrathecal delivery, the practicalities of procedural access, cerebrospinal fluid dynamics, and tissue penetrance are reviewed. Finally, in the context of direct intraparenchymal delivery, the technical aspects of therapy administration, local and systemic spread, and immune response are highlighted. Each delivery method provides a different balance of procedural, targeting, and inflammatory considerations, which may affect future therapeutic agent selection and trial design. This framework highlights that delivery-route selection should be individualized according to therapeutic modality, target anatomy, desired distribution, procedural risk, and clinical infrastructure.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"10430342261488959"},"PeriodicalIF":4.6,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001630","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":"Development of a Recombinant Adeno-Associated Virus Vector for Human T Lymphocyte- and Natural Killer Cell-Targeted Gene Therapy.","authors":"Hendrik Jahnz, Martin V Hamann, Hongil Kim, Yaping Sun, Natalia Salazar-Quiroz, Li Zhu, Sabrina M Leddy, Umm E Swaiba, Carola Schneider, Daniel Foth, Niklas Beschorner, Priti Kumar, Ulrike C Lange","doi":"10.1177/10430342261487919","DOIUrl":"10.1177/10430342261487919","url":null,"abstract":"<p><p>Recombinant adeno-associated virus (rAAV) vectors are widely used for gene delivery but show limited efficiency in immune cells, including T lymphocytes and natural killer (NK) cells. To overcome this barrier, we have developed a CD7-targeted rAAV vector (CD7-AAV6/9) featuring a nanobody-fused hybrid capsid derived from a rationally selected chimeric combination of AAV6 and AAV9. CD7-AAV6/9 enables efficient and selective transduction of immortalized and primary human T and NK cells <i>in vitro</i> and <i>in vivo</i> in a humanized mouse model, achieves high production titers, and exhibits markedly reduced off-target transduction compared with wild-type serotypes. Incorporation of a human gene-derived intron into the vector genome to overcome host-mediated transcriptional repression enables robust transgene expression in human CD7⁺ T lymphocyte and NK cell populations. Together, our findings establish an integrated capsid-genome design framework for targeting human T and NK cells, notoriously challenging immune cell populations for gene therapy, and provide a versatile platform readily adaptable to alternative surface markers and therapeutic payloads.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"10430342261487919"},"PeriodicalIF":4.6,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148982526","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":"Development of an AAV-Encoded Adenine Base Editor for Duchenne Muscular Dystrophy.","authors":"Ina Luksch, Christine M Poch, Aylin Mayer, Eleonore Baier, Raphaela Moser, Seyed Amir Shakouri, Vijayanand Rajendran, Julian Grünewald, Alessandra Moretti, Karl-Ludwig Laugwitz, Christian Kupatt, Tarik Bozoglu, Tilman Ziegler","doi":"10.1177/10430342261486117","DOIUrl":"https://doi.org/10.1177/10430342261486117","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is a devastating X-linked disorder caused by out-of-frame mutations in the <i>DMD</i> gene, most commonly large deletions or duplications, as well as nonsense and splice site mutations, that result in the absence of functional dystrophin protein. These mutations lead to progressive skeletal and cardiac muscle failure. In particular, exon 52 of the DMD gene represents a mutational hotspot in DMD patients. Deletion of exon 52 (<i>DMD</i>Δ52) disrupts the reading frame, leading to premature termination of translation. Here, we used a dual recombinant adeno-associated virus (rAAV) system employing an intein-mediated split strategy to deliver ABE8e using the PAM-less SpRY Cas9 nickase for adenine base editing of splice acceptor sites (SAS) in the dystrophin gene. Targeting the SAS of exon 51 or exon 53 in a <i>DMD</i>Δ52 background aims to induce exon skipping, thereby restoring the open reading frame, in effect converting the severe DMD phenotype into a milder Becker muscular dystrophy (BMD)-like phenotype. We systematically screened sgRNAs in porcine kidney fibroblasts and human embryonic kidney cells (HEK293T), identifying a guide RNA targeting the SAS of exon 53 as the most effective candidate with high on-target editing efficacies and minimal bystander editing. In human DMDΔ52 iPSC-derived cardiomyocytes cultivated as 2D monolayers, high editing efficiencies were achieved with the optimized 1:2 ratio of N-Terminus to C-Terminus. Functional assessment in 3D engineered heart patches revealed a trend toward normalization of the arrhythmic DMD phenotype with an increase in the effective refractory period (ERP) and a reduction in arrhythmic load compared with untreated DMD patches, despite lower editing efficacy in the 3D setting. These findings suggest that even modest levels of base editing-mediated exon skipping may ameliorate the DMD cardiac phenotype toward a BMD-like state, supporting the translational potential of this dual rAAV base editing approach for DMD cardiomyopathy.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"10430342261486117"},"PeriodicalIF":4.6,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148976252","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":"InsightRP2-An Interdisciplinary Approach Toward Therapy Development in <i>RP2</i>-Associated Retinopathy.","authors":"Nina Bögershausen, Gökhan Yigit, Alisa Fedorenko, Rozhin Bayati, Patricia Döring, Maximilian Gerhardt, Carolin Strohmeyer, Oscar Gutiérrez-Gutiérrez, Behnam Javanmardi, Marianne Gaubert, Emrah Kaygusuz, Peter Krawitz, Marius Ueffing, Hans Hoerauf, Nicolas Feltgen, Stylianos Michalakis, Hildegard Büning, Lukas Cyganek, Bernd Wollnik","doi":"10.1177/10430342261480906","DOIUrl":"https://doi.org/10.1177/10430342261480906","url":null,"abstract":"<p><p>Advancing the development of specific gene therapies for rare genetic eye disorders is a major challenge in modern translational vision research. It requires integrated clinical, molecular, mechanistic, and regulatory expertise, yet these aspects are often addressed in isolation. Combining complementary skills, knowledge, and expertise within an integrated, highly interactive research framework has the capacity to drive and advance therapeutic development. Moreover, early-stage involvement of patients and targeted clinical observation, alongside molecular and therapeutic research, potentially enable clinical trial readiness and support the translation of preclinical therapeutic innovations into clinical care. In this Perspective article, we present the InsightRP2 framework, an integrated translational strategy that incorporates clinical data, artificial intelligence-supported imaging analysis, experimental disease modeling, and adeno-associated virus design with the aim to facilitate the development of a targeted gene therapy for <i>RP2</i>-associated retinitis pigmentosa.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"10430342261480906"},"PeriodicalIF":4.6,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148968195","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":"Chimeric Antigen Receptor T Cell Targeting of Natural Killer Cells in Peripheral Blood and Tissues of Rhesus Macaques.","authors":"Taylor M Oeschger, Benjamin Varco-Merth, Carly E Starke, Nikhita H Poole, Sowmya S Reddy, Adriana Cruz, Manuel Medina, Rachel Dannay, Sashi P Singh, Michael Nekorchuk, Tonya Swanson, Rhonda McAllister, Rachele Bochart, Caralyn Labriola, Diogo M Magnani, James M Olson, Jason P Price, Jacob D Estes, Christopher W Peterson, Afam A Okoye","doi":"10.1177/10430342261486115","DOIUrl":"https://doi.org/10.1177/10430342261486115","url":null,"abstract":"<p><p>Natural killer (NK) cells lead a rapid and potent innate immune response following exposure to infectious agents, but their activity may also contribute to chronic inflammation and augmented disease pathogenesis. Previous reports have shown that Janus kinase 3 inhibitors or anti-IL-15 monoclonal antibodies potently deplete NK cells in nonhuman primates (NHPs). However, they also disrupt T cell homeostasis, making it difficult to use these reagents to delineate the nonredundant role of NK cells in NHPs. To induce the specific depletion of NK cells <i>in vivo</i>, we designed chimeric antigen receptor (CAR) T cells targeting either a broad (CD16⁺) or narrow (NKG2A/C⁺) proportion of NK-inclusive innate immune subsets in rhesus macaques (RM). <i>Ex vivo</i> screening assays identified anti-CD16 and anti-NKG2A/C CAR constructs that potently and specifically depleted CD16⁺ and NKG2A/C⁺ cells, respectively, in the presence of autologous peripheral blood mononuclear cells (PBMCs). Adoptive transfer of autologous anti-NKG2A/C CARs was associated with a profound depletion of NK cells in blood and tissues of RM. NK cell depletion occurred despite modest anti-NKG2A/C CAR T cell expansion and persistence. No target cell depletion was observed following anti-CD16 CAR T-cell infusion, potentially due to the CAR T-cell dose and/or infusion frequency, animal-specific factors, or limitations of the CAR construct. Collectively, our pioneering study expands the application of CAR T cells as a basic science tool and further advances the NHP model for studying NK cell activity in disease contexts, such as infectious diseases and allotransplantation.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"10430342261486115"},"PeriodicalIF":4.6,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944678","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":"Capsid Engineering of Adeno-Associated Viruses for Targeted Gene Therapy in Kidney Diseases.","authors":"Mohammadreza Ghaffarzadeh-Esfahani, Yousof Gheisari","doi":"10.1177/10430342261452215","DOIUrl":"10.1177/10430342261452215","url":null,"abstract":"<p><p>The global burden of chronic and genetic kidney diseases poses a significant challenge to healthcare systems. Current therapies, including dialysis, transplantation, and supportive pharmacotherapies, cannot halt disease progression or address root causes, especially in monogenic disorders like Alport syndrome and Fabry disease. Adeno-associated virus (AAV)-based gene therapy is promising, enabling targeted correction of underlying genetic defects. However, renal delivery faces challenges, including cellular heterogeneity, anatomical barriers, and pre-existing immunity. This review evaluates advances in AAV capsid engineering to overcome these obstacles, focusing on strategies to enhance kidney-specific tropism, transduction efficiency, and immune evasion. We outline the evolution from conventional serotype selection to precision engineering via rational design, directed evolution, and in silico approaches. Artificial intelligence (AI) has emerged as a pivotal accelerator, with machine learning models and generative frameworks enabling data-efficient capsid optimization despite limited datasets. Multimodal AI, reinforcement learning, and agentic systems can refine renal targeting by balancing glomerular penetration, cell specificity, and safety. Future progress relies on scaling high-quality datasets through collaborative consortia, lab-in-the-loop validation, and explainable AI. By combining capsid engineering with renal pathophysiology insights, this roadmap paves the way for curative AAV therapies that move beyond current suboptimal treatments to correct underlying pathogenic mechanisms.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"819-832"},"PeriodicalIF":4.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148054136","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 Pioneer Sangamo Files for Chapter 11 Bankruptcy; Agrees to Sell Assets.","authors":"Alex Philippidis","doi":"10.1177/10430342261472589","DOIUrl":"10.1177/10430342261472589","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"811-814"},"PeriodicalIF":4.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148561918","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":"Evaluation of the Toxicity and Efficacy of an Adeno-Associated Viral Vector Expressing <i>BEST1</i> Delivered by Subretinal Injection in a Canine Model of Human Bestrophinopathy.","authors":"Alexa Gray, Jennifer C Kwok, Yu Sato, Charles-Antoine Assenmacher, Mayur Choudhary, Ash Jayagopal, Peiying Hua, Gui-Shuang Ying, Malgorzata Swider, Alexander Sumaroka, Artur V Cideciyan, Aguirre D Gustavo, William A Beltran","doi":"10.1177/10430342261458076","DOIUrl":"10.1177/10430342261458076","url":null,"abstract":"<p><p>To treat patients affected with bestrophinopathies caused by mutations in the <i>BEST1</i> gene, a recombinant adeno-associated virus vector (OPGx-BEST1 or rAAV2/2-VMD2-<i>BEST1</i>) is being developed. The vector construct includes the human BEST1 cDNA under control of the VMD2/BEST1 promoter and is packaged in an AAV2 capsid. This study evaluated the efficacy and toxicity of OPGx-BEST1 administered by subretinal injection in dogs that were homozygous mutant or compound heterozygotes for 3 naturally occurring mutations in <i>BEST1</i>. Twelve BEST1-mutant dogs were divided into 4 groups of 3 animals each, and they received in their left eye a subretinal injection of 0.15 mL of OPGx-BEST1 at 1 of 3 concentrations (9.5 × 10⁹ vector genome [vg]/mL; 3.0 × 10¹⁰ vg/mL; or 3.0 × 10¹¹ vg/mL) of OPGx-BEST1, resulting, respectively, in a low (1.4 × 10⁹ vg), high (4.5 × 10⁹ vg), and highest (4.5 × 10¹⁰ vg) dose or vehicle control. The right eyes were not injected. Subretinal injections were well tolerated and were not associated with any systemic or ocular toxicity. Electroretinography showed improved rod- and cone-mediated responses in eyes treated with OPGx-BEST1. Noninvasive retinal imaging by optical coherence tomography showed improved structural integrity with a reduction or prevention of appearance of vitelliform lesions and reversal of microdetachments in the retinal areas treated with OPGx-BEST1. These results support the use of OPGx-BEST1 in clinical studies with patients affected with bestrophinopathies and define the no-observed-adverse-effect level at 4.5 × 10¹⁰ vg/eye (0.15 mL, 3.0 × 10¹¹ vg/mL).</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"876-886"},"PeriodicalIF":4.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13401768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396702","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}