Human gene therapy最新文献

{"title":"uniQure Submits U.S., U.K. Applications for Huntington's Disease Candidate.","authors":"Alex Philippidis","doi":"10.1177/10430342261490708","DOIUrl":"10.1177/10430342261490708","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"987-990"},"PeriodicalIF":4.6,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148989786","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":"Perivascular Astrocytic Gliosis Induced by Retinal Gene Therapy.","authors":"Maram E A Abdalla Elsayed, Immanuel Philipp Seitz, M Dominik Fischer, Robert E MacLaren","doi":"10.1177/10430342261469741","DOIUrl":"10.1177/10430342261469741","url":null,"abstract":"<p><p>This retrospective follow-on study reviewed 25 consecutive patients with genetically confirmed choroideremia who were treated with subretinal AAV2-CAG-REP1 in dose-escalation gene therapy clinical trials conducted at Oxford University Hospitals NHS Foundation Trust and the University Eye Hospital Tübingen. Six patients in Oxford received 10¹⁰ vector genomes in 100 µL, while a further 19 patients across both centers received 10¹¹ vector genomes in 100 µL. Although the primary safety outcomes of both investigator-led academic studies have previously been reported, retinal imaging changes were observed during follow-up, prompting a more detailed characterization of these findings. Twelve of 25 treated eyes developed imaging features consistent with perivascular astrocytic gliosis during follow-up, representing 48% of the cohort. All affected eyes had received the higher dose, accounting for 12 of 19 eyes treated with 10¹¹ vector genomes. No patients receiving the lower dose (1.0 × 10¹⁰ vector genomes) developed this phenotype. The lesions followed the major vascular arcades toward the optic disc, and optical coherence tomography demonstrated inner retinal thickening with a fine, granular hyperreflective texture, without intraretinal cysts. Longitudinal imaging showed no progressive expansion of the involved regions. Clinically, the findings were silent: no patient reported uveitic symptoms, ocular examinations were largely quiet, and no peripheral cellular immune responses were detected in patients with available assays. Perivascular astrocytic gliosis therefore appears to be a common, clinically silent, nonprogressive, and noninflammatory retinal response after subretinal AAV2-CAG-REP1 gene therapy for choroideremia at a dose of 10¹¹ vector genomes, which is generally accepted as the therapeutic human dose for targeting photoreceptors. We hypothesize that local REP1 overexpression in perivascular astrocytes suppresses FOXO3-mediated apoptosis and engages EGFR/STAT3 signaling, driving benign perivascular astrocytic accumulation analogous to retinal astrocytic hamartomas seen in phacomatoses. Gene therapy involving ubiquitous promoters may have unexpected effects, and while benign, may not be predicted.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"1019-1026"},"PeriodicalIF":4.6,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148792357","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":"Durational Study of Persistent Transduction of Rhesus Macaque Lung and Other Organs Following Single Dosing with AAV1-CFTR.","authors":"Prajita Paul, Tanvi Sharma, Masoud Afshani, Amanda Maxwell, Abhishek Sharma, William B Guggino, Liudmila Cebotaru","doi":"10.1177/10430342261478760","DOIUrl":"10.1177/10430342261478760","url":null,"abstract":"<p><p>Adeno-associated virus (AAV)-mediated gene transfer remains a promising strategy for cystic fibrosis (CF), but durability of expression and optimal dosing intervals are unresolved challenges. Here, we evaluated long-term gene transfer, transduction, and immunological responses following a single pulmonary administration of an AAV1 vector encoding Δ27-264 CFTR to juvenile rhesus macaques. Four animals received 1 × 10¹³ vector genomes via endotracheal spray. Two were untreated. All were analyzed 180 days post-delivery. Vector genomes were detected throughout the conducting airways and distal lung at levels ranging from ∼5 × 10⁶ to 9 × 10⁷ vg/µg genomic DNA. Vector genomes were also detected in extrapulmonary tissues, including liver, pancreas, spleen, heart, and kidney. Cystic fibrosis transmembrane conductance regulator (CFTR) messenger RNA expression was detected in all tissues examined and in several respiratory and extrapulmonary tissues, accompanied by increased CFTR protein expression in multiple tissues. Transgene expression was observed in airway basal cells and FOXI1-positive ionocytes, indicating targeting of key epithelial and progenitor cell populations. Despite persistence of vector genomes, immune activation was limited. Cytokine and chemokine expression profiles showed only sporadic, tissue-specific changes without evidence of coordinated inflammation. Neutralizing antibodies to AAV1 developed in all animals but did not correlate with capsid-specific T cell responses, which remained low and infrequent. These findings indicate sustained gene transfer and transduction for at least 180 days following a single AAV1 administration to the primate lung, with minimal immunopathology. The durability of expression supports the potential feasibility of extended dosing intervals and informs the development of repeatable AAV-based gene therapies for CF.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"1056-1067"},"PeriodicalIF":4.6,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148759130","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":"AAV.hBAG3 Gene Therapy Improves Phenotype in a Valosin Containing Protein Mouse Model of Hereditary Inclusion Body Myositis.","authors":"Burcak Ozes, Lingying Tong, Morgan Myers, Kyle Moss, Edward Son, Tatyana A Vetter, Gabriela Vasquez-Martinez, Diana Zepeda-Orozco, Zarife Sahenk","doi":"10.1177/10430342261466685","DOIUrl":"10.1177/10430342261466685","url":null,"abstract":"<p><p>Mutations in the valosin-containing protein (VCP) gene lead to a hereditary type of inclusion body myositis (hIBM), in which sarcoplasmic and myonuclear inclusions with TAR DNA-binding protein 43 (TDP-43) pathology and mitochondrial abnormalities are observed in histological analysis. Pathophysiological conditions in the cell cause the protein quality control system to depend on the autophagy-lysosome pathway (ALP) for degradation of accumulated misfolded proteins and mitochondrial turnover. BCL2-associated athanogene 3 (BAG3) protein has a role in initiating the ALP. Our aim was to ameliorate disease processes resulting from mitochondrial abnormalities and misfolded protein aggregation by upregulating the ALP through overexpression of human BAG3 (hBAG3). The VCP-A232E mouse, a model for hIBM, received AAVrh74.tMCK.hBAG3 systemically at 3 months of age, and outcome measures, including functional, histological, and molecular studies, were assessed 9 months post-gene delivery. hBAG3 treatment improved treadmill running distance and rotarod duration, reduced the number of TDP-43-positive aggregates, and decreased the number of fibers showing abnormalities in mitochondrial enzyme histochemistry, compared with the untreated cohort. Moreover, hBAG3 gene therapy resulted in improvements in mitophagy and mitochondrial homeostasis observed as increased levels in mitophagy markers <i>Parkin</i> and <i>Bnip3,</i> mitochondria biogenesis marker <i>Pgc1α and</i> mitochondrial DNA-encoded subunits of complex IV, <i>Cox1</i> and <i>Cox3</i>. In addition, the LC-II/I ratio increased, indicating increased autophagic flux. Our study presents evidence that the strategy of supporting the ALP system by overexpressing BAG3 has potential therapeutic use for myodegenerative conditions associated with abnormal protein aggregates and mitochondrial turnover.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"1045-1055"},"PeriodicalIF":4.6,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148411520","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":"Hyperthermia-Enhanced Adeno-Associated Virus Gene Therapy: Mechanisms, Delivery Technologies, and Translational Potential.","authors":"Ni-Hsuan Lin, Spyros A Mavropoulos, Kiyotake Ishikawa","doi":"10.1177/10430342261462309","DOIUrl":"10.1177/10430342261462309","url":null,"abstract":"<p><p>Adeno-associated virus (AAV) gene therapy is a promising therapeutic approach for both inherited and acquired disorders, yet its effectiveness is often limited by barriers that reduce target cell uptake and transgene expression. While body temperature is known to have a significant impact on viral infection, its controlled regulation for AAV gene therapy has been little explored. This article reviews therapeutic hyperthermia, carefully controlled mild heating, as a complementary strategy to improve delivery and expression. Evidence from cell and animal studies suggests that transient mild heating can increase blood flow and vessel permeability, promoting viral entry from the bloodstream into tissues. It can also trigger cellular stress responses that facilitate entry and downstream processing. Heating can also serve as an external switch when combined with heat-responsive genetic control systems, allowing gene expression to be activated only in the heated region. We summarize clinically used methods for delivering local, regional, and whole-body hyperthermia and discuss how spatially controlled heating could be integrated with AAV gene therapy workflows. We also highlight opportunities for clinical translation, key risks, and open questions, including thermal dose control, potential loss of viral particle stability with excessive heating, and the possibility of increased inflammatory or immune side effects.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"1008-1018"},"PeriodicalIF":4.6,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148301361","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":"Resolving the Unresolvable: Nanopore Sequencing as a Comprehensive Quality Control Platform for Gene Therapy Vectors.","authors":"Yan Xu, Xiao-Bing Zhang, Jian-Ping Zhang","doi":"10.1177/10430342261454725","DOIUrl":"10.1177/10430342261454725","url":null,"abstract":"<p><p>Cell and gene therapy (CGT) manufacturing has outpaced traditional chemistry, manufacturing, and controls frameworks, leaving a \"black box\" in vector quality control (QC). Legacy assays such as Sanger and short-read next-generation sequencing often fail to resolve complex structures including adeno-associated virus (AAV) inverted terminal repeats, lentiviral recombination, and mRNA poly(A) tails. Oxford Nanopore Technologies enables long-read, native single-molecule sequencing to access these attributes directly. This review summarizes nanopore sequencing across the CGT lifecycle. For plasmid DNA, it confirms full-length circular identity and reveals structural heterogeneity missed by restriction mapping. For viral vectors (AAV and lentivirus), it functions as an integrity assay to distinguish full genomes from truncations and to detect sequence-resolved impurities, including reverse-packaged plasmid backbones. For mRNA therapeutics, direct RNA sequencing profiles poly(A) tail length distributions and base modifications (<i>e.g.,</i> m¹Ψ) in a single assay. We also discuss adaptive sampling for impurity enrichment and native epigenetic profiling of bacterial methylation. Finally, we assess limitations in accuracy and compliance and outline the regulatory path toward moving long-read sequencing from an orthogonal tool to a validated lot-release method. Overall, nanopore sequencing supports risk-based, high-resolution QC while reducing analytical turnaround time.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"991-1007"},"PeriodicalIF":4.6,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148239325","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":"Triple-Target CRISPR Strategy to Block HIV Entry and Replication in Permissive Cells.","authors":"Zahra Safaei, Anna Bellizzi, Hong Liu, Yuru Huang, Ilker K Sariyer, Kamel Khalili","doi":"10.1177/10430342261463565","DOIUrl":"10.1177/10430342261463565","url":null,"abstract":"<p><p>Total elimination of replication-competent human immunodeficiency virus type 1 (HIV-1) remains a major clinical challenge, in part due to random integration of the proviral DNA into host cell chromosomes, which enables lifelong persistence and production of progeny. Although antiretroviral therapies (ARTs) suppress viral replication, they cannot eliminate integrated proviral DNA, which remains a fundamental obstacle to achieving a cure. To overcome this problem, we developed a combinatorial clustered regularly interspaced short palindromic repeats-Cas9 gene editing strategy to disrupt viral replication and inactivate host factors essential for HIV-1 entry and spread. This approach targets C-C chemokine receptor type 5 (CCR5), a chemokine receptor central to HIV-1 host cell entry, and mannosyl-oligosaccharide glucosidase (MOGS), a key enzyme in glycoprotein processing that modifies the HIV-1 envelope glycoprotein gp120, facilitating receptor engagement, viral entry, and morphogenesis of infectious virion. We demonstrate that our strategy, which includes editing of the integrated proviral DNA, in concert with two cellular genes whose products facilitate viral entry, results in robust suppression of viral replication <i>in vitro</i> and in <i>ex vivo</i>-infected cells. Using transmission electron microscopy, HIV-1 p24 ELISA, and GFP-based viral infection assays, we show that the combination knockout of CCR5, MOGS, and viral sequences profoundly reduces HIV-1 replication in an <i>ex vivo</i> cellular model, that is, HIV-1-infected peripheral blood mononuclear human cells, thus offering a pathway to launch further preclinical studies.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"1027-1044"},"PeriodicalIF":4.6,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808487","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":"Food and Drug Administration Grants Ultragenyx's Fayuvi™ First-Ever Approval for Sanfilippo Syndrome Type A Treatment.","authors":"Alex Philippidis","doi":"10.1177/10430342261499483","DOIUrl":"https://doi.org/10.1177/10430342261499483","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"10430342261499483"},"PeriodicalIF":4.6,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223844","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 Technologies and Clinical Breakthroughs: The Evolving Landscape of Gene Therapy in China.","authors":"Junshu Li, Yuntian Deng, Jinhu Ma, Meijuan Huang, Hongxin Deng","doi":"10.1177/10430342261498531","DOIUrl":"https://doi.org/10.1177/10430342261498531","url":null,"abstract":"<p><p>Gene therapy offers a fundamental approach to treating genetic disorders, malignant tumors, and refractory chronic diseases by directly modifying or replacing defective genes at the molecular level. Driven by policy support, increased investment, and technological innovation, China has achieved remarkable progress in adenoviral and adeno-associated virus (AAV) vectors, gene editing, genetically engineered immune cells, oncolytic microorganisms, and small nucleic acid drugs. This review provides a comprehensive narrative overview of the technical principles, product pipelines, and clinical advances in these fields. Notable achievements include the approval of AAV-based gene therapy products in China, the entry of multiple <i>in vivo</i> and <i>ex vivo</i> gene editing therapies into clinical trials, a leading number of CAR-T trials worldwide with expansion into solid tumors and autoimmune diseases, encouraging efficacy of oncolytic virotherapy in liver cancer and melanoma, and positive clinical data of small interfering RNA/antisense oligonucleotide drugs for chronic hepatitis B and hypercholesterolemia. However, challenges remain including suboptimal tissue specificity, off-target risks, limited cargo capacity, high production costs, and poor accessibility. Future directions should focus on tissue-selective vectors, precise editing tools, off-the-shelf cell products, scalable manufacturing, and improved regulatory frameworks. With abundant clinical resources and strong manufacturing capabilities, China is poised to play a significant role in the global gene therapy landscape.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"10430342261498531"},"PeriodicalIF":4.6,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223865","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":"Complement Activation Within Minutes Following Systemic Administration of AAV in the Presence of AAV Immunity.","authors":"Anthony Caragiulo, Jonathan B Rosenberg, Bishnu P De, Stephen M Kaminsky, Heather R Martin, Samuel Butler, Jordi Rodó, Dolan Sondhi, Yael Strulovici, Ronald G Crystal","doi":"10.1177/10430342261495296","DOIUrl":"https://doi.org/10.1177/10430342261495296","url":null,"abstract":"<p><p>A challenge of adeno-associated virus (AAV)-mediated gene therapy is the high prevalence of preexisting anticapsid antibodies, which can reduce vector efficacy and, after high-dose systemic administration, promote formation of antibody-vector complexes that activate complement. Complement-mediated toxicities reported after systemic AAV administration have generally been observed several days after dosing. However, observations in nonhuman primates (NHPs) suggested that complement activation may occur within minutes of vector exposure in the presence of anti-AAV antibodies. To characterize this response, we evaluated complement activation following repeat systemic administration of AAVrh.10 vectors in African Green monkeys and assessed early and delayed time points when NHPs were seronegative and seropositive for anti-AAV antibodies. Five NHPs received intravenous AAVrh.10 vectors (1 × 10¹³ gc/kg) administered 42 days apart. Three animals received AAVrh.10 expressing human C1 esterase inhibitor and two received a transgene-null vector. Serum samples were collected from 10 min to 42 days after the first administration and from 10 min to 21 days after the second. Complement activation was assessed by measuring serum terminal complement complex (TCC) levels and anti-AAVrh.10 immunoglobulin G (IgG) titers were used to monitor humoral immunity. Vector administrations were well tolerated, with no treatment-related abnormalities. Following the initial dose, all animals developed robust anti-AAVrh.10 IgG responses that increased after readministration. No significant complement activation was observed after the first administration. In contrast, in the presence of anti-AAVrh.10 antibodies, all animals demonstrated rapid increases in TCC within 10 min of the second administration, reaching 10-fold above baseline and returning to baseline by 1 day. Complement activation was observed in animals with antivector titers >1/10⁴, whereas little or no response was detected at titers <1/10³. These findings identify rapid, transient complement activation as an underrecognized response to systemic AAV administration in the presence of anti-AAV antibodies and support complement monitoring during the first hour after vector dosing in clinical gene therapy studies.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"10430342261495296"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149193155","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}