Gene Therapy最新文献_第4页

Research progress and development strategies of antibody-oligonucleotide conjugates. 抗体-寡核苷酸偶联物的研究进展与发展策略。

IF 4.5 3区医学

Gene Therapy Pub Date : 2026-05-25 DOI: 10.1038/s41434-026-00621-5

Wenshuang Fan, Weijing Luan, Wenjun Yu, Yan Li, Chao Wei, Xinfeng Liu, Ling Ni, Haiqiang Cao, Chunyan Fang, Yuanlei Fu

{"title":"Research progress and development strategies of antibody-oligonucleotide conjugates.","authors":"Wenshuang Fan, Weijing Luan, Wenjun Yu, Yan Li, Chao Wei, Xinfeng Liu, Ling Ni, Haiqiang Cao, Chunyan Fang, Yuanlei Fu","doi":"10.1038/s41434-026-00621-5","DOIUrl":"https://doi.org/10.1038/s41434-026-00621-5","url":null,"abstract":"Antibody-oligonucleotide conjugates (AOCs) effectively integrate the delivery capability of antibodies with the specific gene regulatory function of oligonucleotides, offering a novel strategy for extrahepatic delivery. Unlike antibody-drug conjugates (ADCs), AOCs employ nucleic acid payloads, enabling specific gene modulation with reduced off-target effects, thus providing new avenues for treating genetic disorders. While AOC candidates for conditions such as Duchenne muscular dystrophy (DMD) have progressed to Phase III trials, their development remains constrained by limited targets like TfR1, and their activity is highly dependent on antibody selection, linker design, and modification strategies. This study delves into the fundamental principles of target selection and antibody engineering, emphasizing that the endocytic efficiency of the target receptor is a critical factor for the successful delivery of AOC therapeutics. Taking TfR1 as an example, it analyzes the advantages and disadvantages of different antibody formats, examines the structure-activity relationships between linker chemistry and pharmacokinetics/pharmacodynamics, and further explores nucleic acid modification strategies aimed at enhancing delivery efficiency. Finally, the study outlines future directions for AOC development, including advances in bispecific antibodies, peptide conjugation, gene editing, and artificial intelligence-driven approaches, aiming to provide forward-looking perspectives and a theoretical foundation for the design of AOC therapeutics.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148015225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

rAAV8 encapsidated HMR-001/z enables high efficiency hepatic transduction and restores hemostasis in hemophilic mice. rAAV8包封的HMR-001/z能够在血友病小鼠中实现高效的肝转导并恢复止血。

IF 4.5 3区医学

Gene Therapy Pub Date : 2026-05-16 DOI: 10.1038/s41434-026-00619-z

Xiaomo Wu, Jinying Zhong, Xiaorong He, Ming Wu, Yu He, Jiguang Wu, Chunping Zhang, Jinyan Zhang, Meijun Guo, Xiaochang Jiang, Junyong Wong

{"title":"rAAV8 encapsidated HMR-001/z enables high efficiency hepatic transduction and restores hemostasis in hemophilic mice.","authors":"Xiaomo Wu, Jinying Zhong, Xiaorong He, Ming Wu, Yu He, Jiguang Wu, Chunping Zhang, Jinyan Zhang, Meijun Guo, Xiaochang Jiang, Junyong Wong","doi":"10.1038/s41434-026-00619-z","DOIUrl":"https://doi.org/10.1038/s41434-026-00619-z","url":null,"abstract":"Hemophilia A (HA), an X-linked bleeding disorder caused by factor VIII (FVIII) deficiency, is primarily managed with exogenous therapeutic agents; however, this treatment approach remains burdensome and fails to provide durable hemostatic control. Adeno-associated viral (AAV) vectors enabling endogenous FVIII expression have emerged as promising alternatives to address these limitations, but existing vectors show limited transduction efficiency and declining activity over time. Here, we report the development and preclinical evaluation of two bioengineered AAV8 vectors, HMR-001 and its codon-optimized variant HMR-001z, designed to enhance genome integrity, hepatocellular delivery, and translational efficiency. In hemophilia A mice, intravenous administration of HMR-001 induced dose-dependent and sustained FVIII expression, achieving substantial hemostatic improvement at the highest investigated dose (2 × 10¹³ vg/kg), with blood loss reduced to levels comparable to Xyntha prophylaxis. High-order triple-linkage ddPCR quantification revealed dose-dependent increases in full-length vector genome abundance, reaching 3.74, 21.55, and 48.52 copies per diploid genome at doses of 2 × 10¹², 8 × 10¹², and 2 × 10¹³ vg/kg, respectively. Building on these markedly improved genome delivery and preservation profiles, HMR-001z achieved complete hemostatic correction at a dose of 1 × 10¹³ vg/kg, exhibiting approximately 30-fold higher FVIII expression than HMR-001 and reaching ~400 IU/dL. Collectively, these findings demonstrate that genome-level optimization combined with codon-usage refinement synergistically enhances AAV8-mediated FVIII expression, establishing HMR-001z as a durable and translationally advanced gene therapy candidate for hemophilia A.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147948266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A dose-escalation and safety gene therapy study in a model of CMT4C neuropathy. CMT4C神经病变模型的剂量递增和安全性基因治疗研究。

IF 4.5 3区医学

Gene Therapy Pub Date : 2026-05-12 DOI: 10.1038/s41434-026-00616-2

Elena Georgiou, Alexia Kagiava, Andreas Hentschel, Irene Sargiannidou, Revekka Papacharalampous, Marina Stavrou, Christina Tryfonos, Jan Richter, Andreas Roos, Kleopas A Kleopa

{"title":"A dose-escalation and safety gene therapy study in a model of CMT4C neuropathy.","authors":"Elena Georgiou, Alexia Kagiava, Andreas Hentschel, Irene Sargiannidou, Revekka Papacharalampous, Marina Stavrou, Christina Tryfonos, Jan Richter, Andreas Roos, Kleopas A Kleopa","doi":"10.1038/s41434-026-00616-2","DOIUrl":"https://doi.org/10.1038/s41434-026-00616-2","url":null,"abstract":"Charcot-Marie-Tooth disease type 4C is a demyelinating neuropathy caused by loss of function mutations in the SH3TC2 gene, that is highly expressed in myelinating Schwann cells. We generated and tested a clinical stage vector with a minimal human MPZ promoter driving expression of SH3TC2. Groups of 1-month old Sh3tc2-/- mice were treated with 3 different doses of AAV9-hMPZmini.SH3TC2.SV40pA or the formulation buffer by lumbar intrathecal injection. Outcomes were compared 8 weeks post injection by behavioral, electrophysiological, proteomics, morphological analysis and evaluation of tissue integrity and inflammatory responses. Vector biodistribution to the peripheral nerves and high rates of cell-specific therapeutic gene expression in Schwann cells resulted in significant therapeutic benefits in the CMT4C model. Treated mice showed improved motor performance in grip strength and motor nerve conduction velocities. Morphological analysis revealed significant improvement in g-ratios, myelin thickness and ratios of demyelinated fibers in lumbar roots and femoral nerves of treated mice. Proteomic profiles showed correction of muscle denervation associated pathobiochemical processes in treated mice. Not observed tissue toxicity or immune reactions in neural tissues or peripheral organs. This study provides proof of principle for dose-dependent effectiveness and safety of intrathecal AAV9-mediated gene replacement paving the way for clinical translation.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147928634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Clinical response to systemic AAV gene therapy in a large animal model of late-stage lysosomal storage disease 晚期溶酶体贮积病大型动物模型对系统性AAV基因治疗的临床反应

IF 5.9 3区医学

Gene Therapy Pub Date : 2026-05-04 DOI: 10.1038/s41434-026-00618-0

Jacqueline E. Hunter, Caitlyn M. Molony, Dana L. Clarke, Wojciech Panek, Charles H. Vite, Sanjeev Chawla, Harish Poptani, John H. Wolfe

{"title":"Clinical response to systemic AAV gene therapy in a large animal model of late-stage lysosomal storage disease","authors":"Jacqueline E. Hunter, Caitlyn M. Molony, Dana L. Clarke, Wojciech Panek, Charles H. Vite, Sanjeev Chawla, Harish Poptani, John H. Wolfe","doi":"10.1038/s41434-026-00618-0","DOIUrl":"10.1038/s41434-026-00618-0","url":null,"abstract":"The benefit of early diagnosis and treatment has been demonstrated in animal models of several lysosomal storage diseases. In a clinical setting, however, diagnoses are often not made until after patients become symptomatic. The lysosomal storage disease alpha-mannosidosis is caused by a genetic deficiency of lysosomal alpha-mannosidase, leading to the widespread presence of storage lesions throughout the brain and other tissues. In a feline model of alpha-mannosidosis, we previously demonstrated complete correction of the brain following delivery of AAVhu.32-fMANB via the carotid artery in the early symptomatic stage. Here, we investigate the efficacy of AAV gene therapy on globally distributed storage lesions in animals with advanced disease. Some improvements in clinical parameters were observed, however these improvements were less than in animals with less advanced disease. Although the treated animals were improved compared to untreated animals, increasing the vector dose did not further improve clinical outcomes. These results further demonstrate the importance of early detection and treatment of a lysosomal storage disease to successful outcomes. Despite this, partial correction extended the lifespan of diseased cats and may be medically beneficial to patients by slowing or stabilizing the progressive degenerative course of disease.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"33 4","pages":"1-9"},"PeriodicalIF":5.9,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41434-026-00618-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837164","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}

引用次数: 0

AAV2 capsid clearance and neuronal trafficking dynamics in the central nervous system 中枢神经系统AAV2衣壳清除和神经元运输动力学。

IF 5.9 3区医学

Gene Therapy Pub Date : 2026-04-30 DOI: 10.1038/s41434-026-00617-1

Thanvi Gullapalli, Jake W. Willows, Ahmad Karkhah, Vikas Munjal, Abigail Nimmo, Kaya E. Ceyhan, Meika Travis, Allison O’Brien, Matthew T. Rocco, Anitvir S. Taunque, Kristy L. Townsend, Lluis Samaranch

{"title":"AAV2 capsid clearance and neuronal trafficking dynamics in the central nervous system","authors":"Thanvi Gullapalli, Jake W. Willows, Ahmad Karkhah, Vikas Munjal, Abigail Nimmo, Kaya E. Ceyhan, Meika Travis, Allison O’Brien, Matthew T. Rocco, Anitvir S. Taunque, Kristy L. Townsend, Lluis Samaranch","doi":"10.1038/s41434-026-00617-1","DOIUrl":"10.1038/s41434-026-00617-1","url":null,"abstract":"Adeno-associated virus serotype 2 (AAV2) remains one of the most common vectors for CNS gene delivery. Yet, its long-term intraparenchymal trafficking and the relationship between capsid persistence and transgene expression remain poorly understood. In this study, we tracked the spatial and temporal patterns of AAV2 following direct striatal infusion in rats, analyzing tissue at 3 days, 3 weeks, 12 weeks, 30 weeks, and 67 weeks after injection. Using immunofluorescence for the human aromatic L-amino acid decarboxylase (AADC) transgene and an epitope detecting intact AAV2 capsids (A20), we mapped capsid localization, clearance, and axonal transport over more than a year. Following direct striatal infusion, AAV2 capsids rapidly localized to striatal neurons, with early accumulation in the substantia nigra pars reticulata (SNpr) detectable by 3 days post-infusion, but without evidence of nigral neuron transduction. Transgene expression increased over time and peaked locally at 12 weeks, with a delayed yet robust AADC signal in striatonigral terminals by 30 weeks. By 67 weeks, capsid signal was minimal while AADC expression remained stable. These findings clarify the long-term dynamics of AAV2 distribution, capsid persistence, and axonal transport in the adult brain, informing our understanding of vector behavior and durability following intraparenchymal AAV2 gene delivery.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"33 5","pages":"628-634"},"PeriodicalIF":5.9,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41434-026-00617-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147769146","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}

引用次数: 0

Correction: Genetic mutations in HSV-1 replication-defective vectors: Implications for their safety in gene therapy applications 修正：HSV-1复制缺陷载体的基因突变：对其在基因治疗应用中的安全性的影响。

IF 5.9 3区医学

Gene Therapy Pub Date : 2026-04-20 DOI: 10.1038/s41434-026-00615-3

Stefano Cattaneo, Barbara Bettegazzi, Selene Ingusci, Gianluca Verlengia, Anna Sofia Tascini, Silvia Zucchini, Franca Codazzi, Marco J. Morelli, Marco Marzulli, Joseph C. Glorioso, Michele Simonato

引用次数: 0

Beneficial bystander-enhanced cryptic splice rescue of cardiac-type Fabry GLA IVS4+919G>A by adenine base editing in patient fibroblasts 通过腺嘌呤碱基编辑在患者成纤维细胞中有益的旁观者增强隐剪接挽救心脏型Fabry GLA IVS4+919G>A。

IF 5.9 3区医学

Gene Therapy Pub Date : 2026-04-18 DOI: 10.1038/s41434-026-00612-6

Hua-Chuan Chao, Yu-Ying Lu, Yu-Ting Chiang, Yun-Ru Chen, Ching-Tzu Yen, Chun-Ying Huang, Sheng-Kai Chang, Yen-Fu Cheng, Yung-Hsiu Lu, Dau-Ming Niu

{"title":"Beneficial bystander-enhanced cryptic splice rescue of cardiac-type Fabry GLA IVS4+919G>A by adenine base editing in patient fibroblasts","authors":"Hua-Chuan Chao, Yu-Ying Lu, Yu-Ting Chiang, Yun-Ru Chen, Ching-Tzu Yen, Chun-Ying Huang, Sheng-Kai Chang, Yen-Fu Cheng, Yung-Hsiu Lu, Dau-Ming Niu","doi":"10.1038/s41434-026-00612-6","DOIUrl":"10.1038/s41434-026-00612-6","url":null,"abstract":"The IVS4+919G>A mutation in the GLA gene, prevalent in East Asian populations, causes cardiac-type Fabry disease by creating an abnormal splice site. This results in the insertion of a 57-nucleotide segment between exon 4 and exon 5, introducing a premature stop codon and leading to a truncated, non-functional α-Gal A protein. We evaluated whether adenine base editing (ABEmax) can modulate this allele-induced cryptic splice event in patient-derived fibroblasts in vitro as a proof-of-concept. Two ABEmax/sgRNA constructs targeting intron 4 (ABEmax-sgRNA1 and ABEmax-sgRNA2) were tested; both induced on-target +919 A → G conversion with frequent bystander edits at +918/+920. Edited bulk populations and single-cell–derived clones showed restoration of correctly spliced GLA mRNA with reduced aberrant transcripts, increased GLA protein, higher α-Gal A activity (approaching wild-type levels in some clones), and reduced intracellular Gb3 signal. A focused next-generation sequencing panel identified a low-frequency intronic change at one predicted off-target locus without predicted coding consequences. These findings demonstrate in vitro splice rescue of a deep intronic, cardiac-type Fabry disease variant by adenine base editing and suggest that bystander edits in non-coding sequence can further enhance correction by suppressing cryptic splicing, with concordant improvements in α-Gal A activity and Gb3 signals.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"33 5","pages":"532-540"},"PeriodicalIF":5.9,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41434-026-00612-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147716525","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}

引用次数: 0

Retraction Note: Local administration of transcription factor decoy oligonucleotides to nuclear factor-κB prevents carrageenin-induced inflammation in rat hind paw 注：局部给药核因子-κB转录因子诱饵寡核苷酸可预防卡拉胶诱导的大鼠后爪炎症。

IF 5.9 3区医学

Gene Therapy Pub Date : 2026-04-15 DOI: 10.1038/s41434-026-00614-4

F D’Acquisto, A Ialenti, A Ianaro, R Di Vaio, R Carnuccio

引用次数: 0

CRISPR/Cas9-mediated gene correction of Wilson disease H1069Q point mutation in patient-specific induced pluripotent stem cells. 患者特异性诱导多能干细胞中威尔森病H1069Q点突变的CRISPR/ cas9介导的基因纠正

IF 5.9 3区医学

Gene Therapy Pub Date : 2026-04-14 DOI: 10.1038/s41434-026-00611-7

Viktoria Iwan, Oksana Nadzemova, Matthias Weiand, Andree Zibert, Hartmut H Schmidt, Phil-Robin Tepasse, Robert Schierwagen, Jonel Trebicka, Vanessa Sandfort

{"title":"CRISPR/Cas9-mediated gene correction of Wilson disease H1069Q point mutation in patient-specific induced pluripotent stem cells.","authors":"Viktoria Iwan, Oksana Nadzemova, Matthias Weiand, Andree Zibert, Hartmut H Schmidt, Phil-Robin Tepasse, Robert Schierwagen, Jonel Trebicka, Vanessa Sandfort","doi":"10.1038/s41434-026-00611-7","DOIUrl":"10.1038/s41434-026-00611-7","url":null,"abstract":"The innovative clustered regularly interspaced short palindromic repeats (CRISPR) associated nuclease 9 (Cas9) gene editing technique may represent a suitable therapeutic opportunity for the treatment of inherited diseases such as Wilson disease (WD). This monogenetic liver disease is based on a mutation of the ATP7B gene and leads to a functional deterioration in copper (Cu) excretion. Excess Cu accumulations in organs such as the liver and brain lead to severe cytotoxicity, followed by acute or chronic liver failure and/or neurological symptoms, and even death, which makes cellular Cu excretion indispensable for any potential WD therapy, e.g., gene therapy. A life-long treatment with zinc or chelators such as D-penicillamine may improve the course of the disease, but serious side effects have been observed in a significant portion of patients. In this study, isolated urinary epithelial cells from a WD patient carrying the ATP7B H1069Q mutation were reprogrammed into induced pluripotent stem cells (iPSCs). Using the CRISPR/Cas9 technology, ATP7B H1069Q was corrected by the additional use of single-stranded oligo DNA nucleotides (ssODNs). After differentiation into hepatocyte-like cells (HLCs), a high resistance to Cu was observed, plus a recovery of ATP7B trafficking. This is the first study to confirm that CRISPR/Cas9-mediated correction of the ATP7B point mutation H1069Q is possible and could open new possibilities for future applications.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147689785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Antimicrobial resistance and gene therapy: emerging molecular strategies for a global health threat 抗微生物药物耐药性和基因治疗：应对全球健康威胁的新兴分子策略。

IF 4.5 3区医学

Gene Therapy Pub Date : 2026-04-13 DOI: 10.1038/s41434-026-00613-5

A. Vitiello, M. Boccellino, A. Zovi, M. Bassetti

引用次数: 0