Molecular Therapy最新文献_第7页

Triple-AAV intein-mediated gene therapy ameliorates dystrophic phenotype in MDC1A mice 三aav介导的基因治疗改善MDC1A小鼠的营养不良表型

IF 12.4 1区医学

Molecular Therapy Pub Date : 2026-09-28 DOI: 10.1016/j.ymthe.2026.09.028

Núria Rafel-Millan,Carles Bayod-Girón,Maria Pallarès-Masmitjà,Cristina Fernández-Avilés,Keilisa Figuereo-Moya,Ángel Edo,Miguel Chillón,Miquel Vila-Perelló,Silvia Frutos,Marc Güell

引用次数: 0

Decoupling reactogenicity from efficacy enables safer mRNA vaccines, AAV gene delivery, and in vivo base editing 将反应原性与有效性解耦，可以实现更安全的mRNA疫苗、AAV基因递送和体内碱基编辑

IF 12.4 1区医学

Molecular Therapy Pub Date : 2026-09-28 DOI: 10.1016/j.ymthe.2026.09.033

Duško Lainšček,Špela Malenšek,Vida Forstnerič,Anja Golob-Urbanc,Sara Orehek,Jure Bohinc,Mateja Manček Keber,Timotej Sotošek,Hana Esih,Peter Pečan,Jelica Pantović-Žalig,Mojca Benčina,Romina Bester,Ulrike Protzer,Roman Jerala

{"title":"Decoupling reactogenicity from efficacy enables safer mRNA vaccines, AAV gene delivery, and in vivo base editing","authors":"Duško Lainšček,Špela Malenšek,Vida Forstnerič,Anja Golob-Urbanc,Sara Orehek,Jure Bohinc,Mateja Manček Keber,Timotej Sotošek,Hana Esih,Peter Pečan,Jelica Pantović-Žalig,Mojca Benčina,Romina Bester,Ulrike Protzer,Roman Jerala","doi":"10.1016/j.ymthe.2026.09.033","DOIUrl":"https://doi.org/10.1016/j.ymthe.2026.09.033","url":null,"abstract":"Nucleic-acid therapeutics, including mRNA vaccines, genome editors, and viral vectors, are constrained by acute innate reactogenicity that limits dosing flexibility, tissue targeting, and safety. Here we identify a conserved early innate inflammatory program, peaking approximately six hours after administration, that governs reactogenicity across mRNA formulated lipid nanoparticle (LNP), adenoviral vectors and AAV9. Using pharmacological and biochemical probes, we show that this program is driven predominantly by nucleic-acid cargo sensing, rather than lipid components, and is mechanistically separable from antigen expression, adaptive immune priming, and in vivo genome-editing efficacy. Selective modulation of this early cytokine burst achieved here using endosomal nucleic-acid sensing suppressors markedly reduces reactogenicity in multiple mouse models while preserving humoral and cellular immunity to mRNA vaccines, maintaining transgene expression, protecting blood–brain barrier integrity during stereotactic AAV9 delivery, and mitigating LNP-associated hepatotoxicity and thrombocytopenia. These findings define a unifying innate-sensing architecture for nucleic-acid therapeutics and establish that reactogenicity is not required for effective vaccination or gene delivery, enabling a broadly applicable strategy to widen the safety window of mRNA medicines, viral vectors, and in vivo genome editing.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"36 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149067331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Planning advanced therapy trials for Huntington’s Disease: ethical considerations 计划亨廷顿舞蹈病的高级治疗试验：伦理考虑

IF 12.4 1区医学

Molecular Therapy Pub Date : 2026-09-27 DOI: 10.1016/j.ymthe.2026.09.035

Towns Cindy,Ballantyne Angela,Konstatinova Pavlina,Drew Cheney,Rosser Anne

引用次数: 0

APOBEC3 knockout in lentiviral packaging cells improves therapeutic transgene sequence fidelity. 慢病毒包装细胞敲除APOBEC3提高治疗性转基因序列保真度

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-09-26 DOI: 10.1016/j.ymthe.2026.09.030

Annika Mittelhauser, Rishi Patel, Alex B Costa, Shivani Mohapatra, Kevyn Hart, Bojana Stefanovska, Michael A Carpenter, Reuben S Harris, Roger P Hollis, Donald B Kohn

{"title":"APOBEC3 knockout in lentiviral packaging cells improves therapeutic transgene sequence fidelity.","authors":"Annika Mittelhauser, Rishi Patel, Alex B Costa, Shivani Mohapatra, Kevyn Hart, Bojana Stefanovska, Michael A Carpenter, Reuben S Harris, Roger P Hollis, Donald B Kohn","doi":"10.1016/j.ymthe.2026.09.030","DOIUrl":"10.1016/j.ymthe.2026.09.030","url":null,"abstract":"Lentiviral vectors are a well-established method of delivering transgenes into target cells. These vectors have a strong efficacy and safety profile, but transgene fidelity remains an area of concern. Loss-of-function mutations within the integrated transgene may reduce therapeutic efficacy. Gain-of-function mutations within proto-oncogenic transgenes could cause malignant transformation of the transduced cell. Transgene mutations have long been attributed to reverse transcription errors. However, through deep sequencing of transgenes integrated into CD34+ hematopoietic stem and progenitor cells, we detected a disproportionately high frequency of cytosine-to-thymine mutations. We, therefore, hypothesized that blocking the APOBEC3 family of antiviral cytosine deaminases would improve transgene fidelity. We demonstrated that CRISPR-Cas9-mediated knockout of the APOBEC3 locus in HEK293T packaging lines reduced total lentiviral transgene mutations by over 90%. Conversely, disrupting the murine leukemia virus's APOBEC3 defenses caused an approximately 30-fold increase in C/G-to-T/A mutations. Furthermore, we determined that APOBEC3 knockout is compatible with a multi-gene knockout packaging line designed to enhance titer. This novel combination resulted in \"CHAI\" (CRISPRed HEK293Ts with Antiviral Inhibition), a HEK293T-based cell line that produces high-titer lentiviral vectors with near-perfect transgene fidelity.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Novel HIV fusion-inhibitory lipopeptides exhibit dramatically improved activity against resistant mutants. 新型HIV融合抑制脂肽对耐药突变体表现出显著改善的活性。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-09-26 DOI: 10.1016/j.ymthe.2026.09.031

Yuanmei Zhu, Ting Chen, Nian Liu, Xiuzhu Geng, Na Li, Jiahan Lu, Fei Wang, Jiasen Yang, Zhe Cong, Bo Qin, Huihui Chong, Sheng Cui, Jing Xue, Yuxian He

{"title":"Novel HIV fusion-inhibitory lipopeptides exhibit dramatically improved activity against resistant mutants.","authors":"Yuanmei Zhu, Ting Chen, Nian Liu, Xiuzhu Geng, Na Li, Jiahan Lu, Fei Wang, Jiasen Yang, Zhe Cong, Bo Qin, Huihui Chong, Sheng Cui, Jing Xue, Yuxian He","doi":"10.1016/j.ymthe.2026.09.031","DOIUrl":"10.1016/j.ymthe.2026.09.031","url":null,"abstract":"LP-98 is a potent HIV fusion-inhibitory lipopeptide but displays reduced activity against resistant mutants. In this study, we rationally designed a group of new lipopeptides by adding different lengths of gp41 pocket-binding sequence into the N terminus of LP-98. It was found that a single pocket-inserting residue Ile124 critically determined the anti-HIV activity, whereas incorporation of additional pocket-inserting residues Trp120 and Trp117 generated lipopeptides with greatly reduced activity. As indicated by LP-101 and LP-108, while Ile124-modified lipopeptides maintained or improved the inhibitory activity of LP-98 against divergent HIV and simian immunodeficiency virus (SIV) isolates, they had dramatically increased potencies on the resistant mutants. In both the HIV-infected humanized mice and SIV-infected rhesus macaques, LP-101 efficiently suppressed viral replication below detection limits. Mechanically, Ile124-modified lipopeptides exhibited greatly enhanced binding affinity with a target-mimic peptide N44. We determined the crystal structure of LP-101 bound to N44, revealing its N-terminal residues penetrating deeper into the gp41 pocket, forming enhanced interactions with the target site. Molecular dynamics simulations also revealed that its flexible N terminus enables adaptive binding to the wild-type and resistant mutants, with improved binding free energies. Therefore, our data inform the structure-activity relationship of this class of HIV fusion inhibitors and offer new candidates for drug development.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Targeting Telomerase with an HLA Class II-Restricted TCR for Cancer Immunotherapy. HLAⅱ类限制性TCR靶向端粒酶用于癌症免疫治疗。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-09-26 DOI: 10.1016/j.ymthe.2026.09.027

Pierre Dillard, Hakan Köksal, Solrun Melkorka Maggadottir, Anna Winge-Main, Sylvie Pollmann, Mathilde Menard, Marit Renée Myhre, Gunhild M Mælandsmo, Vivi Ann Flørenes, Gustav Gaudernack, Gunnar Kvalheim, Sébastien Wälchli, Else Marit Inderberg

引用次数: 0

Retraction Notice to: Gas5 Exerts Tumor-suppressive Functions in Human Glioma Cells by Targeting miR-222. 撤回通知：Gas5通过靶向miR-222在人胶质瘤细胞中发挥肿瘤抑制功能。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-09-26 DOI: 10.1016/j.ymthe.2026.09.018

Xihe Zhao, Ping Wang, Jing Liu, Jian Zheng, Yunhui Liu, Jiajia Chen, Yixue Xue

引用次数: 0

Broad targeting of the cell adhesion machinery: Cancer cell detachment triggered by the alpha1-oleate complex. 广泛靶向细胞粘附机制- α - 1-油酸复合物引发癌细胞脱离。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-09-25 DOI: 10.1016/j.ymthe.2026.09.029

Arunima Chaudhuri, Farhan Haq, Ines Ambite, Atefeh Nazari, Samudra Sabari, Michele Tavecchio, Antonio Pedro Nbm Carneiro, Olof Stenström, Shahram Ahmadi, Hien Tran, Antonin Brisuda, Jaromir Hacek, Marek Babjuk, Catharina Svanborg

{"title":"Broad targeting of the cell adhesion machinery: Cancer cell detachment triggered by the alpha1-oleate complex.","authors":"Arunima Chaudhuri, Farhan Haq, Ines Ambite, Atefeh Nazari, Samudra Sabari, Michele Tavecchio, Antonio Pedro Nbm Carneiro, Olof Stenström, Shahram Ahmadi, Hien Tran, Antonin Brisuda, Jaromir Hacek, Marek Babjuk, Catharina Svanborg","doi":"10.1016/j.ymthe.2026.09.029","DOIUrl":"10.1016/j.ymthe.2026.09.029","url":null,"abstract":"A new approach to targeting cell adhesion in oncology was recently suggested by observations made in patients with bladder cancer. Intravesical alpha1-oleate treatment triggered rapid tumor cell detachment into the urine and a parallel reduction in tumor number and size. This study identified alpha1-oleate as a potent inhibitor of multiple cell adhesion families in shed cells and tumor biopsies from treated patients, confirmed in cellular models. Alpha1-oleate targeted claudins and focal adhesion constituents and disrupted tight junctions, focal adhesions, and adherens junctions, but gap junctions or desmosomes were not affected. The effects on cell adhesion were dose dependent, with stronger cell detachment and broader inhibition of adhesion-associated genes in patients treated with 8.5 mM of alpha1-oleate than the 1.7 mM dose. These acute and sustained effects identify cell detachment as a contributor to the anti-tumor effects observed clinically. AlphaFold predictions identified claudins and the focal adhesion targeting (FAT) domain of focal adhesion kinase (FAK) as potential alpha1-oleate targets, but inhibitors of claudin and FAK phosphorylation showed less potent effects than alpha1-oleate on cell detachment. The broad effect of alpha1-oleate on the cell adhesion machinery is unprecedented and suggests that therapeutic targeting of the cell adhesion machinery by alpha1-oleate should be further explored.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Base editing-mediated induction of stop codons in HPV18 E6/E7 for cervical cancer therapy. 碱基编辑介导的HPV18 E6/E7停止密码子治疗宫颈癌

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-09-25 DOI: 10.1016/j.ymthe.2026.09.034

Yue Kang, Yifan Wu, Bingting Bao, Xueqian Wang, Zhiqiang Yu, Chen Cao, Zhi Wang, Zhaojie Wang, Gang Chen, Ding Ma, Tao Yi, Zheng Hu, Xun Tian

{"title":"Base editing-mediated induction of stop codons in HPV18 E6/E7 for cervical cancer therapy.","authors":"Yue Kang, Yifan Wu, Bingting Bao, Xueqian Wang, Zhiqiang Yu, Chen Cao, Zhi Wang, Zhaojie Wang, Gang Chen, Ding Ma, Tao Yi, Zheng Hu, Xun Tian","doi":"10.1016/j.ymthe.2026.09.034","DOIUrl":"10.1016/j.ymthe.2026.09.034","url":null,"abstract":"Persistent infection with high-risk human papillomaviruses (hrHPVs) is a primary driver of cervical carcinogenesis, with the viral oncogenes E6 and E7 playing pivotal roles. Conventional nuclease-based gene-editing strategies are limited by genome-wide off-target effects and genomic perturbations associated with double-strand breaks (DSBs). To address these challenges, we developed BE-PLUS-induction of STOP codons (iSTOP), a DSB-free cytosine base-editing strategy designed to inactivate HPV18 E6/E7 through the precise installation of premature termination codons (PTCs). This strategy achieved high on-target editing efficiencies (51.00% ± 2.94% for E6 and 26.33% ± 2.62% for E7) with minimal insertion or deletion (indel) formation (undetectable for E6 and <0.1% for E7). Functional analyses demonstrated that BE-PLUS-iSTOP effectively reduced E6/E7 protein expression, resulting in robust suppression of malignant phenotypes in HPV18-positive cervical cancer cells. In a subcutaneous xenograft mouse model, intratumoral delivery of BE-PLUS-iSTOP induced extensive tumor necrosis and significantly suppressed tumor growth, with no overt systemic toxicity under the tested conditions. Collectively, these findings establish BE-PLUS-iSTOP as a precise and efficient etiology-directed therapeutic strategy for HPV18-positive cervical cancer, supporting its potential for further translational development and broadening the scope of antiviral gene therapy.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 and biochemical correction of a patient with neurodegenerative mucopolysaccharidosis IIIA using hematopoietic stem cell gene therapy. 造血干细胞基因治疗1例神经退行性粘多糖病IIIA的临床及生化矫正。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-09-25 DOI: 10.1016/j.ymthe.2026.09.032

Jane L Kinsella, Simon A Jones, Karen F Buckland, Rebecca J Holley, Helena Lee, Wendy Ogden, Jane Potter, Heather J Church, Kathryn L Brammeier, Karen L Tylee, Stuart Ellison, Rachel Searle, Claire Booth, Farzin Farzeneh, Louise Sherwin, Adrian J Thrasher, Stewart Rust, Brian W Bigger, Robert F Wynn

{"title":"Clinical and biochemical correction of a patient with neurodegenerative mucopolysaccharidosis IIIA using hematopoietic stem cell gene therapy.","authors":"Jane L Kinsella, Simon A Jones, Karen F Buckland, Rebecca J Holley, Helena Lee, Wendy Ogden, Jane Potter, Heather J Church, Kathryn L Brammeier, Karen L Tylee, Stuart Ellison, Rachel Searle, Claire Booth, Farzin Farzeneh, Louise Sherwin, Adrian J Thrasher, Stewart Rust, Brian W Bigger, Robert F Wynn","doi":"10.1016/j.ymthe.2026.09.032","DOIUrl":"10.1016/j.ymthe.2026.09.032","url":null,"abstract":"Autologous hematopoietic stem cell gene therapy (HSC-GT) is an emerging therapy for treatment-refractory neurodegenerative lysosomal storage disorders (LSDs). Mucopolysaccharidosis IIIA (MPSIIIA) is a devastating LSD where pathogenic variants in the gene SGSH lead to toxic heparan sulfate accumulation, inflammation, and cell death. Children present with developmental delay, neurodegeneration, and significant behavioral disturbance and die in late teens. We report 80-month outcomes for a patient with severe MPSIIIA following treatment with investigational autologous HSC-GT (OTL-201) at 30 months of age. Hematopoietic stem and progenitor cells (HSPCs) were collected from peripheral blood following mobilization with granulocyte colony stimulating factor (G-CSF) and plerixafor. HSPCs were transduced with a lentiviral vector containing SGSH and the CD11b promoter. The product was infused following myeloablative conditioning with busulfan. Product engraftment was rapid, with production of sustained supra-physiological SGSH enzyme measured in leukocytes, plasma, and cerebrospinal fluid (CSF) and reductions in substrate heparan sulfate to within the normal range in urine, plasma, and CSF. Neurocognitive outcomes on the Bayley Scale of Infant Development (BSID-III) and parent-reported outcomes showed improvements compared to natural history. This demonstrates sustained long-term efficacy and safety of HSC-GT in a patient with severe MPSIIIA, setting the scene for a phase 1/2 clinical trial in younger patients.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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