Molecular Therapy最新文献

Restoring miRNA biogenesis in ALS: Enoxacin enhances DICER activity in a first-in-human trial. 在ALS中恢复miRNA生物发生：依诺沙星在首次人体试验中增强DICER活性。

IF 12 1区医学

Molecular Therapy Pub Date : 2026-05-08 DOI: 10.1016/j.ymthe.2026.04.040

Ramakrishnan Sivasubramanian, Jared Sterneckert

引用次数: 0

Administration of Neuritin as a novel therapeutic strategy for autoimmune and inflammatory diseases. 神经素作为自身免疫性和炎症性疾病的新治疗策略。

IF 12 1区医学

Molecular Therapy Pub Date : 2026-05-08 DOI: 10.1016/j.ymthe.2026.04.059

Ping Wei, Kaimin Zhang, Yiping Hu, Xu Gao, Yingnan Hou, Farooq Riaz, Zhenzhen Zhang, Juan He, Miaomiao Zhang, Yikui Li, Fangfang Li, Aiting Wang, Taowen Zhao, Biyi Zhang, Xingchi Li, Anmei Jiang, Lin Wu, Youhai H Chen, Zusen Fan, Jing Huang, Qingwen Wang, Fan Pan

{"title":"Administration of Neuritin as a novel therapeutic strategy for autoimmune and inflammatory diseases.","authors":"Ping Wei, Kaimin Zhang, Yiping Hu, Xu Gao, Yingnan Hou, Farooq Riaz, Zhenzhen Zhang, Juan He, Miaomiao Zhang, Yikui Li, Fangfang Li, Aiting Wang, Taowen Zhao, Biyi Zhang, Xingchi Li, Anmei Jiang, Lin Wu, Youhai H Chen, Zusen Fan, Jing Huang, Qingwen Wang, Fan Pan","doi":"10.1016/j.ymthe.2026.04.059","DOIUrl":"https://doi.org/10.1016/j.ymthe.2026.04.059","url":null,"abstract":"Autoimmune and inflammatory diseases are characterized by dysregulated T cell-mediated immune responses leading to tissue damage. Despite therapeutic advancements, patients remain resistant to treatment, highlighting the urgent need for alternative therapeutic strategies. Here, we identified Neuritin (NRN), an immunosuppressive molecule, capable of restraining effector CD4+ T cell responses and mitigating autoimmune and inflammatory diseases. NRN is downregulated in CD4+ T cells of rheumatoid arthritis (RA) patients, driving T cell-mediated autoimmune pathology. Nrnfl/flCD4Cre mice exacerbate both experimental autoimmune encephalomyelitis (EAE) and DSS-induced colitis, characterized by Treg depletion and expansion of IFN-γ+ and IL-17+ pro-inflammatory cells. Mechanistically, NRN selectively binds to cannabinoid receptor 2 (CB2), but not to CB1, specifically through its threonine residues at positions T78 and T81. Meanwhile, mice lacking CB2 (CB2-/- or CB2fl/flCD4Cre) exhibit worsened colitis, with an increased IFN-γ+ and IL-17+ cells, mirroring the Nrnfl/flCD4Cre phenotype. T-cell specific Nrn knock-in (NrnKI/KICD4Cre) or exogenous NRN administration ameliorated disease severity in multiple autoimmune models, including DSS-induced colitis, IMQ-induced psoriasis, and collagen-induced arthritis, by promoting Treg expansion and suppressing IFN-γ+ and IL-17+ pro-inflammatory cells. However, these protective effects of NRN were abolished in CB2-deficient mice. Overall, NRN is an immunosuppressive molecule with therapeutic potential in autoimmune and inflammatory diseases.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.0,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856836","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

Engineering immune tolerance for AAV gene therapy: The Norse way. AAV基因治疗的工程免疫耐受：挪威方式。

IF 12 1区医学

Molecular Therapy Pub Date : 2026-05-07 DOI: 10.1016/j.ymthe.2026.04.042

Moanaro Biswas, Roland W Herzog

引用次数: 0

High-capacity adenoviral vector-mediated expression of an LDLR/transferrin chimeric protein in muscle reduces atherosclerosis in Ldlr^-/- mice. 辅助依赖腺病毒载体介导的低密度脂蛋白受体/转铁蛋白嵌合蛋白在肌肉中的表达可安全减少低密度脂蛋白缺陷小鼠的动脉粥样硬化。

IF 12 1区医学

Molecular Therapy Pub Date : 2026-05-06 Epub Date: 2026-02-13 DOI: 10.1016/j.ymthe.2026.02.014

Maria Vitale, Filippo Scialò, Ludovica Coluccino, Anna D'Agostino, Lorella Tripodi, Raffaella Pagliaro, Andrea Bianco, Giuseppe Castaldo, Vincenzo Cerullo, Lucio Pastore

{"title":"High-capacity adenoviral vector-mediated expression of an LDLR/transferrin chimeric protein in muscle reduces atherosclerosis in Ldlr-/- mice.","authors":"Maria Vitale, Filippo Scialò, Ludovica Coluccino, Anna D'Agostino, Lorella Tripodi, Raffaella Pagliaro, Andrea Bianco, Giuseppe Castaldo, Vincenzo Cerullo, Lucio Pastore","doi":"10.1016/j.ymthe.2026.02.014","DOIUrl":"10.1016/j.ymthe.2026.02.014","url":null,"abstract":"Familial hypercholesterolemia (FH) is a genetic disorder caused by mutations in the low-density lipoprotein (LDL) receptor, leading to impaired uptake of LDL and its accumulation in arterial walls and other tissues. This accumulation results in cardiovascular disease and early mortality. Treatments, including statins, ezetimibe, PCSK9 inhibitors, and bempedoic acid, are often insufficient in homozygous FH patients, particularly those with null mutations in the LDL receptor (LDLR). To address this unmet need, we have developed two helper-dependent adenoviral (HD-Ad) vectors for the expression of the murine and human versions of a protein composed of the extracellular portion of the LDLR fused to transferrin. In both cassettes, expression is driven by the murine creatine kinase promoter to obtain high levels of expression restricted to muscle cells, to mitigate host response to the fusion protein. Both human and murine proteins restored LDL uptake in Ldlrf-deficient cells, correcting the phenotype in vitro. A single intramuscular administration of the HD-Ad vector induced the expression of the murine fusion protein, leading to a 12-month improvement in the lipid profile, with a reduction in aortic atherosclerosis in Ldlr-deficient mice. Furthermore, we observed no major systemic toxicity, indicating that the present strategy may represent more effective therapy for FH patients.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2879-2889"},"PeriodicalIF":12.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13154320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Reprogramming CD22 CAR-T cells in vivo using CD8-targeted mRNA-LNPs to treat hematological malignancies. 利用cd8靶向mRNA-LNPs对体内CD22 CAR-T细胞进行重编程治疗血液系统恶性肿瘤

IF 12 1区医学

Molecular Therapy Pub Date : 2026-05-06 Epub Date: 2026-02-13 DOI: 10.1016/j.ymthe.2026.02.020

Viktor T Lemgart, Andrew J Sawyer, William Kuhlman, Aaron P Griset, Mir M Ali, Allison Caron, Dharini Shah, Tiffany Le, Laura Strauss, Jing Jiao, Francis J Descamps, Sampa Maiti, Michael T Monte, Ralston Augspurg, Eyoung Shin, Ernesto Luna, Pankaj Agrawal, Jan Pype, Olga Lihoradova, James Cao, Brandon Quido, Laura Powers, Fazila Nasimi, Jacob Scantland, Kavana Girish, Rasika D Kunden, Jennifer Richards, Samantha Stewart, Seunghee Lee, Garry Cuneo, Janina Schwarte, Christian Mueller, Christopher M Borges, Austin W Boesch, Valeria R Fantin, Ulrik B Nielsen, Donald R Shaffer, Daryl C Drummond

{"title":"Reprogramming CD22 CAR-T cells in vivo using CD8-targeted mRNA-LNPs to treat hematological malignancies.","authors":"Viktor T Lemgart, Andrew J Sawyer, William Kuhlman, Aaron P Griset, Mir M Ali, Allison Caron, Dharini Shah, Tiffany Le, Laura Strauss, Jing Jiao, Francis J Descamps, Sampa Maiti, Michael T Monte, Ralston Augspurg, Eyoung Shin, Ernesto Luna, Pankaj Agrawal, Jan Pype, Olga Lihoradova, James Cao, Brandon Quido, Laura Powers, Fazila Nasimi, Jacob Scantland, Kavana Girish, Rasika D Kunden, Jennifer Richards, Samantha Stewart, Seunghee Lee, Garry Cuneo, Janina Schwarte, Christian Mueller, Christopher M Borges, Austin W Boesch, Valeria R Fantin, Ulrik B Nielsen, Donald R Shaffer, Daryl C Drummond","doi":"10.1016/j.ymthe.2026.02.020","DOIUrl":"10.1016/j.ymthe.2026.02.020","url":null,"abstract":"Ex vivo chimeric antigen receptor (CAR) T cell therapy has proven successful in patients with B cell hematologic malignancies. However, current approaches are limited by the requirement for personal manufacturing processes and by barriers such as limited efficacy against solid tumors, treatment-associated toxicities, insufficient CAR-T cell trafficking to the tumor microenvironment, on-target off-tumor effects, and tumor antigen escape. Here, we describe a novel delivery platform that overcomes many of these barriers by employing targeted lipid nanoparticles (LNPs) to reprogram circulating human T cells in vivo. Using a NANOBODYVHH (variable heavy domain of heavy chain)-based targeting moiety, we deliver mRNA encoding a novel CD22 CAR specifically to CD8+ cells, enabling transient functional CAR expression in vitro and in vivo. Our targeted LNP formulation allows for repeated dosing and minimizes mRNA expression in off-target cells. Furthermore, in a humanized Nalm6 tumor mouse model, non-stimulated T cells reprogrammed in vivo inhibit tumor cell growth. Our platform is a flexible and broadly applicable CAR-T treatment for hematologic malignancies, which promises to be adaptable to other diseases.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2621-2636"},"PeriodicalIF":12.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13154270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

An RNA time capsule in living cells. 活细胞中的RNA时间胶囊。

IF 12 1区医学

Molecular Therapy Pub Date : 2026-05-06 Epub Date: 2026-04-29 DOI: 10.1016/j.ymthe.2026.04.019

Yu-Kai Chao, Fei Chen

引用次数: 0

Anti-CD45 PBD-based antibody-drug conjugates are effective targeted conditioning agents for gene therapy and stem cell transplant. 基于抗cd45 pbd的抗体-药物偶联物是基因治疗和干细胞移植的有效靶向调理剂。

IF 12 1区医学

Molecular Therapy Pub Date : 2026-05-06 Epub Date: 2026-04-27 DOI: 10.1016/j.ymthe.2026.04.029

Jenny Yeung, Aiyin Liao, Matthew Shaw, Soraia Silva, Winston Vetharoy, Diego Leon Rico, Ian Kirby, Francesca Zammarchi, Karin Havenith, Lolke de Haan, Patrick H van Berkel, Neil Sebire, Olumide K Ogunbiyi, Claire Booth, H Bobby Gaspar, Adrian J Thrasher, Kerry A Chester, Persis J Amrolia

引用次数: 0

Herbacetin as a novel therapeutic agent for pulmonary and renal fibrosis by targeting TGF-βRⅡ for degradation. herbacettin作为一种靶向TGF-βRⅡ降解肺和肾纤维化的新型治疗剂。

IF 12 1区医学

Molecular Therapy Pub Date : 2026-05-06 DOI: 10.1016/j.ymthe.2026.04.062

Feng Liao, Peng Liu, Liumei Wu, Tingjing Zhong, Jiaxiao Li, Jiafan Chen, Chen Wu, Ya Liu, Junzhe Chen, Geng Li, Wenbiao Wang

引用次数: 0

CD55-displaying oncolytic vaccinia virus treated metastatic cancers by evading the effect of host innate and adaptive humoral responses. 显示cd55的溶瘤痘苗病毒通过逃避宿主先天和适应性体液反应的影响治疗转移性癌症。

IF 12 1区医学

Molecular Therapy Pub Date : 2026-05-06 Epub Date: 2026-02-05 DOI: 10.1016/j.ymthe.2026.01.043

Eunhye Kim, Yeonsoo Yang, Solchan Won, Namhee Lee, Young-In Kim, Suk-Kyung Shin, Songyi Lee, Mi-Ju Park, Hang-Rae Kim, Keunhee Oh, Dong-Sup Lee

{"title":"CD55-displaying oncolytic vaccinia virus treated metastatic cancers by evading the effect of host innate and adaptive humoral responses.","authors":"Eunhye Kim, Yeonsoo Yang, Solchan Won, Namhee Lee, Young-In Kim, Suk-Kyung Shin, Songyi Lee, Mi-Ju Park, Hang-Rae Kim, Keunhee Oh, Dong-Sup Lee","doi":"10.1016/j.ymthe.2026.01.043","DOIUrl":"10.1016/j.ymthe.2026.01.043","url":null,"abstract":"Oncolytic viruses offer promising immunotherapy for cancer but face challenges such as delivery, targeting, and immune clearance. Our prior work showed that vaccinia virus (VACV) displaying the complement regulator CD55 evaded complement-mediated clearance, enhancing delivery and targeting in xenograft models. Importantly, this modified VACV also escaped neutralizing antibodies (NAbs) in vitro, a finding with significant implications. To improve translational relevance, we independently evaluated NAb evasion in immunocompetent in vivo models and against human-derived NAbs. Our novel platform virus, SJ-650-a CD55-displaying VACV expressing murine GM-CSF-retained superior antitumor efficacy despite the presence of NAbs in syngeneic breast cancer models. Additionally, SJ-650 effectively evaded NAbs derived from the serum of a clinical VACV trial (REN026). NAb evasion was CD55 dependent, occurred independently of complement activity, and was mediated by steric hindrance via the extracellular CD55 motif. NAb pretreatment masked binding of the key viral entry proteins A27, L1, and H3 in control viruses lacking CD55, but these interactions remained intact in SJ-650. By circumventing both complement and antibody responses, SJ-650 significantly inhibited tumor growth in two metastasis models, inducing immunogenic cell death and reprogramming the tumor microenvironment. These findings support SJ-650's potential as a robust oncolytic platform with broad translational applicability.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3039-3055"},"PeriodicalIF":12.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13154265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

2025 Advancing Cell and Gene Therapies for Cancer post-meeting report. 2025年癌症细胞和基因治疗进展会议报告。

IF 12 1区医学

Molecular Therapy Pub Date : 2026-05-06 DOI: 10.1016/j.ymthe.2026.04.017

Paola Grandi, Maria G Castro, Evanthia Galanis, Michael C Milone, Saad Kenderian

引用次数: 0