Pub Date : 2025-11-26DOI: 10.1126/scitranslmed.adp5849
Philipp Gobrecht, Jeannette Gebel, Günter Gisselmann, Kirsten Haastert-Talini, Dietmar Fischer
Diabetes mellitus impairs axon regeneration, leading to chronic functional deficits after nerve injury. Here, we used a streptozotocin-induced model of type 1 diabetes and leptin receptor–deficient db/db mice representing type 2 diabetes to identify a key molecular mechanism underlying this failure and propose targeted strategies to restore regenerative capacity. As determined by Western blotting and immunohistochemistry, sensory neurons from diabetic mice displayed elevated p35 abundance, leading to cyclin-dependent kinase 5 (CDK5) hyperactivation and glycogen synthase kinase 3β (GSK3β)–dependent inhibitory phosphorylation of collapsin response mediator protein 2 (CRMP2), a critical regulator of axon growth. These changes, coinciding with impaired axon regeneration in injured sciatic nerves, occurred before the onset of diabetes-induced neuropathy in mice. Disrupting this pathway, through expression of constitutively active CRMP2, p35 knockdown, or blockade of the p35-CDK5 interaction by expression of the inhibitory protein CIP or injection of a TAT (transactivator of transcription) peptide, restored axon regeneration of cultured adult sensory neurons and accelerated motor and sensory recovery of diabetic mice. These manipulations did not affect nerve regeneration in nondiabetic mice. Similarly, GSK3β knockout prevented CRMP2 inactivation and rescued growth in diabetic neurons. Systemic administration of the peptide also enhanced motor and sensory nerve repair in long-term diabetic mice with established neuropathy. These findings identify p35 and CRMP2 as central effectors of diabetes-induced regenerative failure in mice, suggesting that the p35-CDK5-CRMP2 axis and GSK3β are promising therapeutic targets for promoting nerve repair in patients with diabetes.
{"title":"Failure of nerve regeneration in mouse models of diabetes is caused by p35-mediated CDK5 hyperactivity","authors":"Philipp Gobrecht, Jeannette Gebel, Günter Gisselmann, Kirsten Haastert-Talini, Dietmar Fischer","doi":"10.1126/scitranslmed.adp5849","DOIUrl":"10.1126/scitranslmed.adp5849","url":null,"abstract":"<div >Diabetes mellitus impairs axon regeneration, leading to chronic functional deficits after nerve injury. Here, we used a streptozotocin-induced model of type 1 diabetes and leptin receptor–deficient <i>db/db</i> mice representing type 2 diabetes to identify a key molecular mechanism underlying this failure and propose targeted strategies to restore regenerative capacity. As determined by Western blotting and immunohistochemistry, sensory neurons from diabetic mice displayed elevated p35 abundance, leading to cyclin-dependent kinase 5 (CDK5) hyperactivation and glycogen synthase kinase 3β (GSK3β)–dependent inhibitory phosphorylation of collapsin response mediator protein 2 (CRMP2), a critical regulator of axon growth. These changes, coinciding with impaired axon regeneration in injured sciatic nerves, occurred before the onset of diabetes-induced neuropathy in mice. Disrupting this pathway, through expression of constitutively active CRMP2, p35 knockdown, or blockade of the p35-CDK5 interaction by expression of the inhibitory protein CIP or injection of a TAT (transactivator of transcription) peptide, restored axon regeneration of cultured adult sensory neurons and accelerated motor and sensory recovery of diabetic mice. These manipulations did not affect nerve regeneration in nondiabetic mice. Similarly, GSK3β knockout prevented CRMP2 inactivation and rescued growth in diabetic neurons. Systemic administration of the peptide also enhanced motor and sensory nerve repair in long-term diabetic mice with established neuropathy. These findings identify p35 and CRMP2 as central effectors of diabetes-induced regenerative failure in mice, suggesting that the p35-CDK5-CRMP2 axis and GSK3β are promising therapeutic targets for promoting nerve repair in patients with diabetes.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 826","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145600112","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}
Pub Date : 2025-11-26DOI: 10.1126/scitranslmed.adt8617
Giulia Hardouin, Pierre Martinucci, Samantha Scaramuzza, Panagiotis Antoniou, Federico Corradi, Alexandra Tachtsidi, Guillaume Corre, Margaux Mombled, Jessika Chermont, Sandra Manceau, Cécile Rouillon, Cécile Masson, Laure Joseph, Isabelle Thuret, Catherine Badens, Sarah Szepetowsky, Eric Allemand, Mario Amendola, Oriana Romano, Giuliana Ferrari, Annarita Miccio
Gene therapy has emerged as a promising curative treatment for β-hemoglobinopathies, the most common genetic disorders worldwide. However, current approved approaches still have some limitations in terms of safety and efficacy. Here, we used highly processive adenine base editor (ABE) variants to precisely correct some of the most prevalent and severe β-thalassemia–causing mutations in the β-globin–encoding HBB gene, including CD39 and IVS2-1, using NRCH-ABE8e and SpRY-ABE8e, respectively. More than 90% of editing of hematopoietic stem and progenitor cells (HSPCs) led to improved β-globin expression in their erythroid progeny and persistent correction of both β-thalassemia and sickle cell–β-thalassemia phenotypes. The safety of this strategy was confirmed in HSPCs in vitro and in vivo through the absence of gene dysregulation and any meaningful impact on the DNA mutational burden, RNA deamination, β-globin gene locus integrity, and the clonality of the HSPC graft, as assessed by RNA sequencing, whole-exome sequencing, long-read sequencing, and human HSPC transplantation in immunodeficient mice. Overall, these preclinical studies suggest that base editing–mediated gene correction may be a safe and effective strategy for treating β-hemoglobinopathies.
{"title":"Base editing of β0-thalassemia mutations as a therapeutic strategy for severe β-hemoglobinopathies","authors":"Giulia Hardouin, Pierre Martinucci, Samantha Scaramuzza, Panagiotis Antoniou, Federico Corradi, Alexandra Tachtsidi, Guillaume Corre, Margaux Mombled, Jessika Chermont, Sandra Manceau, Cécile Rouillon, Cécile Masson, Laure Joseph, Isabelle Thuret, Catherine Badens, Sarah Szepetowsky, Eric Allemand, Mario Amendola, Oriana Romano, Giuliana Ferrari, Annarita Miccio","doi":"10.1126/scitranslmed.adt8617","DOIUrl":"10.1126/scitranslmed.adt8617","url":null,"abstract":"<div >Gene therapy has emerged as a promising curative treatment for β-hemoglobinopathies, the most common genetic disorders worldwide. However, current approved approaches still have some limitations in terms of safety and efficacy. Here, we used highly processive adenine base editor (ABE) variants to precisely correct some of the most prevalent and severe β-thalassemia–causing mutations in the β-globin–encoding <i>HBB</i> gene, including CD39 and IVS2-1, using NRCH-ABE8e and SpRY-ABE8e, respectively. More than 90% of editing of hematopoietic stem and progenitor cells (HSPCs) led to improved β-globin expression in their erythroid progeny and persistent correction of both β-thalassemia and sickle cell–β-thalassemia phenotypes. The safety of this strategy was confirmed in HSPCs in vitro and in vivo through the absence of gene dysregulation and any meaningful impact on the DNA mutational burden, RNA deamination, β-globin gene locus integrity, and the clonality of the HSPC graft, as assessed by RNA sequencing, whole-exome sequencing, long-read sequencing, and human HSPC transplantation in immunodeficient mice. Overall, these preclinical studies suggest that base editing–mediated gene correction may be a safe and effective strategy for treating β-hemoglobinopathies.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 826","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145600115","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}
Pub Date : 2025-11-26DOI: 10.1126/scitranslmed.adu3313
Ulrike Höckendorf, Sayantanee Dutta, Arnold Kloos, Marah Runtsch, Carina Zötsch, Sebastian Vosberg, Yongjie Wang, Sophie Kienreich, Bettina Flasch, Grazia Malovan, Vanessa Jäger, Stefanie Stanzer, Stefanie Prein, Timo O. Odinius, Celina V. Wagner, Lars Buschhorn, Veronika Dill, Bianca Perfler, Torsten Haferlach, Konstanze Döhner, Katharina S. Götze, Jürgen Ruland, Florian Bassermann, Adam Wahida, Mathias Heikenwälder, Caterina Branca, Johannes Schmöllerl, Johannes Zuber, Ann-Cathrin Burk, Robert Zeiser, Heinz Sill, Ashok Kumar Jayavelu, Armin Zebisch, Michael Heuser, Michael A. Dengler, Philipp J. Jost
Acute myeloid leukemia (AML) is characterized by frequent relapse, which is driven by resistant leukemic stem or progenitor cells (LSCs). Here, we reported on a tumor-suppressive mechanism that can be harnessed to simultaneously clear LSCs and promote healthy hematopoiesis. Genetic deletion of the tumor necrosis factor (TNF) superfamily member lymphotoxin alpha (Lta) blocked cell death and accelerated leukemogenesis in murine AML models. Accordingly, exposure of leukemic cells to exogenous recombinant lymphotoxin alpha (LTα3) induced myeloid differentiation and, in part, cell death in AML progenitors. In syngeneic and patient-derived xenograft mouse models, exposure to recombinant LTα3 resulted in deep and durable remissions. LTα3 repressed leukemia by depleting tumor necrosis factor receptor (TNFR)–associated factor 2 (TRAF2) through activation of TNF receptors TNFR1 and TNFR2. In contrast with conventional therapies, LTα3 exerted only minimal toxicity on the healthy hematopoiesis but instead promoted hematopoietic progenitors. Leveraging this endogenous tumor-suppressive mechanism may decouple treatment efficacy on malignant cells from undesired bone marrow suppression.
{"title":"Lymphotoxin alpha eradicates acute myeloid leukemia and simultaneously promotes healthy hematopoiesis in mice","authors":"Ulrike Höckendorf, Sayantanee Dutta, Arnold Kloos, Marah Runtsch, Carina Zötsch, Sebastian Vosberg, Yongjie Wang, Sophie Kienreich, Bettina Flasch, Grazia Malovan, Vanessa Jäger, Stefanie Stanzer, Stefanie Prein, Timo O. Odinius, Celina V. Wagner, Lars Buschhorn, Veronika Dill, Bianca Perfler, Torsten Haferlach, Konstanze Döhner, Katharina S. Götze, Jürgen Ruland, Florian Bassermann, Adam Wahida, Mathias Heikenwälder, Caterina Branca, Johannes Schmöllerl, Johannes Zuber, Ann-Cathrin Burk, Robert Zeiser, Heinz Sill, Ashok Kumar Jayavelu, Armin Zebisch, Michael Heuser, Michael A. Dengler, Philipp J. Jost","doi":"10.1126/scitranslmed.adu3313","DOIUrl":"10.1126/scitranslmed.adu3313","url":null,"abstract":"<div >Acute myeloid leukemia (AML) is characterized by frequent relapse, which is driven by resistant leukemic stem or progenitor cells (LSCs). Here, we reported on a tumor-suppressive mechanism that can be harnessed to simultaneously clear LSCs and promote healthy hematopoiesis. Genetic deletion of the tumor necrosis factor (TNF) superfamily member <i>lymphotoxin alpha</i> (<i>Lta</i>) blocked cell death and accelerated leukemogenesis in murine AML models. Accordingly, exposure of leukemic cells to exogenous recombinant lymphotoxin alpha (LTα<sub>3</sub>) induced myeloid differentiation and, in part, cell death in AML progenitors. In syngeneic and patient-derived xenograft mouse models, exposure to recombinant LTα<sub>3</sub> resulted in deep and durable remissions. LTα<sub>3</sub> repressed leukemia by depleting tumor necrosis factor receptor (TNFR)–associated factor 2 (TRAF2) through activation of TNF receptors TNFR1 and TNFR2. In contrast with conventional therapies, LTα<sub>3</sub> exerted only minimal toxicity on the healthy hematopoiesis but instead promoted hematopoietic progenitors. Leveraging this endogenous tumor-suppressive mechanism may decouple treatment efficacy on malignant cells from undesired bone marrow suppression.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 826","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145600117","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}
Pub Date : 2025-11-26DOI: 10.1126/scitranslmed.ads8680
Megan O’Driscoll, Nathanaël Hozé, Noémie Lefrancq, Gabriel Ribeiro dos Santos, Damien Hoinard, Mohammed Ziaur Rahman, Kishor Kumar Paul, Abu Mohd Naser Titu, Mohammad Shafiul Alam, Mohammad Enayet Hossain, Jessica Vanhomwegen, Simon Cauchemez, Emily S. Gurley, Henrik Salje
Multiplex immunoassays can facilitate the parallel measurement of antibody responses against multiple antigenically related pathogens, generating a wealth of high-dimensional data that depict complex antibody-antigen relationships. In this study, we developed a generalizable analytical framework to maximize inferences from multipathogen serological studies. We fit the model to measurements of immunoglobulin antibody binding against 10 arboviral pathogens from a cross-sectional study in northwest Bangladesh with 1453 participants. We used our framework to jointly infer the prevalence of each pathogen by location and age as well as between-pathogen antibody cross-reactivity. Reconstructing immunological profiles, we found evidence of endemic transmission of Japanese encephalitis virus and recent outbreaks of dengue and chikungunya viruses in this district. Our estimates of antibody cross-reactivity were highly correlated with phylogenetic distances inferred from genetic data [correlation coefficient (r) = 0.94], demonstrating how antigenic landscapes can be inferred from population-level serological studies. Furthermore, we showed how our framework could be used to identify the presence of antigenically related pathogens that were not directly tested for, representing a potential opportunity for the detection of emerging pathogens. The presented analytical framework offers a tool that can be applied to a growing number of multipathogen studies and will help support the integration of serological testing into disease surveillance platforms.
{"title":"Epidemiological and antigenic inferences from serological cross-reactivity among arboviruses","authors":"Megan O’Driscoll, Nathanaël Hozé, Noémie Lefrancq, Gabriel Ribeiro dos Santos, Damien Hoinard, Mohammed Ziaur Rahman, Kishor Kumar Paul, Abu Mohd Naser Titu, Mohammad Shafiul Alam, Mohammad Enayet Hossain, Jessica Vanhomwegen, Simon Cauchemez, Emily S. Gurley, Henrik Salje","doi":"10.1126/scitranslmed.ads8680","DOIUrl":"10.1126/scitranslmed.ads8680","url":null,"abstract":"<div >Multiplex immunoassays can facilitate the parallel measurement of antibody responses against multiple antigenically related pathogens, generating a wealth of high-dimensional data that depict complex antibody-antigen relationships. In this study, we developed a generalizable analytical framework to maximize inferences from multipathogen serological studies. We fit the model to measurements of immunoglobulin antibody binding against 10 arboviral pathogens from a cross-sectional study in northwest Bangladesh with 1453 participants. We used our framework to jointly infer the prevalence of each pathogen by location and age as well as between-pathogen antibody cross-reactivity. Reconstructing immunological profiles, we found evidence of endemic transmission of Japanese encephalitis virus and recent outbreaks of dengue and chikungunya viruses in this district. Our estimates of antibody cross-reactivity were highly correlated with phylogenetic distances inferred from genetic data [correlation coefficient (<i>r</i>) = 0.94], demonstrating how antigenic landscapes can be inferred from population-level serological studies. Furthermore, we showed how our framework could be used to identify the presence of antigenically related pathogens that were not directly tested for, representing a potential opportunity for the detection of emerging pathogens. The presented analytical framework offers a tool that can be applied to a growing number of multipathogen studies and will help support the integration of serological testing into disease surveillance platforms.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 826","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145600114","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}
Pub Date : 2025-11-26DOI: 10.1126/scitranslmed.adt1938
Edward C. Parkinson, W. John Watkins, Sarah Edkins, James E. McLaren, Michelle N. Clements, Robert Andrews, Federico Liberatore, Irja Lutsar, Mark A. Turner, Emmanuel Roilides, Paul T. Heath, Michael Sharland, Louise F. Hill, Peter Ghazal, on behalf of the NeoVanc Consortium
Sepsis is a leading cause of mortality and morbidity in neonates yet remains difficult to diagnose. This leads to widespread empiric antibiotic therapy, which can facilitate the development of antimicrobial resistance. How the dysregulated host response to infection and sepsis evolves after antibiotic treatment is poorly understood. Temporal gene expression in neonates with microbiologically confirmed sepsis, treated with the antibiotic vancomycin as part of a randomized controlled trial, was profiled to reveal a treatment-responsive gene signature. The signature exhibited a rapid reversal of the septic state, observable within 24 hours of the initiation of therapy. Unexpectedly, response rates associated with the adaptive immune system were among the fastest, and these changes were reproduced in both pediatric and adult patients with sepsis, indicating conservation and reversibility of sepsis signatures across the life course. We demonstrated how these treatment-responsive genes could be translated into a prognostic clinical measure, exhibiting strong agreement with clinical assessments. Network modeling of sepsis-responsive genes identified a signature associated with treatment comprising an early transient elevation of antimicrobial defensive genes, suggesting an impaired bactericidal response in neonatal sepsis. These findings suggest that the host response is regulated in sepsis and offer insights into early prognostic approaches for reducing antibiotic overuse.
{"title":"A rapid time-resolved host gene expression signature predicts responses to antibiotic treatment in neonatal bacterial sepsis","authors":"Edward C. Parkinson, W. John Watkins, Sarah Edkins, James E. McLaren, Michelle N. Clements, Robert Andrews, Federico Liberatore, Irja Lutsar, Mark A. Turner, Emmanuel Roilides, Paul T. Heath, Michael Sharland, Louise F. Hill, Peter Ghazal, on behalf of the NeoVanc Consortium","doi":"10.1126/scitranslmed.adt1938","DOIUrl":"10.1126/scitranslmed.adt1938","url":null,"abstract":"<div >Sepsis is a leading cause of mortality and morbidity in neonates yet remains difficult to diagnose. This leads to widespread empiric antibiotic therapy, which can facilitate the development of antimicrobial resistance. How the dysregulated host response to infection and sepsis evolves after antibiotic treatment is poorly understood. Temporal gene expression in neonates with microbiologically confirmed sepsis, treated with the antibiotic vancomycin as part of a randomized controlled trial, was profiled to reveal a treatment-responsive gene signature. The signature exhibited a rapid reversal of the septic state, observable within 24 hours of the initiation of therapy. Unexpectedly, response rates associated with the adaptive immune system were among the fastest, and these changes were reproduced in both pediatric and adult patients with sepsis, indicating conservation and reversibility of sepsis signatures across the life course. We demonstrated how these treatment-responsive genes could be translated into a prognostic clinical measure, exhibiting strong agreement with clinical assessments. Network modeling of sepsis-responsive genes identified a signature associated with treatment comprising an early transient elevation of antimicrobial defensive genes, suggesting an impaired bactericidal response in neonatal sepsis. These findings suggest that the host response is regulated in sepsis and offer insights into early prognostic approaches for reducing antibiotic overuse.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 826","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145601256","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}
The initiation and progression of multiple myeloma (MM) are intricate processes, and a critical challenge lies in understanding the mechanisms of malignant transformation in MM-initiating cells (MICs) and their driver genes. In this study, we used single-cell sequencing and genetic tracer analysis at each developmental stage, from hematopoietic stem cells to lymphoid lineage differentiation, to identify abnormal differentiation stages in patients with MM. We found that chromosome 1q amplification (1qAmp) originated from a specific subgroup of B cells, whereas chromosome 17p deletion occurred at the plasma cell stage. 1qAmp was present in CD24−FCRL5+ B cell subgroups and initiated B cell transformation into malignant plasma cells by enhancing B cell proliferation and promoting plasma cell differentiation in vitro and in vivo. FCRL5 facilitated B cell differentiation into malignant plasma cells through its interaction with the IRF4/SPI1 complex. The use of targeted FCRL5 CAR T cells in patients with relapsed or refractory MM (RRMM) showed promising safety and efficacy. Together, our work identified genetic events linked to the initiation and malignant transformation of MM along the B cell lineage. These findings form the foundation for identifying potential therapeutic strategies for patients with RRMM by targeting MICs and their driving oncogenes.
多发性骨髓瘤（MM）的发生和发展是一个复杂的过程，关键的挑战在于了解MM启动细胞（mic）及其驱动基因的恶性转化机制。在这项研究中，我们使用单细胞测序和遗传示踪分析在每个发育阶段，从造血干细胞到淋巴系分化，以确定MM患者的异常分化阶段。我们发现染色体1q扩增（1q Amp）起源于特定的B细胞亚群，而染色体17p缺失发生在浆细胞阶段。1q Amp存在于CD24−FCRL5 + B细胞亚群中，通过体外和体内增强B细胞增殖和促进浆细胞分化，启动B细胞向恶性浆细胞的转化。FCRL5通过与IRF4/SPI1复合物的相互作用促进B细胞向恶性浆细胞分化。在复发或难治性MM （RRMM）患者中使用靶向FCRL5 CAR - T细胞显示出良好的安全性和有效性。总之，我们的工作确定了与B细胞谱系中MM的起始和恶性转化相关的遗传事件。这些发现为通过靶向mic及其驱动癌基因确定RRMM患者的潜在治疗策略奠定了基础。
{"title":"Targeting the origins of multiple myeloma along hematopoietic stem cell lymphoid lineage differentiation","authors":"Jiaojiao Guo, Yaru Li, Zhiling Yan, Qing Li, Zhenhao Liu, Zhengjiang Li, Ruiqi Zhou, Nihan He, Yinghong Zhu, Xiaoshuang Wang, Xun Chen, Yi Qiu, Liang Zhao, Fangming Shi, Yanjuan He, Sha Hao, Jia Yu, Lu Xie, Jiaxi Zhou, Jian Li, Gang An, Xiangling Feng, Wei Jia, Xiaochen Bo, Kailin Xu, Tao Cheng, Hebing Chen, Wen Zhou","doi":"10.1126/scitranslmed.adu0114","DOIUrl":"10.1126/scitranslmed.adu0114","url":null,"abstract":"<div >The initiation and progression of multiple myeloma (MM) are intricate processes, and a critical challenge lies in understanding the mechanisms of malignant transformation in MM-initiating cells (MICs) and their driver genes. In this study, we used single-cell sequencing and genetic tracer analysis at each developmental stage, from hematopoietic stem cells to lymphoid lineage differentiation, to identify abnormal differentiation stages in patients with MM. We found that chromosome 1q amplification (1q<sup>Amp</sup>) originated from a specific subgroup of B cells, whereas chromosome 17p deletion occurred at the plasma cell stage. 1q<sup>Amp</sup> was present in CD24<sup>−</sup>FCRL5<sup>+</sup> B cell subgroups and initiated B cell transformation into malignant plasma cells by enhancing B cell proliferation and promoting plasma cell differentiation in vitro and in vivo. FCRL5 facilitated B cell differentiation into malignant plasma cells through its interaction with the IRF4/SPI1 complex. The use of targeted FCRL5 CAR T cells in patients with relapsed or refractory MM (RRMM) showed promising safety and efficacy. Together, our work identified genetic events linked to the initiation and malignant transformation of MM along the B cell lineage. These findings form the foundation for identifying potential therapeutic strategies for patients with RRMM by targeting MICs and their driving oncogenes.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 825","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545437","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}
Pub Date : 2025-11-19DOI: 10.1126/scitranslmed.ads4214
Anna Maria Giudice, Stephanie Matlaga, Sydney L. Roth, Guillem Pascual-Pasto, Patrick M. Schürch, Geoffrey Rouin, Brendan McIntyre, Grant P. Grothusen, Evan Cresswell-Clay, Rawan Shraim, David Groff, Vincent Zecchino, Simona Lombardi, Daniel Martinez, Lynn A. Spruce, Elizabeth M. Brown, Hossein Fazelinia, Sarah E. Henrickson, Jonas Nance, C. Patrick Reynolds, Kristopher R. Bosse
Glypican-2 (GPC2) and the disialoganglioside GD2 are validated CAR T cell targets in neuroblastoma, but durable clinical responses remain limited. This modest chimeric antigen receptor T cell (CAR T cell) efficacy is in part due to suboptimal T cell persistence, antigen down-regulation, and a hostile tumor microenvironment, which includes immune cell–modulating extracellular vesicles (EVs). Neuroblastoma-derived EVs may contain CAR targets or other immunoregulatory elements that can modulate CAR T cell antitumor activity. Thus, we first profiled the surfaceome of neuroblastoma EVs and assessed their impact on both GPC2 and GD2 CAR T cell function. Neuroblastoma EVs displayed GPC2 and GD2, with minimal expression of programmed death-ligand 1 (PD-L1), and were detected in blood from tumor-bearing mice and patients. These EVs directly activated paired CAR T cells, suggesting a role for a peripheral source of CAR antigen. To exploit this therapeutically, we engineered nontumor-derived GPC2+ synthetic EVs (SyntEVs) as CAR T cell enhancers and armored them with either albumin-binding domains or GD2-binding domains. In mice harboring human neuroblastoma cell line–derived or patient-derived xenografts, serial infusion of armored SyntEVs after GPC2 CAR T cells enhanced tumor control by boosting peripheral CAR T cell persistence. Moreover, GD2-targeting SyntEVs decorated low-antigen tumor cells with GPC2, circumventing antigen down-regulation. This SyntEV platform offers a versatile system to address the therapeutic limitations of CAR T cells in solid tumors.
{"title":"Target antigen–displaying extracellular vesicles boost CAR T cell efficacy in cell and mouse models of neuroblastoma","authors":"Anna Maria Giudice, Stephanie Matlaga, Sydney L. Roth, Guillem Pascual-Pasto, Patrick M. Schürch, Geoffrey Rouin, Brendan McIntyre, Grant P. Grothusen, Evan Cresswell-Clay, Rawan Shraim, David Groff, Vincent Zecchino, Simona Lombardi, Daniel Martinez, Lynn A. Spruce, Elizabeth M. Brown, Hossein Fazelinia, Sarah E. Henrickson, Jonas Nance, C. Patrick Reynolds, Kristopher R. Bosse","doi":"10.1126/scitranslmed.ads4214","DOIUrl":"10.1126/scitranslmed.ads4214","url":null,"abstract":"<div >Glypican-2 (GPC2) and the disialoganglioside GD2 are validated CAR T cell targets in neuroblastoma, but durable clinical responses remain limited. This modest chimeric antigen receptor T cell (CAR T cell) efficacy is in part due to suboptimal T cell persistence, antigen down-regulation, and a hostile tumor microenvironment, which includes immune cell–modulating extracellular vesicles (EVs). Neuroblastoma-derived EVs may contain CAR targets or other immunoregulatory elements that can modulate CAR T cell antitumor activity. Thus, we first profiled the surfaceome of neuroblastoma EVs and assessed their impact on both GPC2 and GD2 CAR T cell function. Neuroblastoma EVs displayed GPC2 and GD2, with minimal expression of programmed death-ligand 1 (PD-L1), and were detected in blood from tumor-bearing mice and patients. These EVs directly activated paired CAR T cells, suggesting a role for a peripheral source of CAR antigen. To exploit this therapeutically, we engineered nontumor-derived GPC2+ synthetic EVs (SyntEVs) as CAR T cell enhancers and armored them with either albumin-binding domains or GD2-binding domains. In mice harboring human neuroblastoma cell line–derived or patient-derived xenografts, serial infusion of armored SyntEVs after GPC2 CAR T cells enhanced tumor control by boosting peripheral CAR T cell persistence. Moreover, GD2-targeting SyntEVs decorated low-antigen tumor cells with GPC2, circumventing antigen down-regulation. This SyntEV platform offers a versatile system to address the therapeutic limitations of CAR T cells in solid tumors.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 825","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.ads4214","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545436","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}
Severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging tick-borne phlebovirus, poses a growing public health threat, with no approved vaccines or targeted therapies. Its genetic diversity and rapid reassortment have hindered the development of broadly effective interventions. Here, we isolated and characterized broadly neutralizing camelid nanobodies generated by a heterologous immunization strategy. These nanobodies exhibited cross-subtype neutralization and conferred protection against disease in humanized and lethal murine models of SFTSV infection. Structural analysis revealed binding to distinct, nonoverlapping epitopes on the viral glycoprotein complex. A rationally designed cocktail leveraging this epitope diversity achieved complete viral inhibition through synergistic mechanisms. In both murine and immunocompetent ferret models, the cocktail enabled efficient viral clearance and full protection against lethal challenge. These results demonstrate the therapeutic potential of nanobody cocktails for SFTSV infection and establish a generalizable framework for nanobody-based countermeasures against genetically variable emerging viruses, including other members of the Bunyavirales order.
{"title":"A rationally designed cocktail of nanobodies elicited by heterologous vaccination confers protection against SFTSV in preclinical models","authors":"Xilin Wu, Linjing Zhu, Shengjian Liang, Zhen Chang, Yaxin Wang, Qingcui Zou, Zhili Xu, Doudou Zhang, Jiaqian Hu, Shengya Geng, Zhifeng Li, Wenkui Yu, Zhiliang Hu, Ming Chen, Ke Cao, Bei Jia, Hongxia Wei, Rentian Cai, Junyi Long, Xiaoman Yang, Qiaojiang Yang, Zhanjing Yu, Lingen Shi, Binghong Xu, Yangwu Zheng, Shengrui Meng, Jiameng Cai, Guangfeng Zhou, Kerui Zhu, Yunbo Dou, Zhiyong Lou, Minghua Li, Yan Wu, Zhiwei Wu","doi":"10.1126/scitranslmed.ady9025","DOIUrl":"10.1126/scitranslmed.ady9025","url":null,"abstract":"<div >Severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging tick-borne phlebovirus, poses a growing public health threat, with no approved vaccines or targeted therapies. Its genetic diversity and rapid reassortment have hindered the development of broadly effective interventions. Here, we isolated and characterized broadly neutralizing camelid nanobodies generated by a heterologous immunization strategy. These nanobodies exhibited cross-subtype neutralization and conferred protection against disease in humanized and lethal murine models of SFTSV infection. Structural analysis revealed binding to distinct, nonoverlapping epitopes on the viral glycoprotein complex. A rationally designed cocktail leveraging this epitope diversity achieved complete viral inhibition through synergistic mechanisms. In both murine and immunocompetent ferret models, the cocktail enabled efficient viral clearance and full protection against lethal challenge. These results demonstrate the therapeutic potential of nanobody cocktails for SFTSV infection and establish a generalizable framework for nanobody-based countermeasures against genetically variable emerging viruses, including other members of the Bunyavirales order.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 825","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545438","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}
Numerous G protein–coupled receptors (GPCRs) expressed in the gastrointestinal tract serve as crucial transducers to regulate a variety of physiological functions upon activation. Takeda G protein–coupled receptor 5 (TGR5), a prominent gastrointestinal GPCR expressed on enteroendocrine L cells, is activated by intestinal bile acids and plays a role in glucose utilization. However, the development of TGR5 agonists has been hindered by the hepatobiliary toxicity associated with long-term supplementation with exogenous agonists. Here, we designed and characterized a biomimetic receptor agonist, which we termed TGR5-targeted carrier-drug conjugate (TGR5-CaDC), that combined the TGR5-activating capabilities of deoxycholic acid, a TGR5 agonist, with the nonabsorbable properties of a carrier. Unlike traditional agonists or carrier-based drug delivery systems, nonabsorbable TGR5-CaDC remained localized in the intestines of mice and pigs, providing high surface concentrations of TGR5 agonists in addition to ensuring strong L cell specificity and TGR5 affinity. TGR5-CaDC treatment also promoted TGR5 cluster aggregation, signal amplification, and increased glucagon-like peptide 1 secretion. Notably, TGR5-CaDC demonstrated sustained glycemic effects with reduced toxicity compared with deoxycholic acid alone or liraglutide in diabetic mice and Bama minipigs. By targeting extracellular binding domains and mimicking native ligand-receptor binding patterns, the design concept underlying this carrier-drug conjugate has the potential for applications in a variety of GPCR-mediated gastrointestinal diseases.
{"title":"Intestinal TGR5-targeted carrier-drug conjugate improves glycemic control in mice and pigs","authors":"Yaqi Zhang, Hui Huang, Yaying Wang, Xiang Li, Peizhou Hou, Miaorong Yu, Zhuan Zhang, Shiyan Guo, Chang Liu, Zilong Zhang, Yan Zhuo, Chunliu Zhu, Pengcheng Zhang, Shisheng Wang, Hu Zhou, Yong Gan","doi":"10.1126/scitranslmed.ado5177","DOIUrl":"10.1126/scitranslmed.ado5177","url":null,"abstract":"<div >Numerous G protein–coupled receptors (GPCRs) expressed in the gastrointestinal tract serve as crucial transducers to regulate a variety of physiological functions upon activation. Takeda G protein–coupled receptor 5 (TGR5), a prominent gastrointestinal GPCR expressed on enteroendocrine L cells, is activated by intestinal bile acids and plays a role in glucose utilization. However, the development of TGR5 agonists has been hindered by the hepatobiliary toxicity associated with long-term supplementation with exogenous agonists. Here, we designed and characterized a biomimetic receptor agonist, which we termed TGR5-targeted carrier-drug conjugate (TGR5-CaDC), that combined the TGR5-activating capabilities of deoxycholic acid, a TGR5 agonist, with the nonabsorbable properties of a carrier. Unlike traditional agonists or carrier-based drug delivery systems, nonabsorbable TGR5-CaDC remained localized in the intestines of mice and pigs, providing high surface concentrations of TGR5 agonists in addition to ensuring strong L cell specificity and TGR5 affinity. TGR5-CaDC treatment also promoted TGR5 cluster aggregation, signal amplification, and increased glucagon-like peptide 1 secretion. Notably, TGR5-CaDC demonstrated sustained glycemic effects with reduced toxicity compared with deoxycholic acid alone or liraglutide in diabetic mice and Bama minipigs. By targeting extracellular binding domains and mimicking native ligand-receptor binding patterns, the design concept underlying this carrier-drug conjugate has the potential for applications in a variety of GPCR-mediated gastrointestinal diseases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 825","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545435","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}
Pub Date : 2025-11-19DOI: 10.1126/scitranslmed.adu8579
Matthew D. Slein, Iara M. Backes, Lesle M. Jiménez, Natasha S. Kelkar, Callaghan R. Garland, Urjeet S. Khanwalkar, Anton M. Sholukh, Christine Johnston, David A. Leib, Margaret E. Ackerman
Herpes simplex virus (HSV) encodes surface glycoproteins that are host defense evasion molecules. For example, glycoproteins E and I (gE/gI) form a viral Fc receptor (vFcR) for most subclasses and allotypes of human IgG, promoting evasion of humoral immune responses. Although monoclonal antibodies (mAbs) protect mice from neonatal HSV (nHSV) infections, the impact of vFcR activity on mAb-mediated protection is unknown. Using HSV-1 with intact and ablated gE-mediated Fc binding, as well as Fc-engineered mAbs with modified ability to interact with gE/gI, we investigated the role of the vFcR in mAb-mediated protection from nHSV. HSV-specific mAbs modified to lack binding to gE exhibited enhanced neutralization in vitro and superior protection in vivo compared with their native IgG1 forms. Improved protection was dependent on the presence of vFcR activity and was observed for mAbs specific for both glycoprotein D and glycoprotein B, as well as for a nonneutralizing mAb, and for both laboratory-adapted and clinical isolates of HSV-1 and HSV-2. Further, human IgG3 allotypes, including those lacking vFcR binding, also exhibited enhanced antiviral activity in vivo, identifying a unique viral susceptibility to this subclass. In summary, this study demonstrates that rendering mAbs insensitive to the vFcR can improve protection against HSV, offering prospects for antibody-based interventions.
{"title":"Eliminating interactions with the viral Fc receptor improves antibody-mediated protection against neonatal HSV infection in mice","authors":"Matthew D. Slein, Iara M. Backes, Lesle M. Jiménez, Natasha S. Kelkar, Callaghan R. Garland, Urjeet S. Khanwalkar, Anton M. Sholukh, Christine Johnston, David A. Leib, Margaret E. Ackerman","doi":"10.1126/scitranslmed.adu8579","DOIUrl":"10.1126/scitranslmed.adu8579","url":null,"abstract":"<div >Herpes simplex virus (HSV) encodes surface glycoproteins that are host defense evasion molecules. For example, glycoproteins E and I (gE/gI) form a viral Fc receptor (vFcR) for most subclasses and allotypes of human IgG, promoting evasion of humoral immune responses. Although monoclonal antibodies (mAbs) protect mice from neonatal HSV (nHSV) infections, the impact of vFcR activity on mAb-mediated protection is unknown. Using HSV-1 with intact and ablated gE-mediated Fc binding, as well as Fc-engineered mAbs with modified ability to interact with gE/gI, we investigated the role of the vFcR in mAb-mediated protection from nHSV. HSV-specific mAbs modified to lack binding to gE exhibited enhanced neutralization in vitro and superior protection in vivo compared with their native IgG1 forms. Improved protection was dependent on the presence of vFcR activity and was observed for mAbs specific for both glycoprotein D and glycoprotein B, as well as for a nonneutralizing mAb, and for both laboratory-adapted and clinical isolates of HSV-1 and HSV-2. Further, human IgG3 allotypes, including those lacking vFcR binding, also exhibited enhanced antiviral activity in vivo, identifying a unique viral susceptibility to this subclass. In summary, this study demonstrates that rendering mAbs insensitive to the vFcR can improve protection against HSV, offering prospects for antibody-based interventions.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 825","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545440","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}
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