Pub Date : 2026-01-14DOI: 10.1126/scitranslmed.adr1557
Holly Holliday, Aaminah Khan, Anahid Ehteda, Hieu Nguyen, Samuel E. Ross, Nisitha Jayatilleke, Anjana Gopalakrishnan, Eyden Wang, Yolanda Colino Sanguino, Daisy Kavanagh, Xinyi Guo, Jie Liu, David Lawrence, Claire X. Sun, Rebecca Lehmann, Chi Kin Ip, Alvin Lee, Laura Rangel-Sanchez, Wenyan Li, Robert Salomon, Ron Firestein, Robert J. Weatheritt, Fatima Valdes-Mora, Marcel E. Dinger, Timothy N. Phoenix, Chelsea Mayoh, Benjamin S. Rayner, Maria Tsoli, David S. Ziegler
Aberrant epigenetic regulation is a hallmark of diffuse midline glioma (DMG), an incurable pediatric brain tumor. The H3K27M driver histone mutation leads to transcriptional dysregulation, indicating that targeting the epigenome and transcription may be key therapeutic strategies against this highly aggressive cancer. One such target is the facilitates chromatin transcription (FACT) histone chaperone. We found FACT to be enriched at developmental gene promoters, coinciding with open chromatin and binding motifs of core DMG regulatory transcription factors. Furthermore, FACT co-occurred with the bromodomain and extraterminal domain (BET) protein BRD4 at promoters and enhancers, suggesting functional cooperation between FACT and BRD4 in DMG. In vitro, a combinatorial therapeutic approach using the FACT inhibitor CBL0137, coupled with BET inhibition, revealed potent and synergistic cytotoxicity across a range of DMG cultures. These results were recapitulated in vivo, extending survival in three independent orthotopic patient–derived xenograft models of DMG. Mechanistically, we show that CBL0137 treatment decreased chromatin accessibility and combined with BET inhibition to cause broad transcriptional collapse; silencing of several key oncogenes including MYC, PDGFRA, MDM4, and SOX2; and alterations to the splicing landscape. This combination also elicited immune-related effects, including activation of the interferon response and antigen presentation mechanisms in DMG cells and induction of an activated state in macrophages and T cells, as demonstrated in an immunocompetent setting with spatial transcriptomics. Together, our data highlight the therapeutic promise of simultaneously targeting FACT and BET proteins in DMG, offering a dual tumor–intrinsic and immune-mediated strategy for combating this devastating pediatric brain tumor.
{"title":"Combined inhibition of FACT and BET disrupts transcription to suppress tumor growth in mouse models of diffuse midline glioma","authors":"Holly Holliday, Aaminah Khan, Anahid Ehteda, Hieu Nguyen, Samuel E. Ross, Nisitha Jayatilleke, Anjana Gopalakrishnan, Eyden Wang, Yolanda Colino Sanguino, Daisy Kavanagh, Xinyi Guo, Jie Liu, David Lawrence, Claire X. Sun, Rebecca Lehmann, Chi Kin Ip, Alvin Lee, Laura Rangel-Sanchez, Wenyan Li, Robert Salomon, Ron Firestein, Robert J. Weatheritt, Fatima Valdes-Mora, Marcel E. Dinger, Timothy N. Phoenix, Chelsea Mayoh, Benjamin S. Rayner, Maria Tsoli, David S. Ziegler","doi":"10.1126/scitranslmed.adr1557","DOIUrl":"10.1126/scitranslmed.adr1557","url":null,"abstract":"<div >Aberrant epigenetic regulation is a hallmark of diffuse midline glioma (DMG), an incurable pediatric brain tumor. The H3K27M driver histone mutation leads to transcriptional dysregulation, indicating that targeting the epigenome and transcription may be key therapeutic strategies against this highly aggressive cancer. One such target is the facilitates chromatin transcription (FACT) histone chaperone. We found FACT to be enriched at developmental gene promoters, coinciding with open chromatin and binding motifs of core DMG regulatory transcription factors. Furthermore, FACT co-occurred with the bromodomain and extraterminal domain (BET) protein BRD4 at promoters and enhancers, suggesting functional cooperation between FACT and BRD4 in DMG. In vitro, a combinatorial therapeutic approach using the FACT inhibitor CBL0137, coupled with BET inhibition, revealed potent and synergistic cytotoxicity across a range of DMG cultures. These results were recapitulated in vivo, extending survival in three independent orthotopic patient–derived xenograft models of DMG. Mechanistically, we show that CBL0137 treatment decreased chromatin accessibility and combined with BET inhibition to cause broad transcriptional collapse; silencing of several key oncogenes including <i>MYC</i>, <i>PDGFRA</i>, <i>MDM4</i>, and <i>SOX2</i>; and alterations to the splicing landscape. This combination also elicited immune-related effects, including activation of the interferon response and antigen presentation mechanisms in DMG cells and induction of an activated state in macrophages and T cells, as demonstrated in an immunocompetent setting with spatial transcriptomics. Together, our data highlight the therapeutic promise of simultaneously targeting FACT and BET proteins in DMG, offering a dual tumor–intrinsic and immune-mediated strategy for combating this devastating pediatric brain tumor.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 832","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145964516","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 : 2026-01-07DOI: 10.1126/scitranslmed.aea0947
Nina Pennetzdorfer, Vidula Naik, Sally Demirdjian, Matthew R. Hendricks, Cooper S. Jamieson, Jason K. Perry, Laurie A. VanderVeen, Stephen R. Yant, Hadas Dvory-Sobol, Onyema Ogbuagu, Samir K. Gupta, Nicolas A. Margot, Christian Callebaut
Lenacapavir (LEN) is a long-acting HIV-1 capsid inhibitor that binds to the HIV-1 capsid protein with picomolar antiviral activity, disrupting its function and inhibiting viral replication. Here, we identified capsid mutations in samples from individuals treated with LEN across two clinical trials that were considered potential LEN resistance–associated mutations. The gag encoding regions of clinical isolates with capsid mutations, as well as associated site-directed mutants, were cloned into the infectious molecular clone pXXLAI and pNL4-3-JRFL-secNLuc, encoding replication-competent HIV-1. Their effects on LEN susceptibility, replication kinetics, and three-dimensional capsid structure were investigated. Phenotypic analyses of the HIV-1 clinical isolates and site-directed mutants revealed that all resistance-associated mutations decreased LEN susceptibility to various degrees but were frequently associated with substantial replication defects. Structural modeling confirmed that LEN binding in the binding pocket was altered in the presence of capsid mutations, with predicted binding affinity changes correlating with observed potency shifts. These findings provide insights into LEN-resistance mechanisms and underscore the unusually high fitness costs associated with treatment-emergent capsid mutations.
{"title":"Lenacapavir treatment–emergent HIV-1 capsid resistance mutations are frequently associated with replication defects","authors":"Nina Pennetzdorfer, Vidula Naik, Sally Demirdjian, Matthew R. Hendricks, Cooper S. Jamieson, Jason K. Perry, Laurie A. VanderVeen, Stephen R. Yant, Hadas Dvory-Sobol, Onyema Ogbuagu, Samir K. Gupta, Nicolas A. Margot, Christian Callebaut","doi":"10.1126/scitranslmed.aea0947","DOIUrl":"10.1126/scitranslmed.aea0947","url":null,"abstract":"<div >Lenacapavir (LEN) is a long-acting HIV-1 capsid inhibitor that binds to the HIV-1 capsid protein with picomolar antiviral activity, disrupting its function and inhibiting viral replication. Here, we identified capsid mutations in samples from individuals treated with LEN across two clinical trials that were considered potential LEN resistance–associated mutations. The <i>gag</i> encoding regions of clinical isolates with capsid mutations, as well as associated site-directed mutants, were cloned into the infectious molecular clone pXXLAI and pNL4-3-JRFL-secNLuc, encoding replication-competent HIV-1. Their effects on LEN susceptibility, replication kinetics, and three-dimensional capsid structure were investigated. Phenotypic analyses of the HIV-1 clinical isolates and site-directed mutants revealed that all resistance-associated mutations decreased LEN susceptibility to various degrees but were frequently associated with substantial replication defects. Structural modeling confirmed that LEN binding in the binding pocket was altered in the presence of capsid mutations, with predicted binding affinity changes correlating with observed potency shifts. These findings provide insights into LEN-resistance mechanisms and underscore the unusually high fitness costs associated with treatment-emergent capsid mutations.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 831","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908260","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 : 2026-01-07DOI: 10.1126/scitranslmed.aee4960
{"title":"Erratum for Research Article \"Cellular senescence inhibits renal regeneration after injury in mice, with senolytic treatment promoting repair\" by K. Mylonas et al.","authors":"","doi":"10.1126/scitranslmed.aee4960","DOIUrl":"10.1126/scitranslmed.aee4960","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 831","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145909379","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 : 2026-01-07DOI: 10.1126/scitranslmed.ado9383
Talia Greenstein, Laura E. Via, Mariana Pereira Moraes, Danielle M. Weiner, Emmanuel K. Dayao, April M. Walker, Ayan Abdi, Joel D. Fleegle, Felipe Gomez, Katelyn M. Repoli, Michael J. Woodcock, Helena I. M. Boshoff, Oluwaseun Egbelowo, Kamunkhwala Gausi, Paolo Denti, Firat Kaya, Matthew Zimmerman, Eric L. Miller, Véronique A. Dartois, Clifton E. Barry III, Bree B. Aldridge
Early bactericidal activity and time to sputum conversion are well-established study end points in both preclinical animal models and clinical trials for testing drug regimens for pulmonary tuberculosis (TB). The development and optimization of treatment-shortening drug regimens for TB have been challenged by disparities between these study end points and nonrelapsing cure. We hypothesized that using lung lesions measured by 2-deoxy-2-[18F]fluoro-d-glucose–positron emission tomography/computed tomography (PET/CT) imaging in infected marmosets could help to interpret treatment efficacies and better understand clinical treatment outcomes. Radiographic changes in lung lesions were measured using PET/CT imaging in a cohort of infected marmosets, which were divided into 22 treatment arms (including monotherapies and combination drug treatments) for 2 months. We used unsupervised clustering to define multivariate treatment response profiles that combined quantitative changes in radiographic pathology and terminal bacterial burden per lung lesion to inform lesion-level responses to drug treatments. These drug response profiles not only aligned with known clinical outcomes but also provided lesion-level insights into clinical successes and failures. We found that the inferiority of the 4-month moxifloxacin-rifampicin-pyrazinamide-ethambutol regimen compared with the 6-month standard of care for individuals with lung cavitary TB could be predicted. The marmoset response profiles were matched to their respective histopathological classifications at necropsy and successfully distinguished cavitary granulomas that responded to treatment from cavitary granulomas that failed to improve or worsened after the first month of treatment. Our findings indicate that a combination of quantitative PET/CT measures is more informative of TB treatment outcomes than bacterial burden.
{"title":"PET/CT imaging of tuberculosis lung lesions in marmosets treated with different drug regimens aligns with human clinical outcomes","authors":"Talia Greenstein, Laura E. Via, Mariana Pereira Moraes, Danielle M. Weiner, Emmanuel K. Dayao, April M. Walker, Ayan Abdi, Joel D. Fleegle, Felipe Gomez, Katelyn M. Repoli, Michael J. Woodcock, Helena I. M. Boshoff, Oluwaseun Egbelowo, Kamunkhwala Gausi, Paolo Denti, Firat Kaya, Matthew Zimmerman, Eric L. Miller, Véronique A. Dartois, Clifton E. Barry III, Bree B. Aldridge","doi":"10.1126/scitranslmed.ado9383","DOIUrl":"10.1126/scitranslmed.ado9383","url":null,"abstract":"<div >Early bactericidal activity and time to sputum conversion are well-established study end points in both preclinical animal models and clinical trials for testing drug regimens for pulmonary tuberculosis (TB). The development and optimization of treatment-shortening drug regimens for TB have been challenged by disparities between these study end points and nonrelapsing cure. We hypothesized that using lung lesions measured by 2-deoxy-2-[<sup>18</sup>F]fluoro-<span>d</span>-glucose–positron emission tomography/computed tomography (PET/CT) imaging in infected marmosets could help to interpret treatment efficacies and better understand clinical treatment outcomes. Radiographic changes in lung lesions were measured using PET/CT imaging in a cohort of infected marmosets, which were divided into 22 treatment arms (including monotherapies and combination drug treatments) for 2 months. We used unsupervised clustering to define multivariate treatment response profiles that combined quantitative changes in radiographic pathology and terminal bacterial burden per lung lesion to inform lesion-level responses to drug treatments. These drug response profiles not only aligned with known clinical outcomes but also provided lesion-level insights into clinical successes and failures. We found that the inferiority of the 4-month moxifloxacin-rifampicin-pyrazinamide-ethambutol regimen compared with the 6-month standard of care for individuals with lung cavitary TB could be predicted. The marmoset response profiles were matched to their respective histopathological classifications at necropsy and successfully distinguished cavitary granulomas that responded to treatment from cavitary granulomas that failed to improve or worsened after the first month of treatment. Our findings indicate that a combination of quantitative PET/CT measures is more informative of TB treatment outcomes than bacterial burden.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 831","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908262","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 : 2026-01-07DOI: 10.1126/scitranslmed.adt5626
Stephanus T. Malherbe, Ray Y. Chen, Xiang Yu, Bronwyn Smith, Xin Liu, Jingcai Gao, Andreas H. Diacon, Rodney Dawson, Michele Tameris, Hong Zhu, Yahong Qu, Hongjian Jin, Shouguo Pan, Lori E. Dodd, Jing Wang, Lisa C. Goldfeder, Ying Cai, Kriti Arora, Joel Vincent, Kim Narunsky, Keboile Serole, Rene T. Goliath, Laylah Da Costa, Arshad Taliep, Saalikha Aziz, Remy Daroowala, Friedrich Thienemann, Sandra Mukasa, Richard Court, Bianca Sossen, Petri Ahlers, Simon C. Mendelsohn, Lisa White, Aurélie Gouel, Chuen-Yen Lau, Samy Hassan, Lili Liang, Hongfei Duan, Gita K. Moghaddam, Praveen Paripati, Saher Lahouar, Michael Harris, Kurt Wollenberg, Brendan Jeffrey, Mike Tartakovsky, Alex Rosenthal, Michael Duvenhage, Derek T. Armstrong, Taeksun Song, Jill Winter, Qian Gao, Laura E. Via, Robert J. Wilkinson, Gerhard Walzl, Clifton E. Barry III
Six months of drug treatment is standard of care for drug-sensitive pulmonary tuberculosis (TB). Understanding the factors determining the length of treatment required for durable cure would allow individualization of treatment durations. We conducted a prospective, randomized, controlled noninferiority trial (PredictTB) of 4 versus 6 months of chemotherapy in patients with pulmonary TB in South Africa and China. Seven hundred and four participants with newly diagnosed, drug-sensitive TB were enrolled and stratified on the basis of radiographic disease characteristics assessed by FDG PET/CT imaging. Participants with less extensive disease (n = 273) were randomly assigned at week 16 to complete therapy after 4 months or continue receiving treatment for 6 months. This study was stopped early after an interim analysis revealed that patients assigned to the 4-month treatment arm had a higher risk of relapse. Among participants who received 4 months of chemotherapy, 17 of 141 (12.1%) experienced TB-specific unfavorable outcomes compared with only 2 of 132 (1.5%) who completed 6 months of treatment. In the nonrandomized arm that included participants with more extensive disease, only 8 of 248 (3.2%) experienced unfavorable outcomes. Total lung cavity volume and lesion glycolysis at week 16 were associated with the risk of unfavorable outcomes. PET/CT imaging at TB recurrence showed that bacteriological relapses predominantly occurred in active cavities originally present at baseline. Subsequent post hoc automated segmentation of serial PET/CT scans combined with machine learning enabled the classification of participants according to their likelihood of relapse.
{"title":"Clinical testing of drug treatment shortening in patients with TB using PET/CT imaging of lung lesions","authors":"Stephanus T. Malherbe, Ray Y. Chen, Xiang Yu, Bronwyn Smith, Xin Liu, Jingcai Gao, Andreas H. Diacon, Rodney Dawson, Michele Tameris, Hong Zhu, Yahong Qu, Hongjian Jin, Shouguo Pan, Lori E. Dodd, Jing Wang, Lisa C. Goldfeder, Ying Cai, Kriti Arora, Joel Vincent, Kim Narunsky, Keboile Serole, Rene T. Goliath, Laylah Da Costa, Arshad Taliep, Saalikha Aziz, Remy Daroowala, Friedrich Thienemann, Sandra Mukasa, Richard Court, Bianca Sossen, Petri Ahlers, Simon C. Mendelsohn, Lisa White, Aurélie Gouel, Chuen-Yen Lau, Samy Hassan, Lili Liang, Hongfei Duan, Gita K. Moghaddam, Praveen Paripati, Saher Lahouar, Michael Harris, Kurt Wollenberg, Brendan Jeffrey, Mike Tartakovsky, Alex Rosenthal, Michael Duvenhage, Derek T. Armstrong, Taeksun Song, Jill Winter, Qian Gao, Laura E. Via, Robert J. Wilkinson, Gerhard Walzl, Clifton E. Barry III","doi":"10.1126/scitranslmed.adt5626","DOIUrl":"10.1126/scitranslmed.adt5626","url":null,"abstract":"<div >Six months of drug treatment is standard of care for drug-sensitive pulmonary tuberculosis (TB). Understanding the factors determining the length of treatment required for durable cure would allow individualization of treatment durations. We conducted a prospective, randomized, controlled noninferiority trial (PredictTB) of 4 versus 6 months of chemotherapy in patients with pulmonary TB in South Africa and China. Seven hundred and four participants with newly diagnosed, drug-sensitive TB were enrolled and stratified on the basis of radiographic disease characteristics assessed by FDG PET/CT imaging. Participants with less extensive disease (<i>n</i> = 273) were randomly assigned at week 16 to complete therapy after 4 months or continue receiving treatment for 6 months. This study was stopped early after an interim analysis revealed that patients assigned to the 4-month treatment arm had a higher risk of relapse. Among participants who received 4 months of chemotherapy, 17 of 141 (12.1%) experienced TB-specific unfavorable outcomes compared with only 2 of 132 (1.5%) who completed 6 months of treatment. In the nonrandomized arm that included participants with more extensive disease, only 8 of 248 (3.2%) experienced unfavorable outcomes. Total lung cavity volume and lesion glycolysis at week 16 were associated with the risk of unfavorable outcomes. PET/CT imaging at TB recurrence showed that bacteriological relapses predominantly occurred in active cavities originally present at baseline. Subsequent post hoc automated segmentation of serial PET/CT scans combined with machine learning enabled the classification of participants according to their likelihood of relapse.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 831","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908258","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 : 2026-01-07DOI: 10.1126/scitranslmed.adw9930
Yuri Ciervo, Pietro Rigoni, Linda Bucciarelli, Martina Lombi, Federico Pratesi, Nadia Bologna, Massimo Accardo, Chiara Recchi, Rita Milazzo, Valentina Poletti, Alessandra Biffi
Autologous hematopoietic stem/progenitor cell (HSC)–gene therapy (GT) represents a promising therapeutic option for progranulin (PGRN)–related neurodegenerative diseases due to mutations in the PGRN encoding gene (GRN), such as frontotemporal dementia (FTD) and neuronal ceroid lipofuscinosis 11 (CLN11). These conditions are characterized by a deficiency in PGRN, have no cure, and represent an unmet medical need. We report on the efficacy and feasibility of an HSC GT approach that used a lentiviral vector encoding the human GRN complementary DNA to transduce HSCs that then were transplanted into a Grn−/− mouse model, which mirrors both FTD and CLN11 phenotypes. Two promoters, one with medium-low strength (HLA-DRA gene–based promoter regulated by inflammation) and the other with medium-high strength [ubiquitous phosphoglycerate kinase (PGK) promoter], were compared for HSC transduction. Moreover, intravenous and intracerebroventricular HSC administration were compared. Under all tested conditions, a partial reconstitution of PGRN production by microglia-like cells (MLCs) derived from genetically corrected Grn−/− HSCs was observed, which uniformly led to a correction of lipid accumulation, reduced gliosis, and improved social recognition in Grn−/− mice. Therapeutic effects were similarly achieved with either of the promoters and administration routes and particularly also when the PGRN-expressing cells and their MLC progeny had engrafted exclusively in the central nervous system (CNS) after intracerebroventricular transplantation. These findings suggest that a durable yet modest restoration of PGRN expression in the CNS is sufficient to correct pathology.
{"title":"Restoration of progranulin by engineered hematopoietic stem cell–derived microglia corrects phenotypes of granulin knockout mice","authors":"Yuri Ciervo, Pietro Rigoni, Linda Bucciarelli, Martina Lombi, Federico Pratesi, Nadia Bologna, Massimo Accardo, Chiara Recchi, Rita Milazzo, Valentina Poletti, Alessandra Biffi","doi":"10.1126/scitranslmed.adw9930","DOIUrl":"10.1126/scitranslmed.adw9930","url":null,"abstract":"<div >Autologous hematopoietic stem/progenitor cell (HSC)–gene therapy (GT) represents a promising therapeutic option for progranulin (PGRN)–related neurodegenerative diseases due to mutations in the PGRN encoding gene (<i>GRN</i>), such as frontotemporal dementia (FTD) and neuronal ceroid lipofuscinosis 11 (CLN11). These conditions are characterized by a deficiency in PGRN, have no cure, and represent an unmet medical need. We report on the efficacy and feasibility of an HSC GT approach that used a lentiviral vector encoding the human <i>GRN</i> complementary DNA to transduce HSCs that then were transplanted into a <i>Grn</i><sup>−/−</sup> mouse model, which mirrors both FTD and CLN11 phenotypes. Two promoters, one with medium-low strength (<i>HLA-DRA</i> gene–based promoter regulated by inflammation) and the other with medium-high strength [ubiquitous phosphoglycerate kinase (PGK) promoter], were compared for HSC transduction. Moreover, intravenous and intracerebroventricular HSC administration were compared. Under all tested conditions, a partial reconstitution of PGRN production by microglia-like cells (MLCs) derived from genetically corrected <i>Grn</i><sup>−/−</sup> HSCs was observed, which uniformly led to a correction of lipid accumulation, reduced gliosis, and improved social recognition in <i>Grn</i><sup>−/−</sup> mice. Therapeutic effects were similarly achieved with either of the promoters and administration routes and particularly also when the PGRN-expressing cells and their MLC progeny had engrafted exclusively in the central nervous system (CNS) after intracerebroventricular transplantation. These findings suggest that a durable yet modest restoration of PGRN expression in the CNS is sufficient to correct pathology.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 831","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908259","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 : 2026-01-07DOI: 10.1126/scitranslmed.adt1228
Greta Moschini, Archana G. Mohanan, Izabella S. Niewczas, Diane E. Taylor, Patrick K. Jaeger, Guillermo Turiel, Amro A. Hussien, Stefania L. Wunderli, Olivia Baumberger, Maja Wolleb, Florence Marti, Barbara Niederoest, Maja Bollhalder, Raphaela Ardicoglu, Nathalie Tisch, Evi Masschelein, Shauni Loopmans, Sarah Morice, Santiago Ardiles, Lieke Mous, Bart Ghesquière, Matthew R. Aronoff, Monika Hilbe, Farah Selman, Karl Wieser, Sandro F. Fucentese, Fabian S. Passini, Ulrich Blache, Didier Surdez, Helma Wennemers, Dirk Elewaut, Jonathan Clark, Katrien De Bock, Jess G. Snedeker
Tendons are sparsely vascularized connective tissues that link muscles to bones, withstanding some of the highest mechanical stresses in the body. Mechanical overloading and tissue hypervascularity are implicated in tendinopathy, a common musculoskeletal disorder, yet their mechanistic roles remain unclear. Here, we identify hypoxia-inducible factor 1α (HIF1α) as not only a marker but also a driver of tendinopathy. Histological and multiomics evaluation of human tendinopathic samples revealed extensive extracellular matrix remodeling, including pathological collagen cross-linking coinciding with active hypoxic signaling. Hypothesizing a causal contribution of hypoxia signaling, we generated mice with tenocyte-targeted deletions of the von Hippel–Lindau (Vhl) gene, which controls hypoxia signaling by regulating HIFα degradation. Vhl inactivation was sufficient to induce pathological hallmarks of tendinopathy, such as collagen matrix disorganization, cross-linking, altered mechanics, and neurovascular ingrowth. This phenotype was HIF1α dependent given that codeleting HIF1α rescued tendon morphology and mechanics. Moreover, deleting vascular endothelial growth factor A (Vegfa) alongside VHL effectively suppressed neovascularization but failed to rescue extracellular matrix abnormalities or restore mechanical function, emphasizing a direct role of HIF1α in driving tendon disease independently of angiogenesis. Mechanistically, we found that HIF1α activation was strain dependent in primary cultured human tendon cells and induced by mechanical overload in murine tendon explants. Furthermore, genetically removing Hif1α from tenocytes prevented aberrant tendon remodeling in response to chronic overload. These findings position HIF1α signaling as a central driver of tendinopathy that acts through a maladaptive tissue response to chronic overload, providing mechanistic insights that could be leveraged for therapeutic approaches.
{"title":"HIF1α gates tendon response to overload and drives tendinopathy independently of vascular recruitment","authors":"Greta Moschini, Archana G. Mohanan, Izabella S. Niewczas, Diane E. Taylor, Patrick K. Jaeger, Guillermo Turiel, Amro A. Hussien, Stefania L. Wunderli, Olivia Baumberger, Maja Wolleb, Florence Marti, Barbara Niederoest, Maja Bollhalder, Raphaela Ardicoglu, Nathalie Tisch, Evi Masschelein, Shauni Loopmans, Sarah Morice, Santiago Ardiles, Lieke Mous, Bart Ghesquière, Matthew R. Aronoff, Monika Hilbe, Farah Selman, Karl Wieser, Sandro F. Fucentese, Fabian S. Passini, Ulrich Blache, Didier Surdez, Helma Wennemers, Dirk Elewaut, Jonathan Clark, Katrien De Bock, Jess G. Snedeker","doi":"10.1126/scitranslmed.adt1228","DOIUrl":"10.1126/scitranslmed.adt1228","url":null,"abstract":"<div >Tendons are sparsely vascularized connective tissues that link muscles to bones, withstanding some of the highest mechanical stresses in the body. Mechanical overloading and tissue hypervascularity are implicated in tendinopathy, a common musculoskeletal disorder, yet their mechanistic roles remain unclear. Here, we identify hypoxia-inducible factor 1α (HIF1α) as not only a marker but also a driver of tendinopathy. Histological and multiomics evaluation of human tendinopathic samples revealed extensive extracellular matrix remodeling, including pathological collagen cross-linking coinciding with active hypoxic signaling. Hypothesizing a causal contribution of hypoxia signaling, we generated mice with tenocyte-targeted deletions of the von Hippel–Lindau (<i>Vhl</i>) gene, which controls hypoxia signaling by regulating HIFα degradation. <i>Vhl</i> inactivation was sufficient to induce pathological hallmarks of tendinopathy, such as collagen matrix disorganization, cross-linking, altered mechanics, and neurovascular ingrowth. This phenotype was HIF1α dependent given that codeleting HIF1α rescued tendon morphology and mechanics. Moreover, deleting vascular endothelial growth factor A (<i>Vegfa</i>) alongside VHL effectively suppressed neovascularization but failed to rescue extracellular matrix abnormalities or restore mechanical function, emphasizing a direct role of HIF1α in driving tendon disease independently of angiogenesis. Mechanistically, we found that HIF1α activation was strain dependent in primary cultured human tendon cells and induced by mechanical overload in murine tendon explants. Furthermore, genetically removing <i>Hif1</i>α from tenocytes prevented aberrant tendon remodeling in response to chronic overload. These findings position HIF1α signaling as a central driver of tendinopathy that acts through a maladaptive tissue response to chronic overload, providing mechanistic insights that could be leveraged for therapeutic approaches.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 831","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908261","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 : 2026-01-07DOI: 10.1126/scitranslmed.adx2876
Felix Polten, Mircea-Andrei Sandu, Jan Faix, Jan Hegermann, Nils Kriedemann, Robert Zweigerdt, Thomas Thum, Johann Bauersachs, Hans W. Niessen, Andrew L. Koenig, Kory J. Lavine, Andreas Pich, Yong Wang, Marc R. Reboll, Mortimer Korf-Klingebiel, Kai C. Wollert
Tissue repair after myocardial infarction entails a vigorous angiogenic response that mitigates scarring and worsening of heart function. Angiogenesis in the infarct wound is guided by incompletely defined myeloid cell–endothelial cell interactions. Here, we identify the 75–amino acid microprotein BRICK1 (BRK1) as an indispensable driver of postinfarction angiogenesis in a mouse model of reperfused myocardial infarction. We show that BRK1 is preferentially expressed by myeloid cells and translocates to the extracellular space after myocardial infarction in mice and humans. As a subunit of the intracellular actin-regulatory WAVE complex, BRK1 was not previously known to function outside the cell. We find that BRK1 is not actively secreted but released during myeloid cell death. Cre-loxP–driven myeloid cell–selective genetic deletion of Brk1 or antibody-mediated neutralization of extracellular BRK1 impaired microvessel formation in the infarct border zone and resulted in severe postinfarction heart failure in mice. Conversely, treatment with recombinant BRK1 preserved heart function in infarcted mice. Mechanistically, BRK1 induced an angiogenic phenotype in human cardiac endothelial cells by signaling via the small GTPase Ras-related protein Rap-1 and mitogen-activated protein kinases 1 and 3 to promote retinoblastoma protein hyperphosphorylation and E2F transcription factor activation. BRK1 thus emerges as an angiogenic factor linking myeloid cell death to ischemic tissue repair, potentially enabling a protein-based therapy for myocardial infarction.
{"title":"Extracellular BRICK1 drives heart repair after myocardial infarction in mice","authors":"Felix Polten, Mircea-Andrei Sandu, Jan Faix, Jan Hegermann, Nils Kriedemann, Robert Zweigerdt, Thomas Thum, Johann Bauersachs, Hans W. Niessen, Andrew L. Koenig, Kory J. Lavine, Andreas Pich, Yong Wang, Marc R. Reboll, Mortimer Korf-Klingebiel, Kai C. Wollert","doi":"10.1126/scitranslmed.adx2876","DOIUrl":"10.1126/scitranslmed.adx2876","url":null,"abstract":"<div >Tissue repair after myocardial infarction entails a vigorous angiogenic response that mitigates scarring and worsening of heart function. Angiogenesis in the infarct wound is guided by incompletely defined myeloid cell–endothelial cell interactions. Here, we identify the 75–amino acid microprotein BRICK1 (BRK1) as an indispensable driver of postinfarction angiogenesis in a mouse model of reperfused myocardial infarction. We show that BRK1 is preferentially expressed by myeloid cells and translocates to the extracellular space after myocardial infarction in mice and humans. As a subunit of the intracellular actin-regulatory WAVE complex, BRK1 was not previously known to function outside the cell. We find that BRK1 is not actively secreted but released during myeloid cell death. Cre-<i>loxP</i>–driven myeloid cell–selective genetic deletion of <i>Brk1</i> or antibody-mediated neutralization of extracellular BRK1 impaired microvessel formation in the infarct border zone and resulted in severe postinfarction heart failure in mice. Conversely, treatment with recombinant BRK1 preserved heart function in infarcted mice. Mechanistically, BRK1 induced an angiogenic phenotype in human cardiac endothelial cells by signaling via the small GTPase Ras-related protein Rap-1 and mitogen-activated protein kinases 1 and 3 to promote retinoblastoma protein hyperphosphorylation and E2F transcription factor activation. BRK1 thus emerges as an angiogenic factor linking myeloid cell death to ischemic tissue repair, potentially enabling a protein-based therapy for myocardial infarction.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 831","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908263","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 : 2026-01-07DOI: 10.1126/scitranslmed.aed6475
Manish C. Choudhary, Jonathan Z. Li
HIV can take several mutational pathways to become resistant to lenacapavir, each with distinct resistance and fitness profiles (Pennetzdorfer et al., this issue).
{"title":"When HIV pays the price: Fitness costs behind lenacapavir resistance","authors":"Manish C. Choudhary, Jonathan Z. Li","doi":"10.1126/scitranslmed.aed6475","DOIUrl":"10.1126/scitranslmed.aed6475","url":null,"abstract":"<div >HIV can take several mutational pathways to become resistant to lenacapavir, each with distinct resistance and fitness profiles (Pennetzdorfer <i>et al.</i>, this issue).</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 831","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908257","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}
Brain stimulation therapies have been increasingly applied to treat patients with drug-resistant epilepsy or other neuropsychiatric disorders, but identifying effective stimulation targets appropriate for individual patients remains challenging. Using intracranial electrophysiological recordings, we found that fast ripple (FR) activity was tightly correlated with the severity of consciousness impairment during seizures in patients with drug-resistant, consciousness-staged epilepsy. Epileptic network analysis based on FR coincidence across brain regions revealed hubs of ictal FR activity, defined as highly connected nodes, specific to individual patients. A small, exploratory study on eight patients with drug-resistant epilepsy showed that stimulating these hubs reduced FRs, ameliorated consciousness impairments, and reduced seizures during a poststimulation time window of up to 11 days. Moreover, FR hub stimulation showed a lower risk of evoking seizures than stimulating seizure onset zones, a now approved treatment option. These results suggest a potentially safe and effective strategy to alleviate epileptic seizures by stimulating patient-specific FR network hubs.
{"title":"Targeting brain hubs of ictal fast ripple activity to reduce seizures in patients with drug-resistant epilepsy","authors":"Shanshan Liang, Lukang Wang, Kaifeng Shen, Zhiji Wang, Xin Zheng, Qingtian Duan, Xianjun Shi, Lei Zhang, Yang Dai, Yuanxi Zou, Jing Deng, Xinyue Zhang, Hongbo Jia, Shiyong Liu, Hui Yang, Ying Mao, Xiang Liao, Chunqing Zhang, Xiaowei Chen","doi":"10.1126/scitranslmed.adq4423","DOIUrl":"10.1126/scitranslmed.adq4423","url":null,"abstract":"<div >Brain stimulation therapies have been increasingly applied to treat patients with drug-resistant epilepsy or other neuropsychiatric disorders, but identifying effective stimulation targets appropriate for individual patients remains challenging. Using intracranial electrophysiological recordings, we found that fast ripple (FR) activity was tightly correlated with the severity of consciousness impairment during seizures in patients with drug-resistant, consciousness-staged epilepsy. Epileptic network analysis based on FR coincidence across brain regions revealed hubs of ictal FR activity, defined as highly connected nodes, specific to individual patients. A small, exploratory study on eight patients with drug-resistant epilepsy showed that stimulating these hubs reduced FRs, ameliorated consciousness impairments, and reduced seizures during a poststimulation time window of up to 11 days. Moreover, FR hub stimulation showed a lower risk of evoking seizures than stimulating seizure onset zones, a now approved treatment option. These results suggest a potentially safe and effective strategy to alleviate epileptic seizures by stimulating patient-specific FR network hubs.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 830","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813644","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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