Science Translational Medicine最新文献

{"title":"Targeting RBPMS selectively eliminates FOXO1-mediated stem cell signatures in mouse models of acute myeloid leukemia","authors":"Ping Liu,&nbsp;Sulin Zhang,&nbsp;Bing-Yi Chen,&nbsp;Binhe Chang,&nbsp;Yilun Jiang,&nbsp;Xiya Li,&nbsp;Xinchi Chen,&nbsp;Zi-juan Li,&nbsp;Ruirui Yang,&nbsp;Xiaoning Wang,&nbsp;Chun-Hui Xu,&nbsp;Xiaomeng Liu,&nbsp;Na Liu,&nbsp;Yuanyuan Jia,&nbsp;Peng-Cheng Yu,&nbsp;Yong Wang,&nbsp;Li-juan Zong,&nbsp;Cheng-Long Hu,&nbsp;Hui Hou,&nbsp;Duanhua Cao,&nbsp;Xutong Li,&nbsp;Chu-Han Deng,&nbsp;Yi-Yi Ren,&nbsp;Mu-ying Zhao,&nbsp;Xinyi Ma,&nbsp;Rongrong Cui,&nbsp;Dan Teng,&nbsp;Miao Chen,&nbsp;Roujia Wang,&nbsp;Jiacheng Jin,&nbsp;Shi-yu Jiang,&nbsp;Xiaojing Yan,&nbsp;Kai Xue,&nbsp;Qunling Zhang,&nbsp;Jianfeng Li,&nbsp;Enyong Dai,&nbsp;Shuhong Shen,&nbsp;Zhikai Wang,&nbsp;Xueshi Ye,&nbsp;Jin Zhang,&nbsp;Yu Liu,&nbsp;Wenguo Cui,&nbsp;Min Lu,&nbsp;Wei-Li Zhao,&nbsp;Chun-Kang Chang,&nbsp;Peng-Cheng He,&nbsp;Zhu Chen,&nbsp;Sai-Juan Chen,&nbsp;Mingyue Zheng,&nbsp;Xiao-Jian Sun,&nbsp;Lan Wang","doi":"10.1126/scitranslmed.adv8951","DOIUrl":"10.1126/scitranslmed.adv8951","url":null,"abstract":"<div >Leukemia is a malignant tumor with a high recurrence rate and poor prognosis for patients. Thus, there is an urgent need to explore new therapeutic targets that play critical roles in leukemogenesis but have little effect on normal hematopoietic cells. Here, we show that RNA binding protein with multiple splicing (RBPMS), which is highly expressed in acute myeloid leukemia (AML) and associated with poor prognosis of AML, plays critical roles in leukemogenesis. Our study shows that inhibition of RBPMS inhibits self-renewal of leukemia-initiating cells (LICs) and leukemia development but has little effect on normal hematopoiesis. Mechanistically, RBPMS recruits the <i>N</i>⁶-methyladenosine (m⁶A) reader insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3), which promotes the stability of the <i>forkhead box O1</i> (<i>FOXO1</i>) mRNA in an m⁶A-dependent manner. Moreover, RBPMS contributes to the progression of leukemia by directly binding to <i>FOXO1</i> and promoting FOXO1-regulated glycolysis. Overexpression of FOXO1 has been shown to reverse RBPMS inhibition–induced phenotypes in both leukemic cells and mouse models. We also designed a specific inhibitor of RBPMS that has therapeutic effects in AML patient-derived xenograft (PDX) models. We therefore highlight RBPMS as a promising drug target for leukemia therapy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 848","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147827789","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}

{"title":"Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis","authors":"David R. Ziehr,&nbsp;Fei Li,&nbsp;K. Mark Parnell,&nbsp;Nathan M. Krah,&nbsp;Kevin J. Leahy,&nbsp;Christelle Guillermier,&nbsp;Ce Gao,&nbsp;Sean A. Prell,&nbsp;Niv Vigder,&nbsp;Sergio Poli,&nbsp;Jack Varon,&nbsp;Rebecca M. Baron,&nbsp;Bradley A. Maron,&nbsp;Nancy J. Philp,&nbsp;Lida P. Hariri,&nbsp;Edy Y. Kim,&nbsp;Kevin S. Wei,&nbsp;Matthew L. Steinhauser,&nbsp;Rachel S. Knipe,&nbsp;Jared Rutter,&nbsp;William M. Oldham","doi":"10.1126/scitranslmed.ads2673","DOIUrl":"10.1126/scitranslmed.ads2673","url":null,"abstract":"<div >Myofibroblast differentiation, essential for driving extracellular matrix synthesis in pulmonary fibrosis, requires increased glycolysis. Although glycolytic cells must export lactate, the contributions of lactate transporters to myofibroblast differentiation are unknown. In this study, we investigated how monocarboxylate transporters (MCTs) 1 and 4, key pulmonary lactate transporters, influence myofibroblast differentiation and experimental pulmonary fibrosis. Our findings revealed that inhibiting MCT1 or MCT4 using RNA interference or small molecules reduced transforming growth factor–β1 (TGFβ)–stimulated myofibroblast differentiation in lung fibroblasts from healthy donors and patients with idiopathic pulmonary fibrosis. Small-molecule MCT inhibitors also decreased bleomycin-induced pulmonary fibrosis in C57Bl6/N mice aged 10 to 12 weeks. Through bioenergetic analyses, stable isotope tracing, metabolomics, and imaging mass spectrometry in both human cells and mice, we demonstrate that inhibiting lactate transport enhanced oxidative phosphorylation, reduced reactive oxygen species production, and diminished glucose metabolite incorporation into fibrotic lung regions. Furthermore, we introduce VB253, an MCT4 inhibitor, which ameliorates pulmonary fibrosis in both young and aged mice, with comparable efficacy to established antifibrotic therapies. These results underscore the necessity of lactate transport for myofibroblast differentiation, identify MCT1 and MCT4 as promising pharmacologic targets in pulmonary fibrosis, and support further evaluation of lactate transport inhibitors as a therapy for patients with limited treatment options.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 848","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147827788","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}

{"title":"Extracellular traps from myeloid cells as therapeutic targets in traumatic heterotopic ossification","authors":"Shan Jiang,&nbsp;Gesine Eis-Janzyk,&nbsp;Ruben Augustin,&nbsp;Holger Kleinertz,&nbsp;Saskia Schröder,&nbsp;Jan Sevecke,&nbsp;Weixin Xie,&nbsp;Haoyan Pan,&nbsp;Isabell Behrens,&nbsp;Samira Weisselberg,&nbsp;Lilly-Charlotte Albertsen,&nbsp;Elena Müller,&nbsp;Simon von Kroge,&nbsp;Assil-Ramin Alimy,&nbsp;Milad Fal,&nbsp;Michael Amling,&nbsp;Eva Tolosa,&nbsp;Thomas Renné,&nbsp;Karl-Heinz Frosch,&nbsp;Konrad Mader,&nbsp;Tim Rolvien,&nbsp;Anke Baranowsky,&nbsp;Johannes Keller","doi":"10.1126/scitranslmed.ady4761","DOIUrl":"10.1126/scitranslmed.ady4761","url":null,"abstract":"<div >After musculoskeletal injury, a considerable proportion of patients develop heterotopic ossification (HO), the formation of bone at ectopic sites. Traumatic HO is a disabling condition, potentially resulting in loss of joint function and compression of neurovascular structures. Available treatment options are often unsuccessful, frequently necessitating surgical resection of HO lesions with a high risk of recurrence. Given that myeloid cells, including neutrophils and macrophages, are among the first cell types to infiltrate injured tissue, the present study explored the relationship of extracellular traps (ETs) with HO formation in humans and mice. Human HO sample analysis revealed the presence of different stages of ETosis, which are clinically associated with increased ET concentrations in the blood. Experimentally, genetic impairment of ET resolution through combined <i>DNase1</i> and <i>DNase1l3</i> deficiency led to increased traumatic HO in mice, whereas HO was strongly attenuated by additional deletion of the ET generator <i>Padi4</i>. Neutrophil depletion impaired local ET formation, reduced HO formation, and blunted genotype-specific differences in HO outcome. In osteogenic precursors, ETs promoted matrix mineralization, and inhibition of ETosis or degradation of cell-free DNA, a major ET component, resulted in reduced osteogenesis. Pharmacological facilitation of ET clearance by dornase alfa, a US Food and Drug Administration–approved recombinant DNase1, or inhibition of ETs by the PADI4 inhibitor GSK484, resulted in inhibition of traumatic HO formation in mice without adversely affecting systemic bone remodeling. Together, our clinical and experimental findings demonstrate that traumatic HO is mediated by targetable neutrophil-dependent mechanisms, with altered ET formation contributing to these effects.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 848","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147827790","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}

{"title":"CD39+CD49a+CD103+ cytotoxic tissue-resident natural killer cells infiltrate and control solid epithelial tumor growth in mice","authors":"Nina B. Horowitz,&nbsp;Imran A. Mohammad,&nbsp;June Ho Shin,&nbsp;John W. Hickey,&nbsp;Peter Chockley,&nbsp;Gail Snyder,&nbsp;Chen Chen,&nbsp;Keene Lee,&nbsp;Krishna Sharma,&nbsp;Quan Tran,&nbsp;Anahita Nejatfard,&nbsp;Sainiteesh Maddineni,&nbsp;Vasu Divi,&nbsp;Catherine A. Blish,&nbsp;Garry P. Nolan,&nbsp;Jennifer A. Foltz,&nbsp;John B. Sunwoo","doi":"10.1126/scitranslmed.adw5567","DOIUrl":"10.1126/scitranslmed.adw5567","url":null,"abstract":"<div >Human tissue-resident natural killer (NK) cells (trNK cells), broadly defined by markers of tissue residency, such as CD49a [<i>integrin</i> α_<i>1</i> (<i>ITGA1</i>)] and CD103 [<i>integrin</i> α_<i>E</i> (<i>ITGAE</i>)], are increasingly recognized for their immunoregulatory role in host control of infection, malignancy, and autoimmunity. Although the importance of transforming growth factor–β in trNK cell differentiation has been demonstrated, the context in which the differentiation of CD49a⁺CD103⁺ trNK cells occurs can result in either an immunosuppressive phenotype (e.g., decidual NK cells) or a highly cytotoxic one (e.g., some tumor trNK subsets). To understand this dichotomy better, we used a multiomic approach to molecularly characterize these cells. We identified a cytotoxic trNK (ctrNK) cell population, characterized by the expression of CD39. These ctrNK cells exhibited superior cytolytic activity against tumor target cells, enhanced capacity to infiltrate into solid tumor microenvironments, and augmented ability to control solid tumor growth in vivo compared with conventionally activated peripheral NK cells. This heightened cytolytic and infiltrative functionality of ctrNK cells appeared to be conferred, in part, by the expression of CD103 and by avidity for tumor targets. Because adoptive immune cell therapy of solid tumor malignancies has been challenged by the inefficiency of ex vivo expanded immune cells to infiltrate immunosuppressive solid tumor microenvironments, our observations that ctrNK cells can be differentiated and expanded ex vivo present a potential platform for adoptive cell therapy of solid tumor malignancies.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 848","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147827792","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}

{"title":"Erratum for the Research Article “Smartphone-controlled optogenetically engineered cells enable semiautomatic glucose homeostasis in diabetic mice”","authors":"","doi":"10.1126/scitranslmed.aeh9233","DOIUrl":"10.1126/scitranslmed.aeh9233","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 848","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147827791","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}

{"title":"VRC01 with antiretroviral initiation in infants is well tolerated, and higher concentrations associate with greater HIV-1 DNA declines","authors":"Alka Khaitan,&nbsp;Jane C. Lindsey,&nbsp;Edmund V. Capparelli,&nbsp;Camlin Tierney,&nbsp;Anne Coletti,&nbsp;Charlotte Perlowski,&nbsp;Dwight E. Yin,&nbsp;Mary Elizabeth (Betsy) Smith,&nbsp;Hans M. L. Spiegel,&nbsp;Sai Majji,&nbsp;Jack Moye,&nbsp;Lucio Gama,&nbsp;Richard A. Koup,&nbsp;Bob C. Lin,&nbsp;Adrian B. McDermott,&nbsp;Lynette Purdue,&nbsp;Chelsea Krotje,&nbsp;Paul A. Harding,&nbsp;Mark F. Cotton,&nbsp;Diane Costello,&nbsp;Christos J. Petropoulos,&nbsp;Jacqueline D. Reeves,&nbsp;Macpherson Mallewa,&nbsp;Rachel Chihana,&nbsp;Portia Kamthunzi,&nbsp;Tapiwa G. Mbengeranwa,&nbsp;Gaerolwe Masheto,&nbsp;Maria Letícia Santos Cruz,&nbsp;Jose Henrique Pilotto,&nbsp;Ponego L. Ponatshego,&nbsp;Deborah Persaud,&nbsp;Elizabeth J. McFarland,&nbsp;IMPAACT 2008 Team","doi":"10.1126/scitranslmed.adr4509","DOIUrl":"10.1126/scitranslmed.adr4509","url":null,"abstract":"<div >Antiretroviral therapy (ART) in infancy restricts the HIV-1 reservoir but is insufficient for ART-free remission. We hypothesized that broadly neutralizing antibodies (bNAbs) administered at the initiation of ART would be safe and reduce HIV-1 DNA in peripheral blood cells more than ART alone. In a randomized, open-label two-arm study of infants with HIV-1 within 14 days of ART initiation, 30 infants received subcutaneous VRC01 (40 milligrams per kilogram), a bNAb that targets the CD4-binding site of gp120, at weeks 0, 2, 6, and 10, whereas 31 participants received no VRC01. VRC01 was well tolerated with no safety concerns. Decreases in HIV-1 DNA from weeks 0 to 14 were not different between arms overall nor when adjusted for a priori–defined covariates, including baseline resistance to VRC01. Baseline VRC01 resistance and resistance to prescribed ART were detected in a subset of infants treated with VRC01. Plasma VRC01 trough concentrations were below those predicted by pretrial modeling based on studies of infants exposed but uninfected with HIV-1. No anti-VRC01 antibodies were detected to account for low VRC01 concentrations. In post hoc analyses, higher plasma HIV-1 RNA values correlated with lower plasma VRC01 concentrations, whereas larger reductions in HIV-1 DNA were associated with higher VRC01 concentrations and lower plasma HIV-1 RNA, suggesting a concentration-dependent effect of bNAb treatment on HIV-1 DNA. These results highlight the safety of bNAbs for treatment of infants. Studies with more potent bNAbs are needed to assess effects on HIV-1 DNA during early treatment of infants living with HIV-1.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 848","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147827793","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}

{"title":"Polymeric rapamycin nanoparticles encapsulating ponatinib cause regression of venous malformations in mice","authors":"Weimin Tang,&nbsp;Ysabel Li,&nbsp;Elisa Boscolo,&nbsp;Daniel S. Kohane,&nbsp;Kathleen Cullion","doi":"10.1126/scitranslmed.aeb7597","DOIUrl":"10.1126/scitranslmed.aeb7597","url":null,"abstract":"<div >Venous malformations (VMs) are caused by activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) and Abelson murine leukemia viral oncogene homolog 1 (c-ABL) pathways. Daily oral administration of rapamycin (RAPA), an mTOR pathway inhibitor, has limited effectiveness in promoting lesion regression in patients with <i>TEK</i> receptor tyrosine kinase (TIE2)–mutated VMs. This may be due to poor bioavailability, frequent dosing requirements, and off-target effects that make maintaining adherence difficult. Recent preclinical studies have shown that combination treatment with RAPA and a c-ABL inhibitor [ponatinib (PON)] resulted in regression of VMs in a murine model; however, daily oral dosing was required. Here, we describe the formulation of polymeric RAPA, which acts as both a polymeric drug and a drug delivery carrier. The polymer was synthesized by polymerization of methacryloylated RAPA and terminated with polyethylene glycol (PEG-pRAPA). PEG-pRAPA self-assembled to form 30-nanometer nanoparticles (PEG-pRAPA NPs) and enabled the encapsulation of PON (PEG-pRAPA@PON NPs). PEG-pRAPA@PON NPs provided sustained release of both PON and PEG-pRAPA in vitro, reducing AKT phosphorylation comparably to free RAPA and PON. In a murine model of VMs, a single intravenous dose of PEG-pRAPA@PON NPs caused 70% VM regression over 20 days and a 6.3-fold reduction in CD31-positive (human-derived) blood vessels. There was no evidence of systemic toxicity or organ dysfunction after treatment. These findings demonstrated that PEG-pRAPA is an effective polymeric drug and drug delivery platform and support the hypothesis that nanoparticle-based pharmacotherapy can be an effective treatment strategy for VMs.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 848","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147827794","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}

{"title":"Local B cell immunity and durable memory after live-attenuated influenza intranasal vaccination of humans","authors":"Hannah D. Stacey,&nbsp;Lucas Garin-Ortega,&nbsp;Paul G. Lopez,&nbsp;Parham Ramezani-Rad,&nbsp;Sydney I. Ramirez,&nbsp;Farhoud Faraji,&nbsp;Disha Bhavsar,&nbsp;Gina Levi,&nbsp;Florian Krammer,&nbsp;Shane Crotty","doi":"10.1126/scitranslmed.adz8439","DOIUrl":"10.1126/scitranslmed.adz8439","url":null,"abstract":"<div >Seasonal influenza vaccines are most frequently delivered as intramuscular inactivated vaccines, which elicit systemic responses against the immunodominant hemagglutinin (HA) head domain. An intranasally administered, live-attenuated influenza vaccine designed to stimulate mucosal immunity, FluMist, is the sole intranasal vaccine approved in the United States. However, FluMist has lower systemic immunogenicity and efficacy in adults compared with intramuscular formulations. In this study, human mucosal and systemic immunity were examined after seasonal intramuscular or intranasal vaccination. Nasopharyngeal swabs of adenoid tissue were used to longitudinally sample the upper airway. FluMist induced substantial increases in upper respiratory tract IgG⁺ and IgA⁺ HA-specific memory B cells, which displayed an activated CD27⁺CD21⁻ phenotype. H1, H3, and influenza B virus HA-specific memory B cells were all detected in the upper airway after intranasal immunization, remained elevated at 6 months postvaccination, and were associated with the presence of circulating T follicular helper (cT_FH) cells. Recently activated upper airway memory B cells were not readily detected in intramuscular vaccinees, despite the elevation of systemic antibodies and circulating HA-specific memory B cells. Thus, despite minimal immune responses detected in circulation, adults vaccinated with the live-attenuated influenza vaccine generate substantial local antigen-specific memory B cell responses. These findings have implications for improving influenza vaccines and for mucosal vaccination against other respiratory pathogens.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 847","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147779963","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}

{"title":"Adeno-associated virus gene therapy–mediated CCR5 blockade suppresses virus replication long term in SHIV-infected macaques","authors":"Helen L. Wu,&nbsp;Gabriela M. Webb,&nbsp;Sebastian P. Fuchs,&nbsp;Cleiton T. Pessoa,&nbsp;Joseph M. Hwang,&nbsp;Hannah K. Fisher,&nbsp;Allyson J. McCullen,&nbsp;Matthew C. Humkey,&nbsp;Mischa K. Brown,&nbsp;Courtney M. Waytashek,&nbsp;Carla D. Boyle,&nbsp;Kaitlyn A. Kukula,&nbsp;Sofia K. Potter,&nbsp;Garth Devlin,&nbsp;Zachary C. Elmore,&nbsp;Joshua A. Hull,&nbsp;Joanna Zikos,&nbsp;Tonya Swanson,&nbsp;Kimberly Armantrout,&nbsp;Kimberly Chun,&nbsp;Hugh Crank,&nbsp;Lauren Bailey,&nbsp;Riely White,&nbsp;Aaron Barber-Axthelm,&nbsp;Miranda Fischer,&nbsp;Jeremy V. Smedley,&nbsp;Michael K. Axthelm,&nbsp;Christine M. Fennessey,&nbsp;Brandon F. Keele,&nbsp;Ronald C. Desrosiers,&nbsp;Diogo M. Magnani,&nbsp;Aravind Asokan,&nbsp;Jonah B. Sacha","doi":"10.1126/scitranslmed.adw1976","DOIUrl":"10.1126/scitranslmed.adw1976","url":null,"abstract":"<div >Adeno-associated virus (AAV) vectors are promising vehicles for the delivery and long-term expression of antibodies for treatment of chronic diseases. Given the strong link between the C-C chemokine receptor 5 (CCR5)–Δ<i>32/</i>Δ<i>32</i> genotype and protection from HIV, we explored the ability of AAV vectors expressing the CCR5-blocking antibody leronlimab to mediate a functional cure in simian-human immunodeficiency virus (SHIV)–infected rhesus macaques by interrupting viral access to the viral entry co-receptor CCR5. Delivery of AAV-leronlimab to rhesus macaques elicited antidrug antibodies (ADA) and rapid plasma leronlimab clearance in approximately half of the treated macaques. However, in these same animals, we observed spontaneous leronlimab transgene reemergence and detectable CCR5 receptor occupancy approximately 1 year later that subsequently persisted indefinitely without rebound of ADA. In macaques that did not mount robust ADA responses, detectable plasma leronlimab concentrations and CCR5 receptor occupancy were maintained for more than 1 year. Of the nine macaques producing sufficient leronlimab to achieve full CCR5 receptor occupancy on blood CD4⁺ T cells, AAV-leronlimab drove stringent or partial control of SHIV viremia in six macaques long term. In the three macaques with uncontrolled SHIV viremia, short-term administration of exogenous leronlimab induced complete SHIV suppression in two and a 100-fold reduction in the third, indicating that a threshold of leronlimab expression is necessary to effectively halt SHIV replication. These results demonstrate the potential of gene therapy–mediated long-term antibody-based CCR5 blockade for HIV functional cure but highlight challenges in achieving sufficient antibody expression when targeting an abundant self-antigen.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 847","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147779931","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}

{"title":"Erratum for the Research Article “Targeted disruption of the BCL9/β-catenin complex inhibits oncogenic Wnt signaling”","authors":"","doi":"10.1126/scitranslmed.aeh5753","DOIUrl":"10.1126/scitranslmed.aeh5753","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 847","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147779934","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}