Science Translational Medicine最新文献

{"title":"A wearable osmotic microneedle patch provides high-capacity sustained drug delivery in animal models","authors":"Sheng Zhao,&nbsp;Ziyi Lu,&nbsp;Ruisi Cai,&nbsp;Hui Wang,&nbsp;Shukun Gao,&nbsp;Changwei Yang,&nbsp;Ying Zhang,&nbsp;Bowen Luo,&nbsp;Wentao Zhang,&nbsp;Yinxian Yang,&nbsp;Shenqiang Wang,&nbsp;Tao Sheng,&nbsp;Shiqi Wang,&nbsp;Jiahuan You,&nbsp;Ruyi Zhou,&nbsp;Huimin Ji,&nbsp;Haoning Gong,&nbsp;Xiao Ye,&nbsp;Jicheng Yu,&nbsp;Hong-Hu Zhu,&nbsp;Yuqi Zhang,&nbsp;Zhen Gu","doi":"10.1126/scitranslmed.adp3611","DOIUrl":"10.1126/scitranslmed.adp3611","url":null,"abstract":"<div >The maintenance of stable plasma drug concentrations within a therapeutic window can be critical for drug efficacy. Here, we developed a wearable osmotic microneedle (OMN) patch to support sustained drug dosing for at least 24 hours without the use of electronic components. The OMN patch uses an osmotic pressure driving force to deliver drug solution into the skin through three hollow microneedles with diameters of less than 200 micrometers. The rate of drug release was related to the composition and concentration of the osmogen and drug and to the physical properties of the semipermeable membrane separating the low- and high-solute compartments. The OMN patch released the peptide drug exenatide in rats and mice for 24 hours, whereas subcutaneous injection resulted in a burst release and rapid decline in the plasma drug concentration. OMN release of exenatide improved glycemic control in a diabetic mouse model consistent with a sustained effective plasma concentration of the drug. Continuous release of the small-molecule chemotherapeutic drug cytarabine reduced the progression of acute myeloid leukemia in mice more effectively than subcutaneous injection. Further evaluation of the OMN patch in canines demonstrated continuous dosing of cytarabine up to 225 milligrams for 24 hours, satisfying clinical requirements (150 to 300 milligrams daily). OMN patches were well tolerated in human participants with minimal pain or irritation of the skin and a stated preference over other administration routes. This wearable drug delivery system could provide a platform for stable high-dose drug release with convenience and safety.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 775","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740588","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":"Childhood-onset lupus nephritis is characterized by complex interactions between kidney stroma and infiltrating immune cells","authors":"Patrick Danaher,&nbsp;Nicholas Hasle,&nbsp;Elizabeth D. Nguyen,&nbsp;Jordan E. Roberts,&nbsp;Natalie Rosenwasser,&nbsp;Christian Rickert,&nbsp;Elena W. Y. Hsieh,&nbsp;Kristen Hayward,&nbsp;Daryl M. Okamura,&nbsp;Charles E. Alpers,&nbsp;Robyn C. Reed,&nbsp;Sarah K. Baxter,&nbsp;Shaun W. Jackson","doi":"10.1126/scitranslmed.adl1666","DOIUrl":"10.1126/scitranslmed.adl1666","url":null,"abstract":"<div >Children with systemic lupus erythematosus (SLE) are at increased risk of developing kidney disease, termed childhood-onset lupus nephritis (cLN). Single-cell transcriptomics of dissociated kidney tissue has advanced our understanding of LN pathogenesis, but loss of spatial resolution prevents interrogation of in situ cellular interactions. Using a technical advance in spatial transcriptomics, we generated a spatially resolved, single-cell resolution atlas of kidney tissue from eight patients with cLN and four control individuals. Annotated cells were assigned to 30 reference cell types, including major kidney subsets and infiltrating immune cells. Analysis of spatial distribution demonstrated that individual immune lineages localized to specific regions in cLN kidneys, including myeloid cells that trafficked to inflamed glomeruli and B cells that clustered within tubulointerstitial immune hotspots. Gene expression varied as a function of tissue location, demonstrating how incorporation of spatial data can provide new insights into the immunopathogenesis of SLE. Alterations in immune phenotypes were accompanied by parallel changes in gene expression by resident kidney stromal cells. However, there was little correlation between histologic scoring of cLN disease activity and glomerular cell transcriptional signatures at the level of individual glomeruli. Last, we identified modules of spatially correlated gene expression with predicted roles in induction of inflammation and the development of tubulointerstitial fibrosis. Single-cell spatial transcriptomics allowed insights into the molecular heterogeneity of cLN, paving the way toward more targeted and personalized treatment approaches.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 775","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740590","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":"An mRNA-encoded dominant-negative inhibitor of transcription factor RUNX1 suppresses vitreoretinal disease in experimental models","authors":"Michael O’Hare,&nbsp;William P. Miller,&nbsp;Said Arevalo-Alquichire,&nbsp;Dhanesh Amarnani,&nbsp;Evhy Apryani,&nbsp;Paula Perez-Corredor,&nbsp;Claudia Marino,&nbsp;Daisy Y. Shu,&nbsp;Timothy E. Vanderleest,&nbsp;Andres Muriel-Torres,&nbsp;Harper B. Gordon,&nbsp;Audrey L. Gunawan,&nbsp;Bryan A. Kaplan,&nbsp;Karim W. Barake,&nbsp;Romy P. Bejjani,&nbsp;Tri H. Doan,&nbsp;Rose Lin,&nbsp;Santiago Delgado-Tirado,&nbsp;Lucia Gonzalez-Buendia,&nbsp;Elizabeth J. Rossin,&nbsp;Guannan Zhao,&nbsp;Dean Eliott,&nbsp;Christine Weinl-Tenbruck,&nbsp;Frédéric Chevessier-Tünnesen,&nbsp;Joanna Rejman,&nbsp;Fabio Montrasio,&nbsp;Leo A. Kim,&nbsp;Joseph F. Arboleda-Velasquez","doi":"10.1126/scitranslmed.adh0994","DOIUrl":"10.1126/scitranslmed.adh0994","url":null,"abstract":"<div >Messenger RNA (mRNA)–based therapies are a promising approach to medical treatment. Except for infectious diseases, no other disease has mRNA-based therapies available. The eye is an ideal model for mRNA therapeutic development because it requires limited dosing. Proliferative vitreoretinopathy (PVR) is a blinding condition caused by retinal detachment that now lacks available medical treatment, with surgery as the only treatment option. We previously implicated runt-related transcription factor-1 (RUNX1) as a driver of epithelial-to-mesenchymal transition (EMT) in PVR and as a critical mediator of aberrant ocular angiogenesis when up-regulated. On the basis of these findings, an mRNA was designed to express a dominant-negative inhibitor of RUNX1 (RUNX1-Trap). We show that RUNX1-Trap delivered in polymer-lipidoid complexes or lipid nanoparticles sequestered RUNX1 in the cytosol and strongly reduced proliferation in primary cell cultures established from fibrotic membranes derived from patients with PVR. We assessed the preclinical efficacy of intraocular delivery of mRNA-encoded RUNX1-Trap in a rabbit model of PVR and in a laser-induced mouse model of aberrant angiogenesis often used to study wet age-related macular degeneration. mRNA-encoded RUNX1-Trap suppressed ocular pathology, measured as pathological scores in the rabbit PVR model and leakage and lesion size in the laser-induced choroidal neovascularization mouse model. mRNA-encoded RUNX1-Trap also strongly reduced proliferation in a human ex vivo explant model of PVR. These data demonstrate the therapeutic potential of mRNA-encoded therapeutic molecules with dominant-negative properties, highlighting the potential of mRNA-based therapies beyond standard gene supplementation approaches.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 775","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740589","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 “Platelet-derived growth factor C signaling is a potential therapeutic target for radiation proctopathy” by W. Lu et al.","authors":"","doi":"10.1126/scitranslmed.adu4658","DOIUrl":"10.1126/scitranslmed.adu4658","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 775","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740592","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":"Targeting the PDE3B-cAMP-autophagy axis prevents liver injury in long-term supercooling liver preservation","authors":"Xingyuan Jiao,&nbsp;Yihu Li,&nbsp;Zhihang Chen,&nbsp;Qi Zhang,&nbsp;Rui He,&nbsp;Yinbing Huang,&nbsp;Zhixiang Zuo","doi":"10.1126/scitranslmed.adk0636","DOIUrl":"10.1126/scitranslmed.adk0636","url":null,"abstract":"<div >In liver transplantation, donor livers are typically stored in a preservation solution at 4°C for up to 12 hours. However, this short preservation duration can lead to various issues, such as suboptimal donor-recipient matching and limited opportunities for organ sharing. Previous studies have developed a long-term preservation method called supercooling liver preservation (SLP) to address these issues. However, in this study using a rat model, we observed that long-term SLP led to more severe liver damage compared with clinically prevalent traditional static cold storage (SCS) for durations less than 8 hours. To understand the potential mechanism of SLP-induced liver injury, we conducted an integrative metabolomic, transcriptomic, and proteomic analysis. We identified the PDE3B-cAMP-autophagy pathway as a key determinant of SLP-induced liver injury. Specifically, we found that PDE3B was elevated during SLP, which promoted a reduction of cAMP metabolites, triggering an AMPK-dependent autophagy process that led to liver injury in rats. We found that blocking the reduction in cAMP using the PDE3B inhibitor cilostamide inhibited autophagy and substantially ameliorated liver injury during 48-hour SLP in rat livers. Furthermore, we validated the effectiveness of cilostamide treatment in preventing liver injury in pig and human liver 48-hour SLP models. In summary, our results reveal that metabolic reprogramming involving the PDE3B-cAMP-autophagy axis is the key determinant of liver injury in long-term SLP and provide an early therapeutic strategy to prevent liver injury in this setting.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 775","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740595","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":"Seeding-competent TDP-43 persists in human patient and mouse muscle","authors":"Eileen M. Lynch,&nbsp;Sara Pittman,&nbsp;Jil Daw,&nbsp;Chiseko Ikenaga,&nbsp;Sheng Chen,&nbsp;Dhruva D. Dhavale,&nbsp;Meredith E. Jackrel,&nbsp;Yuna M. Ayala,&nbsp;Paul Kotzbauer,&nbsp;Cindy V. Ly,&nbsp;Alan Pestronk,&nbsp;Thomas E. Lloyd,&nbsp;Conrad C. Weihl","doi":"10.1126/scitranslmed.adp5730","DOIUrl":"10.1126/scitranslmed.adp5730","url":null,"abstract":"<div >TAR DNA binding protein 43 (TDP-43) is an RNA binding protein that accumulates as aggregates in the central nervous systems of some patients with neurodegenerative diseases. However, TDP-43 aggregation is also a sensitive and specific pathologic feature found in a family of degenerative muscle diseases termed inclusion body myopathy. TDP-43 aggregates from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia brain lysates may serve as self-templating aggregate seeds in vitro and in vivo, supporting a prion-like spread from cell to cell. Whether a similar process occurs in patient muscle is not clear. We developed a mouse model of inducible, muscle-specific cytoplasmic localized TDP-43. These mice develop muscle weakness with robust accumulation of insoluble and phosphorylated sarcoplasmic TDP-43, leading to eosinophilic inclusions, altered proteostasis, and changes in TDP-43–related RNA processing that resolve with the removal of doxycycline. Skeletal muscle lysates from these mice also have seeding-competent TDP-43, as determined by a FRET-based biosensor, that persists for weeks upon resolution of TDP-43 aggregate pathology. Human muscle biopsies with TDP-43 pathology also contain TDP-43 aggregate seeds. Using lysates from muscle biopsies of patients with sporadic inclusion body myositis (IBM), immune-mediated necrotizing myopathy (IMNM), and ALS, we found that TDP-43 seeding capacity was specific to IBM. TDP-43 seeding capacity anticorrelated with TDP-43 aggregate and vacuole abundance. These data support that TDP-43 aggregate seeds are present in IBM skeletal muscle and represent a unique TDP-43 pathogenic species not previously appreciated in human muscle disease.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 775","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adp5730","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740593","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}

{"title":"Erratum for the Research Article “Neural landscape is associated with functional outcomes in irradiated patients with oropharyngeal squamous cell carcinoma” by S. Islam et al.","authors":"","doi":"10.1126/scitranslmed.adu4652","DOIUrl":"10.1126/scitranslmed.adu4652","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 775","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740591","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":"Vagal stimulation ameliorates murine colitis by regulating SUMOylation","authors":"Ayman Youssef,&nbsp;Ata Ur Rehman,&nbsp;Mohamed Elebasy,&nbsp;Jatin Roper,&nbsp;Shehzad Z. Sheikh,&nbsp;Jorn Karhausen,&nbsp;Wei Yang,&nbsp;Luis Ulloa","doi":"10.1126/scitranslmed.adl2184","DOIUrl":"10.1126/scitranslmed.adl2184","url":null,"abstract":"<div >Inflammatory bowel diseases (IBDs) are chronic debilitating conditions without cure, the etiologies of which are unknown, that shorten the lifespans of 7 million patients worldwide by nearly 10%. Here, we found that decreased autonomic parasympathetic tone resulted in increased IBD susceptibility and mortality in mouse models of disease. Conversely, vagal stimulation restored neuromodulation and ameliorated colitis by inhibiting the posttranslational modification SUMOylation through a mechanism independent of the canonical interleukin-10/α7 nicotinic cholinergic vagal pathway. Colonic biopsies from patients with IBDs and mouse models showed an increase in small ubiquitin-like modifier (SUMO)2 and SUMO3 during active disease. In global genetic knockout mouse models, the deletion of <i>Sumo3</i> protected against development of colitis and delayed onset of disease, whereas deletion of <i>Sumo1</i> halted the progression of colitis. Bone marrow transplants from <i>Sumo1</i>-knockout (KO) but not <i>Sumo3</i>-KO mice into wild-type mice conferred protection against development of colitis. Electric stimulation of the cervical vagus nerve before the induction of colitis inhibited SUMOylation and delayed the onset of colitis in <i>Sumo1</i>-KO mice and resulted in milder symptoms in <i>Sumo3</i>-KO mice. Treatment with TAK-981, a first-in-class inhibitor of the SUMO-activating enzyme, ameliorated disease in three murine models of IBD and reduced intestinal permeability and bacterial translocation in a severe model of the disease, suggesting the potential to reduce progression to sepsis. These results reveal a pathway of vagal neuromodulation that reprograms endogenous stress-adaptive responses through inhibition of SUMOylation and suggest SUMOylation as a therapeutic target for IBD.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 774","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678953","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":"Delayed low-dose oral administration of 4′-fluorouridine inhibits pathogenic arenaviruses in animal models of lethal disease","authors":"Stephen R. Welch,&nbsp;Jessica R. Spengler,&nbsp;Jonna B. Westover,&nbsp;Kevin W. Bailey,&nbsp;Katherine A. Davies,&nbsp;Virginia Aida-Ficken,&nbsp;Gregory R. Bluemling,&nbsp;Kirsten M. Boardman,&nbsp;Samantha R. Wasson,&nbsp;Shuli Mao,&nbsp;Damien L. Kuiper,&nbsp;Michael W. Hager,&nbsp;Manohar T. Saindane,&nbsp;Meghan K. Andrews,&nbsp;Rebecca E. Krueger,&nbsp;Zachary M. Sticher,&nbsp;Kie Hoon Jung,&nbsp;Payel Chatterjee,&nbsp;Punya Shrivastava-Ranjan,&nbsp;Michael K. Lo,&nbsp;JoAnn D. Coleman-McCray,&nbsp;Teresa E. Sorvillo,&nbsp;Sarah C. Genzer,&nbsp;Florine E. M. Scholte,&nbsp;Jamie A. Kelly,&nbsp;M. Harley Jenks,&nbsp;Laura K. McMullan,&nbsp;César G. Albariño,&nbsp;Joel M. Montgomery,&nbsp;George R. Painter,&nbsp;Michael G. Natchus,&nbsp;Alexander A. Kolykhalov,&nbsp;Brian B. Gowen,&nbsp;Christina F. Spiropoulou,&nbsp;Mike Flint","doi":"10.1126/scitranslmed.ado7034","DOIUrl":"10.1126/scitranslmed.ado7034","url":null,"abstract":"<div >Development of broad-spectrum antiviral therapies is critical for outbreak and pandemic preparedness against emerging and reemerging viruses. Viruses inducing hemorrhagic fevers cause high morbidity and mortality in humans and are associated with several recent international outbreaks, but approved therapies for treating most of these pathogens are lacking. Here, we show that 4′-fluorouridine (4′-FlU; EIDD-2749), an orally available ribonucleoside analog, has antiviral activity against multiple hemorrhagic fever viruses in cell culture, including Nipah virus, Crimean-Congo hemorrhagic fever virus, orthohantaviruses, and arenaviruses. We performed preclinical in vivo evaluation of oral 4′-FlU against two arenaviruses, Old World Lassa virus (LASV) and New World Junín virus (JUNV), in guinea pig models of lethal disease. 4′-FlU demonstrated both advantageous pharmacokinetic characteristics and high efficacy in both of these lethal disease guinea pig models. Additional experiments supported protection of the infected animals even when 4′-FlU delivery was reduced to a low dose of 0.5 milligram per kilogram. To demonstrate clinical utility, 4′-FlU treatment was evaluated when initiated late in the course of infection (12 or 9 days after infection for LASV and JUNV, respectively). Delayed treatment resulted in rapid resolution of clinical signs, demonstrating an extended window for therapeutic intervention. These data support the use of 4′-FlU as a potent and efficacious treatment against highly pathogenic arenaviruses of public health concern with a virus inhibition profile suggesting broad-spectrum utility as an orally available antiviral drug against a wide variety of viral pathogens.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 774","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.ado7034","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678332","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}

{"title":"Disrupting the RNA polymerase II transcription cycle through CDK7 inhibition ameliorates inflammatory arthritis","authors":"Xi Chen,&nbsp;Gayathri Shibu,&nbsp;Baila A. Sokolsky,&nbsp;Tamar Nicole Soussana,&nbsp;Logan Fisher,&nbsp;Dinesh K. Deochand,&nbsp;Marija Dacic,&nbsp;Ian Mantel,&nbsp;Daniel C. Ramirez,&nbsp;Richard D. Bell,&nbsp;Tinghu Zhang,&nbsp;Laura T. Donlin,&nbsp;Susan M. Goodman,&nbsp;Nathanael S. Gray,&nbsp;Yurii Chinenov,&nbsp;Robert P. Fisher,&nbsp;Inez Rogatsky","doi":"10.1126/scitranslmed.adq5091","DOIUrl":"10.1126/scitranslmed.adq5091","url":null,"abstract":"<div >Macrophages are key drivers of inflammation and tissue damage in autoimmune diseases including rheumatoid arthritis. The rate-limiting step for transcription of more than 70% of inducible genes in macrophages is RNA polymerase II (Pol II) promoter-proximal pause release; however, the specific role of Pol II early elongation control in inflammation, and whether it can be modulated therapeutically, is unknown. Genetic ablation of a pause-stabilizing negative elongation factor (NELF) in macrophages did not affect baseline Pol II occupancy but enhanced the transcriptional response of paused anti-inflammatory genes to lipopolysaccharide followed by secondary attenuation of inflammatory signaling in vitro and in the K/BxN serum transfer mouse model of arthritis. To pharmacologically disrupt the Pol II transcription cycle, we used two covalent inhibitors of the transcription factor II H-associated cyclin-dependent kinase 7 (CDK7), THZ1 and YKL-5-124. Both reduced Pol II pausing in murine and human macrophages, broadly suppressed induction of pro- but not anti-inflammatory genes, and rapidly reversed preestablished inflammatory macrophage polarization. In mice, CDK7 inhibition ameliorated both acute and chronic progressive inflammatory arthritis. Lastly, CDK7 inhibition down-regulated a pathogenic gene expression signature in synovial explants from patients with rheumatoid arthritis. We propose that interfering with Pol II early elongation by targeting CDK7 represents a therapeutic opportunity for rheumatoid arthritis and other inflammatory diseases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 774","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678330","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}