Science Translational Medicine最新文献

{"title":"The kinase inhibitor dabrafenib halts progression of cerebral cavernous malformations in a BRAF-independent manner","authors":"Maximiliano Arce,&nbsp;Hua Huang,&nbsp;Charlotte Rorsman,&nbsp;Iza Erzar,&nbsp;Joppe Oldenburg,&nbsp;Ying Sun,&nbsp;Ross Smith,&nbsp;Favour C. Onyeogaziri,&nbsp;Stefano Barbera,&nbsp;Frida C. Ahlstrand,&nbsp;Petter Ranefall,&nbsp;Anna Klemm,&nbsp;Mark Richards,&nbsp;Anna Dimberg,&nbsp;Lena Claesson-Welsh,&nbsp;Peetra U. Magnusson","doi":"10.1126/scitranslmed.adr0448","DOIUrl":"10.1126/scitranslmed.adr0448","url":null,"abstract":"<div >Cerebral cavernous malformations (CCMs) constitute the second most common type of intracranial vascular malformations. Cavernomas arise because of somatic or autosomal dominant inherited loss-of-function mutations in <i>CCM</i> genes, forming fragile mulberry-like malformed blood vessel structures that are prone to leak and break. Treatment is limited to surgical removal of solitary cavernomas, and because patients often present with multiple lesions, pharmacological alternatives to surgery are needed. We performed a high-throughput screen of 5200 bioactive molecules in programmed cell death 10 (PDCD10 or CCM3)–deficient mouse endothelial cells, coupled to automated image analysis. This screen identified dabrafenib, a clinically approved BRAF inhibitor, as a compound that restored cell-cell junctions and vascular barrier properties of CCM3-deficient endothelial cells. The potential translatability of dabrafenib was tested in acute and chronic CCM mouse models, where it reduced cerebral lesion burden and suppressed lesion permeability. Dabrafenib also rescued abnormal structural defects present in the developing retina vasculature in an acute CCM mouse model. Mechanistically, dabrafenib targeted extracellular regulated kinase (ERK)5–Krüppel-like factor (KLF)2/4 signaling and suppressed F-actin stress fiber formation in human brain endothelial cells, two potentially independent and central molecular processes involved in CCM pathology. Silencing BRAF did not prevent dabrafenib-induced KLF2/4 inhibition or restoration of cell-cell junctions, suggesting that its dual therapeutic outcome is independent of BRAF pathway inhibition. In conclusion, dabrafenib is a low–molecular weight compound that inhibits cavernoma pathogenesis, suggesting that CCMs could be treated with dabrafenib to block cavernoma growth and vascular leakage.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 872","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149226547","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":"Cas9 nickase–mediated contraction of CAG/CTG repeats is associated with phenotypic improvements in a Huntington’s disease mouse model","authors":"Alvaro Murillo,&nbsp;Melanie Alpaugh,&nbsp;Ruban Rex Peter Durairaj,&nbsp;Emma L. Randall,&nbsp;Meghan Larin,&nbsp;Laura Heraty,&nbsp;Alys N. Aston,&nbsp;Alysha S. Taylor,&nbsp;Alex Mas Monteys,&nbsp;Nina Stöberl,&nbsp;Aeverie E. R. Heuchan,&nbsp;Pascale Aeschlimann,&nbsp;Kyle Fears,&nbsp;Christian Landles,&nbsp;Georgina F. Osborne,&nbsp;Antoine Mangin,&nbsp;Soumyasree Bhattacharyya,&nbsp;Emmanouil Metzakopian,&nbsp;Nicholas D. Allen,&nbsp;Jack Puymirat,&nbsp;Gillian P. Bates,&nbsp;Beverly L. Davidson,&nbsp;Francesca Cicchetti,&nbsp;Mariah J. Lelos,&nbsp;Vincent Dion","doi":"10.1126/scitranslmed.aef9466","DOIUrl":"10.1126/scitranslmed.aef9466","url":null,"abstract":"<div >Expanded CAG/CTG repeats cause more than 15 different diseases that all remain without a disease-modifying treatment. Because repeat length accounts for most of the variation in disease severity, contracting CAG/CTG repeats presents an attractive therapeutic avenue. Here, we show that the CRISPR-Cas9 nickase targeted to CAG/CTG repeats leads to efficient repeat contractions in Huntington’s disease (HD) patient–derived neurons and astrocytes and in myotonic dystrophy type 1 patient–derived neurons. The approach was allele selective and free of detectable off-target mutations. Injection of the Cas9 nickase into the striatum of the R6/1 mouse model of HD using adeno-associated viral vectors led to repeat contractions in more than half of striatal neurons. Upon injection, we observed a reduction in the number of inclusion bodies, an improved gene expression profile, and amelioration of locomotion deficits in the open field test. The effects were greater than expected from the contractions induced, suggesting that non–cell autonomous mechanisms may be involved. Our results provide the proof of concept that correction of CAG/CTG repeats can improve HD phenotypes in a mouse disease model.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 872","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149226262","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":"Single-nucleotide polymorphism–directed design of allele-specific antisense oligonucleotides for spinocerebellar ataxia type 3","authors":"Jacob Helm,&nbsp;Elena Buena-Atienza,&nbsp;Clemens M. Sauter,&nbsp;Linus Wiora,&nbsp;Melanie Kraft,&nbsp;Yvonne Schelling,&nbsp;Jakob Admard,&nbsp;Jeannette Hübener-Schmid,&nbsp;Thomas Klockgether,&nbsp;Matthis Synofzik,&nbsp;Luís Pereira de Almeida,&nbsp;Mafalda Raposo,&nbsp;Paola Giunti,&nbsp;Hector Garcia-Moreno,&nbsp;Magda M. Santana,&nbsp;Jennifer Faber,&nbsp;Holger Hengel,&nbsp;Nicolas Casadei,&nbsp;Ludger Schöls,&nbsp;Stefan Hauser","doi":"10.1126/scitranslmed.adz2140","DOIUrl":"10.1126/scitranslmed.adz2140","url":null,"abstract":"<div >Spinocerebellar ataxia type 3 (SCA3), also called Machado-Joseph disease, the most common form of autosomal dominant cerebellar ataxia, is caused by a CAG repeat expansion in <i>ATXN3</i>. The mutant protein is prone to aggregation and exerts toxic gain-of-function effects, whereas the wild-type protein has important neuroprotective roles as a deubiquitinase. Current treatment strategies for SCA3 lack specificity for the mutant allele. Identifying genetic variants such as single-nucleotide polymorphisms (SNPs) in linkage with the pathogenic CAG expansion offers a promising avenue to develop allele-specific therapeutic interventions, like antisense oligonucleotides (ASOs). To address this, we conducted allele-specific, targeted, multiplexed nanopore sequencing on 79 patients with SCA3 from Germany, UK, and Portugal. We identified almost 200 polymorphisms and grouped them into three haplotype blocks on the basis of linkage disequilibrium. These SNPs were strongly associated with the CAG expansion. Genotypic modeling of our subcohorts indicated that targeting only two SNPs from different blocks could enable allele-specific treatment of the majority of European patients with SCA3. We evaluated 17 candidate ASOs targeting SNPs from different haplotype blocks. Seven of these ASOs caused allele-preferential reduction of more than 65%. A single ASO application in two SCA3 iPSC-derived cortical neurons (AX1, AX2) achieved up to 90% reduction of mutant ATXN3. Toxicity assessments together with RNA sequencing analyses in AX1 did not indicate evidence of toxicity or widespread transcriptional perturbations. These findings highlight that characterizing heterozygosity rates offers valuable opportunities for selective ASO therapies. Our proof-of-principle targeting with ASOs demonstrates the feasibility of haplotype-informed allele-specific silencing in <i>ATXN3</i>.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 872","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adz2140","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149226264","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 “Systematic analysis of cellular cross-talk reveals a role for SEMA6D-TREM2 regulating microglial function in Alzheimer’s disease”","authors":"","doi":"10.1126/scitranslmed.aen0201","DOIUrl":"10.1126/scitranslmed.aen0201","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 872","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149226675","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":"Targeting ZIP12-mediated Zn2+ signaling as a treatment for pulmonary hypertension","authors":"Lan Zhao,&nbsp;Stephanie Hopley,&nbsp;Chien-Nien Chen,&nbsp;Iyobel Kibreab,&nbsp;Chongyang Xie,&nbsp;Nicoleta Baxan,&nbsp;Ali Ashek,&nbsp;Lin Zhao,&nbsp;Adam Fellows,&nbsp;Daria S. Kostyunina,&nbsp;Eduardo Oliver,&nbsp;Lei Wang,&nbsp;Shu Ning,&nbsp;Guy Rutter,&nbsp;Julia Gorelik,&nbsp;Rachel Gurrell,&nbsp;Richard Butt,&nbsp;Paul Hamblin,&nbsp;Martin R. Wilkins","doi":"10.1126/scitranslmed.aee0680","DOIUrl":"10.1126/scitranslmed.aee0680","url":null,"abstract":"<div >ZIP12, a membrane-bound zinc importer, is up-regulated in the remodeled pulmonary arterioles of patients with pulmonary arterial hypertension (PAH). Genetic deletion of its encoding gene, <i>Slc39a12</i>, ameliorates the disease in rodent models. Here, we show that ZIP12 overexpression in human pulmonary artery smooth muscle cells (PASMCs) increased intracellular labile Zn²⁺ and promoted proliferation. ZIP12 siRNA knockdown attenuated pulmonary hypertension in rodent models. We developed a humanized anti-ZIP12 monoclonal antibody, APL-9796, that normalized intracellular Zn²⁺ concentration, suppressed proliferation in fibroblasts derived from patients with PAH and PDGF-stimulated PASMCs, and reduced PDGF-induced cytoskeletal remodeling in PASMCs and contractility in PASMCs and engineered pulmonary artery tissues. APL-9796 showed dose-dependent efficacy in humanized <i>Slc39a12</i> rats, improving cardiopulmonary parameters after induction of pulmonary hypertension and was well tolerated in phase 1 clinical studies. Transcriptomic profiling revealed modulation of several molecular pathways, including those involving AMPK, PPAR, and PI3K-Akt. ZIP12-driven labile Zn²⁺ signaling underpins the pathogenesis of PAH. Targeting ZIP12 with APL-9796 offers a promising therapeutic strategy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 872","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149226265","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":"Innovative roadmaps for sustainable antimicrobial resistance interventions","authors":"Gianmarco Gasperini,&nbsp;Silvia Rossi Paccani,&nbsp;Karen O’Dwyer,&nbsp;David M. Aanensen,&nbsp;Darius Armstrong-James,&nbsp;Francesco Berlanda Scorza,&nbsp;David E. Bloom,&nbsp;Christopher J. Burns,&nbsp;Madalina Elena Carter-Timofte,&nbsp;Felipe J. Colón-González,&nbsp;Shampa Das,&nbsp;Michael N. Dudley,&nbsp;Philippe Denoel,&nbsp;Gordon Dougan,&nbsp;Erin M. Duffy,&nbsp;Alison Holmes,&nbsp;Anders Karlén,&nbsp;Neil Pearson,&nbsp;Rosanna Ŵ. Peeling,&nbsp;Jesus Rodriguez-Manzano,&nbsp;J. P. Sevilla,&nbsp;Shiranee Sriskandan,&nbsp;Sumithra Subramaniam,&nbsp;Herbert W. Virgin,&nbsp;Rino Rappuoli,&nbsp;David Payne,&nbsp;Ennio De Gregorio","doi":"10.1126/scitranslmed.aef8416","DOIUrl":"10.1126/scitranslmed.aef8416","url":null,"abstract":"<div >Integrated strategies to combat antibiotic-resistant bacteria and fungi require innovative commercial models, new discovery platforms, standardized genomic surveillance, and streamlined clinical trials. Machine learning and other new technologies will accelerate the development of diagnostics and therapeutics (small molecules, antibodies, and vaccines) to combat antimicrobial resistance. Next-generation approaches should align societal impact with investment to ensure rapid global public health gains.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 871","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172521","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":"Editorial Expression of Concern for the Research Article “In vivo CRISPR activation screen identifies acyl-CoA–binding protein as a driver of bone metastasis”","authors":"Valda Vinson,&nbsp;Orla Smith","doi":"10.1126/scitranslmed.aem8786","DOIUrl":"10.1126/scitranslmed.aem8786","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 871","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149177787","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":"Preclinical and first-in-human evaluation of VG-3927/SAR448851, an oral small-molecule TREM2 agonist for Alzheimer’s disease","authors":"Borislav Dejanovic,&nbsp;Matthew D. Figley,&nbsp;Elizabeth Weisman,&nbsp;Beril Kiragasi,&nbsp;Frederick W. Gergits,&nbsp;Kelley Larson,&nbsp;Abigail Renoux,&nbsp;Raj Rajagovindan,&nbsp;Bhaumik Pandya,&nbsp;Jonathan Houze,&nbsp;Liyue Huang,&nbsp;Francois Gaudreault,&nbsp;Ryan O’Mara,&nbsp;Jade H. Clarkson,&nbsp;Marion T. Turnbull,&nbsp;Andreas Meier,&nbsp;Marco Colonna,&nbsp;Jessica Stromme,&nbsp;David Gray,&nbsp;Evan A. Thackaberry,&nbsp;Petra Kaufmann,&nbsp;Christian Mirescu","doi":"10.1126/scitranslmed.aec5740","DOIUrl":"10.1126/scitranslmed.aec5740","url":null,"abstract":"<div >Microglial dysfunction is increasingly implicated in Alzheimer’s disease (AD) pathogenesis, with loss-of-function variants in the microglial receptor TREM2 as major risk factors for late-onset AD. We report VG-3927, an oral, CNS-penetrant small-molecule TREM2 agonist that engages the transmembrane domains of TREM2 and its adaptor DAP12 to promote higher-order receptor complex formation and downstream signaling. VG-3927 and tool compound VG-3909 exhibited (sub)nanomolar potency, cooperated with endogenous ligands including amyloid-β (Aβ), and restored signaling in disease-associated TREM2 variants. In human iPSC-derived neuron-microglia-astrocyte cultures, VG-3927 reduced inflammatory cytokines and markers of neuronal damage. In 5xFAD amyloidosis mice expressing the common variant of hTREM2 (5xFAD;hTREM2^CV), VG-3909 induced neuroprotective transcriptional reprogramming of microglia, particularly in the plaque niche; enhanced Aβ phagocytosis; and boosted brain glucose metabolism. By contrast, a TREM2 agonist antibody, which may be sequestered by soluble TREM2 (sTREM2), failed to engage plaque microglia. In a first-in-human, randomized, double-blind, placebo-controlled phase 1 trial (NCT06343636, <i>n</i> = 115), VG-3927 was well tolerated across single and multiple ascending doses of up to 140 milligrams. Pharmacokinetics supported once-daily dosing with high CNS penetration (CSF-to-unbound plasma ratio of 0.91). VG-3927 induced dose-dependent reductions in CSF sTREM2, a biomarker of target engagement, consistent across healthy and elderly participants and participants with AD, supporting further clinical development in AD under the new designation SAR448851.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 871","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172523","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":"Prevention is better than cure","authors":"Mark E. J. Woolhouse","doi":"10.1126/scitranslmed.adw9354","DOIUrl":"10.1126/scitranslmed.adw9354","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 871","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adw9354","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149177786","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":"Metabolomic aging and mortality clocks based on ensemble learning identify systemic aging risk across the human life span in 18,476 individuals","authors":"Linlin Cao,&nbsp;Yifan Chen,&nbsp;Wei Zhang,&nbsp;Huiru Jiang,&nbsp;Honghao Huang,&nbsp;Yudian Xu,&nbsp;Xi Li,&nbsp;Wei Xu,&nbsp;Kun Qian,&nbsp;Jun Pu","doi":"10.1126/scitranslmed.adz4815","DOIUrl":"10.1126/scitranslmed.adz4815","url":null,"abstract":"<div >Aging is characterized by progressive functional decline, yet metabolomic signatures across the human life span remain incompletely defined. Here, we profiled plasma metabolomes from 18,476 participants aged 1 to 96 years across six centers in China using nano-assisted laser desorption/ionization mass spectrometry (LDI-MS) and identified 56 representative age-associated metabolites. In a healthy cohort, we developed a stacking ensemble model to estimate metabolomic age and quantified metabolomic age acceleration (mAA) as each individual’s deviation from chronological age. Higher mAA was associated with health deterioration and unfavorable lifestyles. During follow-up from 2019 to 2025, individuals with accelerated mAA showed increased risk of incident chronic diseases, such as fatty liver disease, hypertension, and diabetes, as well as increased all-cause mortality. In a disease cohort, we further developed a mortality-linked metabolomic metric (age deviation) that quantified individualized departures from age-expected mortality risk inferred from plasma metabolites. Age deviation was associated with established composite health measures and increased with multisystem disease involvement and higher multimorbidity burden. Together, these findings support the potential of plasma metabolomic profiling as a scalable, life span–wide approach for deriving clinically interpretable metabolomic aging metrics associated with health status, chronic disease risk, and mortality.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 871","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adz4815","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172524","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}