Science Translational Medicine最新文献

{"title":"From code to cure: Harnessing AI for antibiotic discovery and design","authors":"Aarti Krishnan,&nbsp;Hanqun Cao,&nbsp;James J. Collins,&nbsp;Cesar de la Fuente-Nunez","doi":"10.1126/scitranslmed.aee4629","DOIUrl":"10.1126/scitranslmed.aee4629","url":null,"abstract":"<div >Artificial intelligence (AI) now enables the exploration of vast chemical and sequence spaces, the design of synthesizable antibiotics, and the prioritization of safe, mechanism-diverse candidates through integrated modeling and accelerated testing. Here, we survey recent advances in AI for both small-molecule and peptide antimicrobial drugs, highlight emerging data and reporting standards, and outline translational pathways and regulatory hurdles needed to bring these agents to patients.</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.aee4629","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172522","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":"Quinolinic acid contributes to maladaptive kidney injury and acute kidney injury–to–chronic kidney disease transition","authors":"Marie Christelle Saade,&nbsp;Afaf Saliba,&nbsp;Amanda J. Clark,&nbsp;Subrata Debnath,&nbsp;Shiqi Zhang,&nbsp;Nagarjunachary Ragi,&nbsp;Valerie Etzrodt,&nbsp;Rahil Al-Humaidi,&nbsp;Kyle Vu,&nbsp;Yu Tao,&nbsp;Esmeralda Trevino,&nbsp;Alejandra L. Lorenzen,&nbsp;Guanshi Zhang,&nbsp;Anders H. Berg,&nbsp;Jason C. O’Connor,&nbsp;Samir M. Parikh,&nbsp;Kumar Sharma","doi":"10.1126/scitranslmed.aec9689","DOIUrl":"10.1126/scitranslmed.aec9689","url":null,"abstract":"<div >The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) remains a major clinical problem with unclear underlying mechanisms. Emerging evidence suggests that alterations in tryptophan metabolism, particularly in the production of downstream metabolites such as quinolinic acid (QA), play a role in renal pathophysiology. QA, an intermediate in de novo nicotinamide adenine dinucleotide biosynthesis, is metabolized by quinolinate phosphoribosyltransferase (QPRT). We investigated whether QA contributes to kidney injury using models of folic acid–induced AKI-to-CKD transition and cisplatin-induced AKI, genetic and exogenous approaches to alter QA, and clinical observations. Untargeted kidney metabolomics identified QA as one of the most elevated metabolites after folic acid injury. After folic acid injury, <i>Qprt</i> haploinsufficiency exacerbated kidney injury and fibrosis-related gene expression; aged <i>Qprt</i>-haploinsufficient mice exhibited increased fibrosis-associated gene expression without overt renal dysfunction. Exogenous QA administration increased serum creatinine in uninjured mice and worsened renal dysfunction and fibrosis-related gene expression in the folic acid AKI-to-CKD model. Conversely, mice deficient in either 3-hydroxyanthranilate 3,4-dioxygenase (HAAO) or kynurenine 3-monooxygenase (KMO), which reduce flux toward QA, showed improved renal outcomes after folic acid injury and cisplatin-induced AKI. Multimodal spatial metabolomics analysis of kidney biopsies from patients with AKI revealed QA accumulation in regions of inflammatory infiltration. Last, children with CKD exhibited higher urinary QA compared with healthy individuals. These findings underscore QA as a potential mediator of kidney injury and a therapeutic target for preventing the progression from AKI to CKD.</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":"149172499","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":"Orthogonal Fc engineering enables multiplexed delivery of mRNA-encoded bispecific antibodies that constrain viral escape","authors":"Anna Z. Wec,&nbsp;Alice Cho,&nbsp;Simone Pecetta,&nbsp;Xiaozhen Hu,&nbsp;Michael F. Bender,&nbsp;Adrian R. Laciak,&nbsp;Jacob Hou,&nbsp;Fanchong Jian,&nbsp;Elif N. Korkmaz,&nbsp;Arvind Sharma,&nbsp;Nathen Bopp,&nbsp;Steve Sazinsky,&nbsp;Daniela Montes-Berrueta,&nbsp;Tessa Speidel,&nbsp;Diana Lee,&nbsp;Pradeep Babu Jagadeesh Reddy,&nbsp;Yunlong Cao,&nbsp;Andrea Carfi,&nbsp;William R. Schief,&nbsp;Laura M. Walker","doi":"10.1126/scitranslmed.aeh1292","DOIUrl":"10.1126/scitranslmed.aeh1292","url":null,"abstract":"<div >The continuous antigenic evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has repeatedly undermined the effectiveness of monoclonal antibody (mAb) therapies, underscoring the need for innovative approaches that improve therapeutic mAb breadth and durability of protection. Here, we engineered messenger ribonucleic acid (mRNA)–encoded bispecific antibodies (bsAbs) that, upon intravenous administration in lipid nanoparticles, achieved high serum concentrations, extended half-life, and serum neutralizing titers exceeding 1:10,000 in human neonatal Fc receptor (FcRn)–expressing mice. To enhance resilience to viral escape, we used structure-guided computational design to introduce Fc modifications that promoted selective homodimerization, thereby enabling codelivery of multiple mRNA-encoded bsAbs with cognate heavy chain pairing. In vivo expression of a triple bsAb combination resulted in broad serum neutralization of historical and contemporary SARS-CoV-2 variants, including the highly mutated BA.3.2.2 lineage. Preexposure prophylaxis with the mRNA-delivered bsAb combination conferred protection against SARS-CoV-2 XBB.1.5 challenge, preventing weight loss and decreasing viral burden in the lungs compared with vehicle control treatment. Together, the results provide proof of principle for mRNA-based delivery of Fc-engineered bsAb combinations to combat SARS-CoV-2 and potentially other rapidly evolving pathogens.</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":"149172501","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":"Retraction of the Research Article “SARS-CoV-2 S2–targeted vaccination elicits broadly neutralizing antibodies”","authors":"Valda Vinson,&nbsp;Orla Smith","doi":"10.1126/scitranslmed.aem5154","DOIUrl":"10.1126/scitranslmed.aem5154","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":"149177817","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":"Rifampicin-resistant TB: An inflection point in antimicrobial resistance","authors":"Cesar Augusto Roque-Borda,&nbsp;João Perdigão,&nbsp;Fernando Rogério Pavan","doi":"10.1126/scitranslmed.aeg5988","DOIUrl":"10.1126/scitranslmed.aeg5988","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.aeg5988","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149177785","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":"Restoration of PP2A AαB56αC trimer formation by RPT04402 molecular glue in high-grade uterine cancer","authors":"Irene Peris,&nbsp;Terrance J. Haanen, III,&nbsp;Alexander Day,&nbsp;Jiang Hu,&nbsp;Catherine Callahan,&nbsp;Gabrielle Hodges-Onishi,&nbsp;Kaitlin P. Zawacki,&nbsp;Brian Tran,&nbsp;Alexis Harold,&nbsp;Amanda Dowdican,&nbsp;Charles A. Nino,&nbsp;Wei Huang,&nbsp;Daniel Leonard,&nbsp;Matthew Hinderman,&nbsp;Kelsey Barrie,&nbsp;Brynne Raines,&nbsp;Jaya Sangodkar,&nbsp;Sophie Boock,&nbsp;Varsha Shankar,&nbsp;Miranda Giambi,&nbsp;Silvia Romero-Murillo,&nbsp;Leah Arbitman,&nbsp;Shirish Shenolikar,&nbsp;George Trainor,&nbsp;Frederic Cachoux,&nbsp;Obdulia Rabal,&nbsp;Olga Gherbovet,&nbsp;Laura Fourmois,&nbsp;David L. Brautigan,&nbsp;Analisa V. DiFeo,&nbsp;Derek J. Taylor,&nbsp;Caitlin M. O’Connor,&nbsp;Goutham Narla","doi":"10.1126/scitranslmed.ady4852","DOIUrl":"10.1126/scitranslmed.ady4852","url":null,"abstract":"<div >The incidence and mortality of high-grade endometrial cancers are increasing, and heterozygous hotspot mutations in <i>PPP2R1A</i> are drivers of the most aggressive forms of uterine cancer. <i>PPP2R1A</i> encodes the Aα scaffolding subunit of the heterotrimeric phosphatase PP2A. These recurrent mutations, specifically at the Pro¹⁷⁹ and Ser²⁵⁶ residues, disrupt the binding of tumor-suppressive substrate-directing B56 and B55 subunits to the PP2A scaffolding subunit while maintaining binding to other regulatory subunits. Here, we identified a series of molecular glues that correct PP2A trimer formation in the context of the P179R (Pro¹⁷⁹→Arg) and S256F (Ser²⁵⁶→Phe) mutants. A small-molecule library was designed to fit into the pocket at the binding interface of the Aα/B56α/C heterotrimer. The lead molecule, RPT04402, promoted B56α heterotrimerization to the Aα^P179R and Aα^S256F mutant scaffolds. In mice, RPT04402 treatment drove tumor regressions and extended median survival in multiple independent mutant cell lines and patient-derived xenografts, proving a robust single-agent activity. This activity was abrogated upon knockout of B56α. Combined, these data demonstrate that PP2A molecular glues are a promising first-in-class therapy that might benefit patients with <i>PPP2R1A</i> mutant uterine cancer by targeting a driver of this aggressive disease.</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":"149172525","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":"Human microglia clear intraneuronal α-synuclein aggregates by GPNMB-mediated trogocytosis","authors":"Hung-Ju Chueh,&nbsp;Antigoni Katsikoudi,&nbsp;Ana Aragón-González,&nbsp;Chor Lai Lam,&nbsp;Liezel Tamon,&nbsp;Ashwin Jainarayanan,&nbsp;Devika Agarwal,&nbsp;Sally A. Cowley,&nbsp;David Sims,&nbsp;George K. Tofaris","doi":"10.1126/scitranslmed.adz9258","DOIUrl":"10.1126/scitranslmed.adz9258","url":null,"abstract":"<div >Microglia are the primary immune cells of the brain, but their role in Parkinson’s disease is not fully understood. Chronic microglial activation is toxic to neurons, but in the early stages of pathology, microglia also exert beneficial functions. We used induced pluripotent stem cell (iPSC)–derived coculture models to investigate how human microglia respond to α-synuclein aggregates that form de novo inside human dopaminergic neurons with α-synuclein gene triplication or are triggered by fibrils. We found that microglia cleared Ser¹²⁹-phosphorylated α-synuclein aggregates through a contact-dependent mechanism. This process was fine-tuned by sensing (P2RY12) and inhibitory (CD22) signals and involved selective phagocytosis of neuronal subcompartments (trogocytosis), independently of TREM2 or phosphatidylserine. In the presence of intraneuronal α-synuclein aggregates, microglia exhibited morphological and transcriptional changes indicative of activation. Using single-cell sequencing, we identified a cluster of disease-associated microglia (DAM) responsible for this beneficial phenotype and the Parkinson’s disease GWAS candidate glycoprotein nonmetastatic melanoma protein B (GPNMB) as a key effector of aggregate clearance by microglial lysosomes. GPNMB interacted with Ser¹²⁹-phosphorylated α-synuclein in iPSC-derived microglia exposed to aggregate-laden dopaminergic neurons and was up-regulated in substantia nigra microglia of individuals with incidental Lewy bodies or Parkinson’s disease. Microglia-specific GPNMB knockdown using CRISPRi reduced intraneuronal aggregate clearance. GPNMB-mediated trogocytosis was negatively regulated by an autocrine IL-10 signaling loop, whereas IL-10 receptor blockade enhanced the phagocytic response. Together, our study identifies a subtype of human microglia capable of removing intraneuronal aggregates and potential therapeutic targets.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 870","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149093289","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":"Turning the tables: Repurposing neuroplasticity to defeat cancer","authors":"Moran Amit","doi":"10.1126/scitranslmed.aei6916","DOIUrl":"10.1126/scitranslmed.aei6916","url":null,"abstract":"<div >Instead of asking what nerves do to cancer, my work reveals how cancer injures and reprograms peripheral nerves to drive immune evasion and how targeting this process restores immunotherapy responses.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 870","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.aei6916","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149093349","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":"Transient receptor potential channel activation targets multiple stages of the schistosome parasite","authors":"Shashank Kulkarni,&nbsp;Sang-Kyu Park,&nbsp;Youssef Hamway,&nbsp;Lukas Friedrich,&nbsp;Jesko Kaiser,&nbsp;Evgeny G. Chulkov,&nbsp;Claudia M. Rohr,&nbsp;Cécile Häberli,&nbsp;Martin Horn,&nbsp;Tobias Hyun Ho Bäurle,&nbsp;Mario Pellegatti,&nbsp;Gary Grosser,&nbsp;Axel Becker,&nbsp;Rana Afshar,&nbsp;Andreas Becker,&nbsp;Nico Alexander Mell,&nbsp;Floriane Lignet,&nbsp;Philip Hewitt,&nbsp;Annika Hansen,&nbsp;Christian Brenneis,&nbsp;Jan Dvorak,&nbsp;Clarissa Prazeres da Costa,&nbsp;Jennifer Keiser,&nbsp;Jonathan S. Marchant,&nbsp;Thomas Spangenberg","doi":"10.1126/scitranslmed.aed8353","DOIUrl":"10.1126/scitranslmed.aed8353","url":null,"abstract":"<div >Schistosomiasis, a neglected tropical disease caused by infection with parasitic blood flukes of the genus <i>Schistosoma</i>, affects more than 250 million people worldwide. Currently, patients rely on a single medicine, praziquantel (PZQ), discovered half a century ago. To combat drug resistance and reach elimination of the schistosome parasite, alternative drugs to PZQ are required that treat and prevent disease. Here, we describe a drug candidate, M5493, with potent activity against multiple parasite life cycle stages. The target is a parasite transient receptor potential ion channel, distinct from the target of PZQ. To circumvent its limited bioavailability, the active agent was converted to prodrug M5493, which displayed robust activity against the schistosome parasite at doses as low as 5 milligrams per kilogram in mice infected with <i>Schistosoma mansoni</i>. Unlike the benzodiazepine meclonazepam, which displays clinical antihelminthic activity through the same target, M5493 showed no sedating side effects given that it did not engage GABA_A receptors. Overall, this compound has the potential to provide single-dose treatment, broad-spectrum efficacy against schistosome parasites at different life cycle stages, and transmission blocking activity.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 870","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149093286","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":"Use of split intein and myotropic AAV vectors enables effective preclinical gene therapy for dysferlinopathy","authors":"Nikki M. McCormack,&nbsp;Stephanie Lee-Diaz,&nbsp;Theodore R. Reyes,&nbsp;Marshall W. Hogarth,&nbsp;Jada L. Covington,&nbsp;Camryn A. Bragg,&nbsp;Zarek O. Harper,&nbsp;Thomas Diehn,&nbsp;James S. Novak,&nbsp;Christine L. Halbert,&nbsp;Jeffrey S. Chamberlain,&nbsp;David L. Mack,&nbsp;Martin K. Childers,&nbsp;Jyoti K. Jaiswal,&nbsp;Hichem Tasfaout","doi":"10.1126/scitranslmed.aei5938","DOIUrl":"10.1126/scitranslmed.aei5938","url":null,"abstract":"<div >Limb-girdle muscular dystrophy type R2 (LGMDR2) is a genetic disorder characterized by progressive skeletal muscle weakness and degeneration. It is caused by mutations in the <i>DYSF</i> gene, which prevent dysferlin expression. Dysferlin protein is essential for muscle cell membrane repair. Gene therapy using adeno-associated viral (AAV) vectors to restore full-length dysferlin expression is a promising therapeutic approach for LGMDR2. However, the large size of the dysferlin cDNA (6.2 kilobases) exceeds the ∼4.7-kilobase packaging capacity of AAV vectors, posing a challenge to effective delivery of the full-length protein. Here, we describe the use of split inteins and myotropic AAV vectors for efficient systemic gene delivery and expression of full-length dysferlin in the muscles of an LGMDR2 mouse model. We generated and validated a potent split-intein version of dysferlin that enables reconstitution of scarless full-length dysferlin protein. In vitro assessment of these constructs demonstrated a high capacity of the reconstituted dysferlin to restore membrane repair defects in dysferlinopathic mouse myoblasts. Systemic administration of split-intein and dysferlin dual AAVMYO1 vectors improved muscle strength, increased contractile force, and reduced histopathological abnormalities in the LGMDR2 mouse model at both the presymptomatic stage and late stage of the disease. Compared with the homologous recombination dual–AAV vector strategy, the split-intein technology demonstrated superior efficiency in restoring the full-length dysferlin protein and resulted in greater functional improvements. These findings demonstrate the curative potential of this split intein–based gene therapy approach for LGMDR2.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 870","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149093285","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}