Nature Medicine最新文献

{"title":"Safety and pharmacokinetics of SARS-CoV-2 DNA-encoded monoclonal antibodies in healthy adults: a phase 1 trial.","authors":"Pablo Tebas, Ami Patel, Joseph T Agnes, Elizabeth M Parzych, Amanda Baer, Maria Caturla, Sukanya Ghosh, Mansi Purwar, Nicole Bedanova, Chungdhak Tsang, Knashawn Morales, Dinah Amante, Paul D Fisher, Joseph R Francica, Laurent Humeau, Daniel W Kulp, Jesper Pallesen, Paul Leon, Mark Esser, Trevor R F Smith, David B Weiner","doi":"10.1038/s41591-025-03969-0","DOIUrl":"https://doi.org/10.1038/s41591-025-03969-0","url":null,"abstract":"<p><p>Local intramuscular administration of synthetic plasmid DNA (pDNA) encoding monoclonal antibodies (mAb) offers an alternative to recombinant protein-based mAb delivery. In this phase 1 dose-escalation study, we evaluated the safety, tolerability and pharmacokinetics of a pDNA cocktail encoding AZD5396 and AZD8076, modified versions of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing mAb cocktail tixagevimab/cilgavimab in healthy adults. Participants received up to four intramuscular doses of pDNA encoding both DNA-based mAbs (DMAbs), administered using CELLECTRA electroporation. The primary endpoints were safety and pharmacokinetics. All 44 participants received at least one dose; DMAbs were detected in 100% of evaluable participants (n = 39), with serum concentrations reaching a peak of 1.61 µg ml^-1. Sustained expression was observed in all participants during the 72 weeks of follow-up. The study product was well tolerated, with no product-related serious adverse events reported. Exploratory analyses demonstrated binding to multiple SARS-CoV-2 Spike protein variants and neutralizing activity in a standard pseudovirus assay. No antidrug antibodies were detected across approximately 1,000 serum samples using validated tiered assays. To our knowledge, these data represent the first-in-human proof-of-concept that synthetic pDNA DMAb technology permits the durable in vivo production of a functional mAb cocktail. This study further underscores the collective importance of synthetic design, formulation and delivery to achieve biologically relevant expression of gene-encoded biologics. DMAb delivery may represent a long-acting, scalable, cold-chain-independent platform against a wide range of diseases that can be targeted with mAbs and their derivatives. ClinicalTrials.gov registration: NCT05293249.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145346250","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":"Teaching machines to doubt.","authors":"Leo Anthony Celi","doi":"10.1038/s41591-025-04013-x","DOIUrl":"https://doi.org/10.1038/s41591-025-04013-x","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145346253","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":"Cardiac gene therapy makes a comeback.","authors":"Oliver J Müller, Susanne Hille, Anca Kliesow Remes","doi":"10.1038/s41591-025-04002-0","DOIUrl":"https://doi.org/10.1038/s41591-025-04002-0","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145346334","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":"Cardiotropic AAV gene therapy for heart failure: a phase 1 trial.","authors":"Timothy D Henry, Eugene S Chung, Monica Alvisi, Ferzin Sethna, David R Murray, Jay H Traverse, Lothar Roessig, Luke Roberts, Swarna Reddy, Youjun Chen, Tugba Guven Ozkan, Stacy Webb, Monika Mittal, Leigh Ervin, Hesham Sadek, Sheila Mikhail, Kobra Haghighi, Canwen Jiang, R Jude Samulski, Evangelia G Kranias, Anna P Tretiakova, Roger J Hajjar","doi":"10.1038/s41591-025-04011-z","DOIUrl":"https://doi.org/10.1038/s41591-025-04011-z","url":null,"abstract":"<p><p>Innovative approaches for the treatment of heart failure are needed beyond conventional medical therapy to reverse ventricular dysfunction and modify the course of the disease. AB-1002, a chimeric cardiotropic adeno-associated viral vector that delivers constitutively active protein phosphatase 1 inhibitor 1 to cardiomyocytes, improves cardiac function in preclinical models of heart failure. Here we carried out a phase 1 study to evaluate the safety and feasibility of a single antegrade coronary artery infusion of AB-1002 in patients with nonischemic cardiomyopathy, New York Heart Association class III heart failure, and a left ventricular ejection fraction of 15-35%. Patients received 3.25 × 10¹³ viral genomes (cohort 1, n = 6) or 1.08 × 10¹⁴ viral genomes (cohort 2, n = 5). In total, nine men and two women were included in the study. No adverse events (AEs) or serious AEs were attributed by the investigators to the study treatment; most AEs were mild or moderate in severity. One death occurred, which was considered not to be related to the treatment with AB-1002. Self-limiting, mild, asymptomatic elevations in liver enzymes occurred, predominantly in cohort 2. The preliminary assessments of efficacy outcomes showed improvements in the New York Heart Association class and left ventricular ejection fraction in both cohorts and improvements in peak oxygen consumption and 6-min walk test performance in cohort 1. These results support the further assessment of AB-1002 in clinical trials. The ClinicalTrials.gov registration was NCT04179643 .</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145346245","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":"Creativity keeps the brain young.","authors":"Karen O'Leary","doi":"10.1038/d41591-025-00063-3","DOIUrl":"https://doi.org/10.1038/d41591-025-00063-3","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337269","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":"Myelin injury precedes axonal injury and symptomatic onset in multiple sclerosis.","authors":"Ahmed Abdelhak, Gabriel Cerono, Fahime Sheikhzadeh, Adil Harroud, Kiarra Ning, Colin R Zamecnik, Gavin M Sowa, John Boscardin, Christian Cordano, Asritha Tubati, Camille Fouassier, Eric D Chow, Refujia Gomez, Adam Santaniello, Kelsey C Zorn, Jill A Hollenbach, Jorge R Oksenberg, Bruce A C Cree, Stephen L Hauser, Jonah R Chan, Sergio E Baranzini, Mitchell T Wallin, Michael R Wilson, Ari J Green","doi":"10.1038/s41591-025-04014-w","DOIUrl":"https://doi.org/10.1038/s41591-025-04014-w","url":null,"abstract":"<p><p>The timing of the biological onset of multiple sclerosis (MS) is unclear. We used high-throughput discovery proteomics and samples from presymptomatic patients with MS and matched healthy controls to define the biological neurological onset and characterize the mechanisms involved. Remarkably, evidence of myelin injury was seen ~7 years before the symptomatic onset and preceded evidence of axonal injury by ~1 year. By contrast, astrocyte involvement became evident only at clinical onset. Numerous changes in the serum proteome indicate the involvement of interleukin 3 and nuclear factor kappa B pathways during the presymptomatic stage. Furthermore, people with MS with a previously reported distinct autoantibody signature showed increased immune cell activity compared to those without. We propose a protein biomarker panel that may help distinguish presymptomatic patients with MS from healthy controls, pending validation in future studies. Our findings can help understand the pathophysiology of MS as well as the cascade of central nervous system injury and might facilitate early detection of MS in high-risk people.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337340","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":"Circulating tumor DNA-guided adjuvant therapy in locally advanced colon cancer: the randomized phase 2/3 DYNAMIC-III trial.","authors":"Jeanne Tie, Yuxuan Wang, Jonathan M Loree, Joshua D Cohen, Rachel Wong, Timothy Price, Niall C Tebbutt, Val Gebski, David Espinoza, Matthew Burge, Sam Harris, James Lynam, Belinda Lee, Margaret M Lee, Daniel Breadner, Marlyse Debrincat, Siavash Foroughi, Lorraine Chantrill, Stephanie H Lim, Sharlene Gill, Chris O'Callaghan, Janine Ptak, Natalie Silliman, Lisa Dobbyn, Maria Popoli, Chetan Bettegowda, Nicholas Papadopoulos, Kenneth W Kinzler, Bert Vogelstein, Peter Gibbs","doi":"10.1038/s41591-025-04030-w","DOIUrl":"https://doi.org/10.1038/s41591-025-04030-w","url":null,"abstract":"<p><p>Adjuvant chemotherapy in stage III colon cancer provides uncertain benefit at the individual level. Circulating tumor DNA (ctDNA) may help refine risk-adjusted treatment selection. In this multicenter, randomized, phase 2/3 trial, patients with stage III colon cancer underwent ctDNA testing 5-6 weeks after surgery and were assigned (1:1) to ctDNA-guided or standard management. In the ctDNA-guided arm, patients negative for ctDNA received de-escalated therapy, whereas ctDNA-positive patients received escalated therapy. Clinicians prespecified the standard regimen. Primary endpoints were 3-year recurrence-free survival (RFS) for ctDNA-negative patients and 2-year RFS for ctDNA-positive patients. Secondary endpoints included treatment-related hospitalization and ctDNA clearance. Among 968 evaluable patients, 702 (72.5%) were ctDNA negative. With a median follow-up of 47 months, ctDNA-negative patients experienced significantly fewer recurrences than ctDNA-positive patients (3-year RFS 87% versus 49%; P < 0.001). In ctDNA-negative patients, de-escalation reduced oxaliplatin use (34.8% versus 88.6%) and hospitalizations (8.5% versus 13.2%) but yielded slightly lower RFS than standard management (85.3% versus 88.1%), not meeting the non-inferiority margin. In ctDNA-positive patients, higher ctDNA burden correlated with recurrence risk (3-year RFS 77% to 23% across quartiles; P < 0.001). Escalated therapy did not improve outcomes over standard management (2-year RFS 51% versus 61%). There was no unexpected toxicity. Persistent ctDNA after treatment predicted markedly worse prognosis (3-year RFS 14% versus 79%). ctDNA is validated as a strong prognostic classifier. ctDNA-guided de-escalation reduced oxaliplatin exposure and adverse events with outcomes approaching standard of care, whereas exploratory chemotherapy intensification conferred no RFS benefit, suggesting a need for novel strategies in ctDNA-positive disease.Australian New Zealand Clinical Trials Registry Identifier: ACTRN12617001566325 .</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337312","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":"Plasma proteome adaptations during feminizing gender-affirming hormone therapy.","authors":"Nhi N L Nguyen, Den Celestra, Lachlan M Angus, Toby Mansell, Rebecca Shepherd, Bo Won Kim, Bridget Arman, Georgiana Cabau, Tania O Crișan, Leo A B Joosten, Camille Laberthonnière, David Burgner, Gilda Tachedjian, Musa Mhlanga, Rachel A Davey, Ken C Pang, Ada S Cheung, Richard Saffery, Boris Novakovic","doi":"10.1038/s41591-025-04023-9","DOIUrl":"https://doi.org/10.1038/s41591-025-04023-9","url":null,"abstract":"<p><p>Sex differences manifest in various traits, as well as in the risk of cardiovascular, metabolic and immunological conditions. Despite the clear physical changes induced by gender-affirming hormone therapy (GAHT), little is known about how it affects underlying physiological and biochemical processes. Here we examined plasma proteome changes over 6 months of feminizing GAHT in 40 transgender individuals treated with estradiol plus one of two antiandrogens: cyproterone acetate or spironolactone. Testosterone levels dropped markedly in the cyproterone group, but less so in those receiving spironolactone. Among 5,279 total proteins measured, feminizing GAHT changed the levels of 245 and 91, in the cyproterone and spironolactone groups, respectively, with most (>95%) showing a decrease. Proteins associated with male spermatogenesis showed a marked decrease in the cyproterone group, attributable specifically to loss of testosterone. Changes in body fat percentage and breast volume following GAHT were also reflected in the plasma proteome, including an increase in leptin expression. We show that feminizing GAHT remodels the proteome toward a cis-female profile, altering 36 (cyproterone) and 22 (spironolactone) of the top 100 sex-associated proteins in UK Biobank adult data. Moreover, 43% of cyproterone-affected proteins overlapped with those altered by menopausal hormone therapy in cis women, showing the same directional changes, with notable exceptions including CXCL13 and NOS3. Feminizing GAHT skewed the protein profile toward that linked to asthma and autoimmunity, while GAHT with cyproterone specifically skewed it away from an atherosclerosis-associated profile, suggesting a protective effect. These results reveal that feminizing GAHT reshapes the plasma proteome in a hormone-dependent manner, with implications for reproductive capacity, immune regulation and long-term health outcomes.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337314","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":"A simple strategy to cut malaria infection rates in babies.","authors":"Karen O'Leary","doi":"10.1038/d41591-025-00061-5","DOIUrl":"https://doi.org/10.1038/d41591-025-00061-5","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337316","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":"YAP/TEAD inhibitor VT3989 in solid tumors: a phase 1/2 trial.","authors":"Timothy A Yap, David J Kwiatkowski, Ibiayi Dagogo-Jack, Michael Offin, Marjorie G Zauderer, Robert Kratzke, Jayesh Desai, Amy Body, Michael Millward, Anthony W Tolcher, Kanwal P S Raghav, Archie Thurston, Len Post, F Andrew Dorr, Tracy T Tang, Yufeng Li, Neelesh Sharma, Hedy L Kindler","doi":"10.1038/s41591-025-04029-3","DOIUrl":"https://doi.org/10.1038/s41591-025-04029-3","url":null,"abstract":"<p><p>Constitutive YAP activation resulting from dysregulated Hippo signaling drives tumor progression in mesothelioma and other cancers. VT3989, a first-in-class potent oral TEAD palmitoylation inhibitor, disrupts YAP transcriptional activity. Here we report the first-in-human phase 1/2 trial findings evaluating VT3989 in refractory solid tumors with a focus on mesothelioma. This study is ongoing, and we report results from the dose escalation and non-prespecified interim efficacy results of the expansion cohorts for which recruitment is ongoing. Dose escalation (n = 85) and expansion (n = 87) cohorts included 172 patients (135 mesothelioma). VT3989 exhibited a favorable safety profile with mostly grade 1-2 toxicities, including increased urine albumin:creatinine ratio (UACR), proteinuria, peripheral edema and fatigue. Proteinuria was reversible with dose adjustment and did not result in renal impairment. The overall response rate (ORR) was 26% in 47 patients with mesothelioma treated at clinically optimized doses, whereas the ORR was 32% (disease control rate 86%; median progression-free survival 10 months) in 22 patients with mesothelioma when clinically optimized doses and UACR thresholds were incorporated. These data provide the first early clinical proof of concept for effectively drugging the Hippo-YAP-TEAD pathway. VT3989 was recently awarded orphan drug designation and fast-track designation for the treatment of mesothelioma by the US Food and Drug Administration (FDA). ClinicalTrials.gov Identifier: NCT04665206 .</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329633","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}