Science Translational Medicine最新文献

{"title":"Islet transplantation in immunomodulatory nanoparticle–remodeled spleens","authors":"Mi Liu,&nbsp;Huiming Deng,&nbsp;Chunyan Liu,&nbsp;Lintao Wang,&nbsp;Zhongkai Liao,&nbsp;Desheng Li,&nbsp;Yan Chen,&nbsp;Jianhui Li,&nbsp;Jianhui Dong,&nbsp;Xuyong Sun,&nbsp;Chunming Wang,&nbsp;Ling Huang,&nbsp;Lei Dong,&nbsp;Jian Xiao","doi":"10.1126/scitranslmed.adj9615","DOIUrl":"10.1126/scitranslmed.adj9615","url":null,"abstract":"<div >Islet transplantation is a promising therapy for insulin-dependent diabetes. However, immune rejection and insufficient vascularization hinder the survival and function of transplanted islets. Here, we show effective engraftment of vascularized and functional mouse and rat islets transplanted into biomaterial-remodeled spleens of nonimmunosuppressed rodents and human islets transplanted into the remodeled spleens of nonhuman primates (NHPs) on varying degrees of immunosuppression. We found evidence that konjac glucomannan–modified silica nanoparticles (KSiNPs) remodeled the spleen into an extracellular matrix (ECM)–rich, immunosuppressive niche to support the survival of syngeneic or xenogeneic islets. Transplanted islets in the remodeled spleens showed improved engraftment, neovascularization, and functionality and restored normoglycemia in streptozotocin (STZ)–induced type 1 diabetic models in the mice and macaques, with stable insulin and C-peptide secretion in mice for 90 days and macaques for 28 days. KSiNP injection and islet transplantation into macaque spleens under B-ultrasound guidance were preclinically feasible. These findings highlight the safety and effectiveness of spleen tissue remodeling in supporting the survival and function of transplanted islets, providing a promising strategy for treating type 1 diabetes mellitus (T1DM).</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 799","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144104219","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":"Human monoclonal antibodies targeting subdominant meningococcal antigens confer cross-protection against gonococcus","authors":"Marco Troisi,&nbsp;Monica Fabbrini,&nbsp;Samuele Stazzoni,&nbsp;Viola Viviani,&nbsp;Filippo Carboni,&nbsp;Valentina Abbiento,&nbsp;Lucia Eleonora Fontana,&nbsp;Sara Tomei,&nbsp;Martina Audagnotto,&nbsp;Laura Santini,&nbsp;Angela Spagnuolo,&nbsp;Giada Antonelli,&nbsp;Ida Paciello,&nbsp;Fabiola Vacca,&nbsp;Dario Cardamone,&nbsp;Eleonora Marini,&nbsp;Pardis Mokhtary,&nbsp;Francesca Finetti,&nbsp;Fabiola Giusti,&nbsp;Margherita Bodini,&nbsp;Giulia Torricelli,&nbsp;Chiara Limongi,&nbsp;Mariangela Del Vecchio,&nbsp;Sara Favaron,&nbsp;Simona Tavarini,&nbsp;Chiara Sammicheli,&nbsp;Alessandro Rossi,&nbsp;Andrea Paola Mandelli,&nbsp;Pietro Fortini,&nbsp;Carla Caffarelli,&nbsp;Stefano Gonnelli,&nbsp;Ranuccio Nuti,&nbsp;Adriana Efron,&nbsp;Cosima T. Baldari,&nbsp;Claudia Sala,&nbsp;Aldo Tagliabue,&nbsp;Silvana Savino,&nbsp;Brunella Brunelli,&nbsp;Nathalie Norais,&nbsp;Elisabetta Frigimelica,&nbsp;Monia Bardelli,&nbsp;Mariagrazia Pizza,&nbsp;Immaculada Margarit,&nbsp;Isabel Delany,&nbsp;Oretta Finco,&nbsp;Emanuele Andreano,&nbsp;Rino Rappuoli","doi":"10.1126/scitranslmed.adv0969","DOIUrl":"10.1126/scitranslmed.adv0969","url":null,"abstract":"<div >Gonococcus, a bacterium resistant to most antibiotics, causes more than 80 million cases of gonorrhea annually and is considered a high-priority pathogen by the World Health Organization. Recently, vaccine development prospects were boosted by reports that licensed meningococcus serogroup B (MenB) vaccines provided partial protection against gonococcal infection. To determine antigens responsible for cross-protection, memory B cells isolated from 4CMenB-vaccinated volunteers were single cell–sorted to identify antibodies that kill gonococcus in a bactericidal assay. Nine different antibodies, all deriving from the <i>IGHV4-34</i> germline and carrying an unusually long heavy-chain complementarity-determining region 3, recognized the PorB protein; four others recognized the lipooligosaccharide; and another four had unknown specificity. One of the PorB-specific antibodies provided protection in a mouse model of gonococcus infection. The identification of PorB and lipooligosaccharide as key antigens of gonococcal and meningococcal immunity provides a mechanistic explanation of the cross-protection observed in the clinic and shows that isolating human monoclonal antibodies from vaccinees can be instrumental for bacterial antigen discovery.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 799","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144104228","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":"Heterogeneity and evolution of DNA mutation rates in microsatellite stable colorectal cancer","authors":"Elena Grassi,&nbsp;Valentina Vurchio,&nbsp;George D. Cresswell,&nbsp;Irene Catalano,&nbsp;Barbara Lupo,&nbsp;Francesco Sassi,&nbsp;Francesco Galimi,&nbsp;Sofia Borgato,&nbsp;Martina Ferri,&nbsp;Marco Viviani,&nbsp;Simone Pompei,&nbsp;Gianvito Urgese,&nbsp;Bingjie Chen,&nbsp;Eugenia R. Zanella,&nbsp;Francesca Cottino,&nbsp;Mariangela Russo,&nbsp;Gianluca Mauri,&nbsp;Filippo Pietrantonio,&nbsp;Maria Giulia Zampino,&nbsp;Luca Lazzari,&nbsp;Silvia Marsoni,&nbsp;Alberto Bardelli,&nbsp;Marco Cosentino Lagomarsino,&nbsp;Andrea Sottoriva,&nbsp;Livio Trusolino,&nbsp;Andrea Bertotti","doi":"10.1126/scitranslmed.ado1641","DOIUrl":"10.1126/scitranslmed.ado1641","url":null,"abstract":"<div >Historically, DNA sequence mutability has been considered relatively uniform and low in tumors with chromosomal instability (CIN), based on the assumption that high mutability would be detrimental in karyotypically aberrant contexts. Recent in silico analyses have challenged this view, suggesting some heterogeneity in mutation rates across CIN tumors; however, these predictions lack experimental validation. It also remains unclear how the intertumor variability of mutation rates compares to intratumor diversification and evolves along disease progression, whether mutation rates are functionally relevant in CIN cancers, and which mutational processes shape mutational accrual during CIN tumor onset and evolution. To address these gaps, we performed mutation accumulation experiments using clonal populations of patient-derived tumoroids from seven CIN, microsatellite-stable colorectal cancers (CRCs), and one microsatellite-unstable CRC. Each tumor exhibited a distinctive mutation rate footprint that was conserved among different clones from the same ancestor. In contrast, mutation rates diverged markedly across different tumors, with variations in magnitude within microsatellite-stable tumors as prominent as those distinguishing them from microsatellite-unstable tumors. New mutations reflected mutational processes associated with defective DNA replication and repair, which were not detected in normal tissues. Last, both mutation accumulation assays and high-depth whole-exome sequencing of subclonal variants showed higher mutation rates in metastatic lesions compared with matched primary tumors, suggesting positive selection for cells with increasing mutability during cancer dissemination. By providing an empirical assessment of mutation rates in human cancer, our data delineate heterogeneity, heritability, and progression-associated evolvability of DNA mutational instability as hallmarks of microsatellite-stable CRC.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 799","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144104220","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":"SARS-CoV-2 induces neutrophil degranulation and differentiation into myeloid-derived suppressor cells associated with severe COVID-19","authors":"Leon L. Hsieh,&nbsp;Elizabeth A. Thompson,&nbsp;Nirvani P. Jairam,&nbsp;Katerina Roznik,&nbsp;Alexis Figueroa,&nbsp;Tihitina Aytenfisu,&nbsp;Weiqiang Zhou,&nbsp;Naina Gour,&nbsp;Kuan-Hao Chao,&nbsp;Aaron M. Milstone,&nbsp;Emily Egbert,&nbsp;Franco D’Alessio,&nbsp;Petros C. Karakousis,&nbsp;Alvaro Ordoñez,&nbsp;Eileen P. Scully,&nbsp;Andrew Pekosz,&nbsp;Andrew H. Karaba,&nbsp;Andrea L. Cox","doi":"10.1126/scitranslmed.adn7527","DOIUrl":"10.1126/scitranslmed.adn7527","url":null,"abstract":"<div >Severe COVID-19 presents with a distinct immunological profile, characterized by elevated neutrophil and reduced lymphocyte counts, seen commonly in fungal and bacterial infections. This study demonstrates that patients hospitalized with COVID-19 show evidence of neutrophil degranulation and have increased expression of neutrophil surface lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a marker of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Both early LOX-1 and programmed death-ligand 1 (PD-L1) expression on neutrophils were associated with development of severe disease. To determine whether tissue damage or inflammation is required to induce PMN-MDSCs or whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly activates neutrophils to become PMN-MDSCs, we incubated healthy human neutrophils with SARS-CoV-2. SARS-CoV-2 rapidly induced LOX-1 surface expression in healthy neutrophils independent of productive infection. LOX-1 induction was dependent on granule exocytosis and promoted up-regulation of reactive oxygen species, CD63, and PD-L1, enabling LOX-1⁺ neutrophils to suppress autologous T cell proliferation in vitro. These results support a role for PMN-MDSCs in mediating severe COVID-19, and inhibition of PD-L1 represents a potential therapeutic strategy for enhancing the immune response in acute SARS-CoV-2 infection.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 799","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adn7527","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144104218","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":"Icosapent ethyl reduces arterial thrombosis by inhibition of cyclooxygenase-1–induced platelet reactivity","authors":"Philipp Mourikis,&nbsp;Marcel Benkhoff,&nbsp;Laura Wildeis,&nbsp;Maike Barcik,&nbsp;Carolin Helten,&nbsp;Cristina Coman,&nbsp;Fiorella A. Solari,&nbsp;Daniel Krahn,&nbsp;Lisa Dannenberg,&nbsp;Samantha Ahlbrecht,&nbsp;Dorothee Zikeli,&nbsp;Amelie Utz,&nbsp;Kajetan Trojovsky,&nbsp;Hannah Richter,&nbsp;Gabrielle Al Kassis,&nbsp;René M’Pembele,&nbsp;Saif Zako,&nbsp;Tim Huckenbeck,&nbsp;Sofia Bauer,&nbsp;Danny Schmitz,&nbsp;Susanne Pfeiler,&nbsp;Norbert Gerdes,&nbsp;Christof Dücker,&nbsp;Joachim Pircher,&nbsp;Zhang Zhe,&nbsp;Manuela Thienel,&nbsp;Qurrat Ul Ain,&nbsp;Petra Keul,&nbsp;Nicholas Kirkby,&nbsp;Dennis Sohn,&nbsp;Wilfried Budach,&nbsp;Thomas Hohlfeld,&nbsp;Karsten Schrör,&nbsp;Bodo Levkau,&nbsp;Tobias Zeus,&nbsp;Steven H. L. Verhelst,&nbsp;Robert Ahrends,&nbsp;Albert Sickmann,&nbsp;Jane Mitchell,&nbsp;Samia Mora,&nbsp;JoAnn E. Manson,&nbsp;Deepak L. Bhatt,&nbsp;Ulf Landmesser,&nbsp;Steffen Massberg,&nbsp;Malte Kelm,&nbsp;Tobias Petzold,&nbsp;Amin Polzin","doi":"10.1126/scitranslmed.ado0610","DOIUrl":"10.1126/scitranslmed.ado0610","url":null,"abstract":"<div >Large, randomized trials testing omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplementation to reduce cardiovascular events have reported contradictory results. Interpretation of these trials is challenging, because different dosages and formulations of ω-3 PUFA were tested. Furthermore, the exact mechanisms for the reduction in cardiovascular events are unclear. In this study, we investigated the effects of ω-3 PUFA on platelet adhesion, degranulation, and aggregation in vitro and in patients with cardiovascular disease using different formulations of ω-3 PUFA. We also investigated the effects of ω-3 PUFA in rodent models of arterial thrombosis and in tail bleeding assays, including in cyclooxygenase-1 (COX-1)–deficient animals. The ω-3 PUFA eicosapentaenoic acid (EPA) dose-dependently reduced platelet adhesion, degranulation, and aggregation in vitro. Moreover, arterial thrombus formation in wild-type mice was inhibited by oral EPA administration before thrombus formation. Photoaffinity labeling and in silico docking analyses suggested a direct, competitive interaction of EPA and arachidonic acid at the level of COX-1. The COX-1 dependency of EPA’s inhibitory effects was confirmed by platelet-specific COX-1–deficient animals that had no reduction of thrombus burden by EPA. In patients with cardiovascular disease, switching from 2 grams of EPA twice daily to 1 gram of docosahexaenoic acid (DHA) (460 milligrams of EPA and 380 milligrams of DHA) once daily completely blunted the platelet inhibition achieved by EPA. Our results may partially explain contradictory results with different ω-3 PUFA formulations in clinical trials.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 799","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144104216","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":"In vivo CRISPR activation screen identifies acyl-CoA–binding protein as a driver of bone metastasis","authors":"Hongqi Teng,&nbsp;Qinglei Hang,&nbsp;Caishang Zheng,&nbsp;Yuelong Yan,&nbsp;Shaomin Liu,&nbsp;Yang Zhao,&nbsp;Yalan Deng,&nbsp;Litong Nie,&nbsp;Weiche Wu,&nbsp;Marisela Sheldon,&nbsp;Zachary Yu,&nbsp;Wei Shi,&nbsp;Jianxuan Gao,&nbsp;Chenling Meng,&nbsp;Consuelo Martinez,&nbsp;Jie Zhang,&nbsp;Fan Yao,&nbsp;Yutong Sun,&nbsp;Di Zhao,&nbsp;Boyi Gan,&nbsp;Tong Meng,&nbsp;Li Ma","doi":"10.1126/scitranslmed.ado7225","DOIUrl":"10.1126/scitranslmed.ado7225","url":null,"abstract":"<div >One of the most common sites of cancer metastasis is to the bone. Bone metastasis is associated with substantial morbidity and mortality, and current therapeutic interventions remain largely palliative. Metastasizing tumor cells need to reprogram their metabolic states to adapt to the nutrient environment of distant organs; however, the role and translational relevance of lipid metabolism in bone metastasis remain unclear. Here, we used an in vivo CRISPR activation screening system coupled with positive selection to identify acyl–coenzyme A (CoA) binding protein (ACBP) as a bone metastasis driver. In nonmetastatic and weakly metastatic cancer cells, overexpression of wild-type ACBP, but not the acyl-CoA–binding deficient mutant, stimulated fatty acid oxidation (FAO) and bone metastasis. Conversely, knockout of ACBP in highly bone metastatic cancer cells abrogated metastatic bone colonization. Mechanistically, ACBP-mediated FAO increased ATP and NADPH production, reduced reactive oxygen species, and inhibited lipid peroxidation and ferroptosis. We found that ACBP expression correlated with metabolic signaling, bone metastatic ability, and poor clinical outcomes. In mouse models, pharmacological blockade of FAO or treatment with a ferroptosis inducer inhibited bone metastasis. Together, our findings reveal the role of lipid metabolism in tumor cells adapting and thriving in the bone and identify ACBP as a key regulator of this process. Agents that target FAO or induce ferroptosis represent a promising therapeutic approach for treating bone metastases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 799","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144104223","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 AAV variant selected through NHP screens robustly transduces the brain and drives secreted protein expression in NHPs and mice","authors":"Luis Tecedor,&nbsp;Yong Hong Chen,&nbsp;David E. Leib,&nbsp;Paul T. Ranum,&nbsp;Megan S. Keiser,&nbsp;Brian C. Lewandowski,&nbsp;Elli M. Carrell,&nbsp;Elena Lysenko,&nbsp;Icnelia Huerta-Ocampo,&nbsp;Sakshi Arora,&nbsp;Congsheng Cheng,&nbsp;Xueyuan Liu,&nbsp;Beverly L. Davidson","doi":"10.1126/scitranslmed.adr2531","DOIUrl":"10.1126/scitranslmed.adr2531","url":null,"abstract":"<div >Recent work has shown that prolonged expression of recombinant proteins after adeno-associated virus (AAV)–mediated delivery of gene therapy to long-lived, ventricle-lining ependymal cells can profoundly affect disease phenotypes in animal models of neurodegenerative diseases. Here, we performed in vivo screens of millions of peptide-modified capsid variants of AAV1, AAV2, and AAV9 parental serotypes in adult nonhuman primates (NHPs) to identify capsids with potent transduction of key brain tissues, including ependyma, after intracerebroventricular injection. Through these screens, we identified an AAV capsid, AAV-Ep⁺, with markedly increased potency in transducing ependymal cells and cerebral neurons in NHPs. AAV-Ep⁺’s potency was conserved in three species of NHP, two mouse strains, and human neurons derived from induced pluripotent stem cells. To apply AAV-Ep⁺ to the treatment of ceroid lipofuscinosis type 2 disease, a lysosomal storage disorder caused by loss-of-function mutations in <i>tripeptidyl-peptidase 1</i> (<i>TPP1</i>), we used the capsid to package the human <i>TPP1</i> transgene (AAV-Ep⁺.hTPP1) and delivered the construct by intracerebroventricular injection into mice lacking TPP1 activity. AAV-Ep⁺ provided robust and therapeutically relevant TPP1 protein concentrations in these mice, significantly improving tremor and life span. In NHPs, high cerebrospinal fluid (CSF) TPP1 concentrations were achieved after intracerebroventricular delivery of AAV-Ep⁺.hTPP1 at a total dose of 1 × 10¹² viral genomes, which was more than 30× lower than previously reported doses in NHPs. These results suggest that AAV-Ep⁺ may be a potent vector for gene therapy applications where CSF protein expression is required.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 798","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950620","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":"Intra-amniotic antisense oligonucleotide treatment improves phenotypes in preclinical models of spinal muscular atrophy","authors":"Beltran Borges,&nbsp;Stephen M. Brown,&nbsp;Wan-Jin Chen,&nbsp;Maria T. Clarke,&nbsp;Akos Herzeg,&nbsp;Jae Hong Park,&nbsp;Joshua Ross,&nbsp;Lingling Kong,&nbsp;Madeline Denton,&nbsp;Amy K. Smith,&nbsp;Tony Lum,&nbsp;Fareha Moulana Zada,&nbsp;Marco Cordero,&nbsp;Nalin Gupta,&nbsp;Sarah E. Cook,&nbsp;Heather Murray,&nbsp;John Matson,&nbsp;Stephanie Klein,&nbsp;C. Frank Bennett,&nbsp;Adrian R. Krainer,&nbsp;Tippi C. MacKenzie,&nbsp;Charlotte J. Sumner","doi":"10.1126/scitranslmed.adv4656","DOIUrl":"10.1126/scitranslmed.adv4656","url":null,"abstract":"<div >Neurological disorders with onset before or at birth are a leading cause of morbidity and mortality in infants and children. Prenatal treatment has the potential to reduce or prevent irreversible neuronal loss and facilitate normal neurodevelopment. We hypothesized that antisense oligonucleotides (ASOs) delivered to the amniotic fluid by intra-amniotic (IA) injection could safely distribute to the fetal central nervous system (CNS) and provide therapeutic benefit in the motor neuron disease spinal muscular atrophy (SMA), caused by mutations of the survival of motor neuron 1 gene (<i>SMN1</i>), leading to deficiency of SMN protein. Although the splice-switching ASO nusinersen ameliorates SMA when delivered postnatally, substantial deficits can remain in severely affected infants. Here, IA injection of ASOs into two mouse models of severe SMA increased SMN expression in the CNS. In SMAΔ7 mice, which manifest pathology in utero, prenatal treatment improved motor neuron numbers, motor axon development, motor behavioral tests, and survival when compared with those in mice treated postnatally (between P1 and P3). To assess the feasibility of prenatal treatment in a large-animal model, ASOs were delivered midgestation to fetal sheep by IA or intracranial injection. ASOs delivered by IA injection distributed to the spinal cord at therapeutic concentrations and to multiple peripheral tissues without evidence of substantial toxicity to the fetus or mother. These data demonstrated that IA delivery of ASOs holds potential as a minimally invasive approach for prenatal treatment of SMA and possibly other severe, early-onset neurological disorders.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 798","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950590","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":"MEK1/2 inhibitors suppress pathological α-synuclein and neurotoxicity in cell models and a humanized mouse model of Parkinson’s disease","authors":"Huilan Wang,&nbsp;Qing Wang,&nbsp;Haoxiang Xu,&nbsp;Yuanzheng Wu,&nbsp;Siulam Cheung,&nbsp;Qianhui Xu,&nbsp;Chengfang Pan,&nbsp;Jingyu Cao,&nbsp;Zhiyuan Cao,&nbsp;Ruonan Yang,&nbsp;Yu Ding,&nbsp;Yiyan Fei,&nbsp;Yongfeng Chen,&nbsp;Jian Wang,&nbsp;Cong Liu,&nbsp;Boxun Lu","doi":"10.1126/scitranslmed.adp4625","DOIUrl":"10.1126/scitranslmed.adp4625","url":null,"abstract":"<div >The abnormal accumulation of misfolded proteins is a common hallmark of many neurodegenerative disorders. Among these proteins, α-synuclein (αsyn) is a well-characterized pathogenic protein in Parkinson’s disease (PD) and other synucleinopathies. αsyn can be hyperphosphorylated and form pathological aggregates, leading to neurodegeneration. Thus, chemical modulators of pathological αsyn may suppress its downstream toxicity and provide entry points to therapeutic intervention. Here, we identified mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitors as negative modulators of basal αsyn in wild-type cells and that pathological αsyn in αsyn preformed fibrils (αsyn-PFF) induced the neuroblastoma cell line SHSY-5Y, PC12 cells, and primary cultured neurons. We further demonstrated that these inhibitors suppressed Ser¹²⁹ phosphorylated αsyn (p-αsyn) through the kinase PLK2 downstream of MEK1/2-ERK2 in PD cell models. We established a humanized PD mouse model by injecting human αsyn-PFF into mice with homozygous knock-in of human <i>SNCA</i>. Oral administration of blood-brain barrier–penetrable MEK1/2 inhibitors lowered pathological αsyn and rescued PD-relevant phenotypes with an acceptable safety profile in these mice. Collectively, these data highlight MEK1/2 inhibitors as a potential therapeutic strategy for PD.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 798","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950611","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 oral norovirus vaccine generates mucosal immunity and reduces viral shedding in a phase 2 placebo-controlled challenge study","authors":"Becca A. Flitter,&nbsp;Joshua Gillard,&nbsp;Susan N. Greco,&nbsp;Maria D. Apkarian,&nbsp;Nick P. D’Amato,&nbsp;Lam Quynh Nguyen,&nbsp;Elena D. Neuhaus,&nbsp;Darreann Carmela M. Hailey,&nbsp;Marcela F. Pasetti,&nbsp;Mallory Shriver,&nbsp;Christina Quigley,&nbsp;Robert W. Frenck Jr.,&nbsp;Lisa C. Lindesmith,&nbsp;Ralph S. Baric,&nbsp;Lee-Jen Wei,&nbsp;Sean N. Tucker,&nbsp;James F. Cummings","doi":"10.1126/scitranslmed.adh9906","DOIUrl":"10.1126/scitranslmed.adh9906","url":null,"abstract":"<div >There are currently no licensed vaccines for norovirus, a leading cause of epidemic and endemic gastroenteritis worldwide. Clinical advancement of promising vaccine candidates from phase 2 studies to phase 3 field trials has been hampered by the lack of robust immunological correlates of protection. Here, we conducted a phase 2b randomized, placebo-controlled vaccination and challenge study to assess the safety, efficacy, immunogenicity, and correlates of protection of VXA-G1.1-NN, an oral tablet norovirus vaccine. VXA-G1.1-NN was safe and well tolerated, conferred protection against norovirus GI.1 challenge, and reduced viral shedding in stool and emesis. Norovirus VP1-specific serum immunoglobulin A (IgA), IgG, and functional blocking antibody titers increased substantially after oral vaccination. Moreover, oral immunization stimulated VP1-specific IgA antibodies in nasal lining fluid, saliva, and fecal samples. Serum and mucosal antibody responses 7 days after vaccination were correlated with the induction of antibody-secreting, α4β7⁺ mucosal-homing B cells. Machine learning analyses of vaccine-stimulated immune components identified serum functional blocking antibody and fecal IgA as robust correlates of protection. These results demonstrate the potential of VXA-G1.1-NN as a safe and effective oral norovirus vaccine and reveal critical immunological features underpinning vaccine efficacy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 798","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adh9906","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950615","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}