Science Translational Medicine最新文献

{"title":"Erratum for the Research Article “A β-Arrestin–Biased Agonist of the Parathyroid Hormone Receptor (PTH1R) Promotes Bone Formation Independent of G Protein Activation” by D. Gesty-Palmer et al.","authors":"","doi":"10.1126/scitranslmed.adr6878","DOIUrl":"10.1126/scitranslmed.adr6878","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983129","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 transferrin receptor to transport antisense oligonucleotides across the mammalian blood-brain barrier","authors":"Scarlett J. Barker,&nbsp;Mai B. Thayer,&nbsp;Chaeyoung Kim,&nbsp;David Tatarakis,&nbsp;Matthew J. Simon,&nbsp;Rebekah Dial,&nbsp;Lizanne Nilewski,&nbsp;Robert C. Wells,&nbsp;Yinhan Zhou,&nbsp;Megan Afetian,&nbsp;Padma Akkapeddi,&nbsp;Alfred Chappell,&nbsp;Kylie S. Chew,&nbsp;Johann Chow,&nbsp;Allisa Clemens,&nbsp;Claire B. Discenza,&nbsp;Jason C. Dugas,&nbsp;Chrissa Dwyer,&nbsp;Timothy Earr,&nbsp;Connie Ha,&nbsp;Yvonne S. Ho,&nbsp;David Huynh,&nbsp;Edwin I. Lozano,&nbsp;Srini Jayaraman,&nbsp;Wanda Kwan,&nbsp;Cathal Mahon,&nbsp;Michelle Pizzo,&nbsp;Yaneth Robles-Colmenares,&nbsp;Elysia Roche,&nbsp;Laura Sanders,&nbsp;Alexander Stergioulis,&nbsp;Raymond Tong,&nbsp;Hai Tran,&nbsp;Y. Joy Yu Zuchero,&nbsp;Anthony A. Estrada,&nbsp;Kapil Gadkar,&nbsp;Christopher M. M. Koth,&nbsp;Pascal E. Sanchez,&nbsp;Robert G. Thorne,&nbsp;Ryan J. Watts,&nbsp;Thomas Sandmann,&nbsp;Lesley A. Kane,&nbsp;Frank Rigo,&nbsp;Mark S. Dennis,&nbsp;Joseph W. Lewcock,&nbsp;Sarah L. DeVos","doi":"10.1126/scitranslmed.adi2245","DOIUrl":"10.1126/scitranslmed.adi2245","url":null,"abstract":"<div >Antisense oligonucleotides (ASOs) are promising therapeutics for treating various neurological disorders. However, ASOs are unable to readily cross the mammalian blood-brain barrier (BBB) and therefore need to be delivered intrathecally to the central nervous system (CNS). Here, we engineered a human transferrin receptor 1 (TfR1) binding molecule, the oligonucleotide transport vehicle (OTV), to transport a tool ASO across the BBB in human TfR knockin (TfR^mu/hu KI) mice and nonhuman primates. Intravenous injection and systemic delivery of OTV to TfR^mu/hu KI mice resulted in sustained knockdown of the ASO target RNA, <i>Malat1</i>, across multiple mouse CNS regions and cell types, including endothelial cells, neurons, astrocytes, microglia, and oligodendrocytes. In addition, systemic delivery of OTV enabled <i>Malat1</i> RNA knockdown in mouse quadriceps and cardiac muscles, which are difficult to target with oligonucleotides alone. Systemically delivered OTV enabled a more uniform ASO biodistribution profile in the CNS of TfR^mu/hu KI mice and greater knockdown of <i>Malat1</i> RNA compared with a bivalent, high-affinity TfR antibody. In cynomolgus macaques, an OTV directed against <i>MALAT1</i> displayed robust ASO delivery to the primate CNS and enabled more uniform biodistribution and RNA target knockdown compared with intrathecal dosing of the same unconjugated ASO. Our data support systemically delivered OTV as a potential platform for delivering therapeutic ASOs across the BBB.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983132","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":"Mechanical ventilation guided by driving pressure optimizes local pulmonary biomechanics in an ovine model","authors":"David Lagier,&nbsp;Congli Zeng,&nbsp;David W. Kaczka,&nbsp;Min Zhu,&nbsp;Kira Grogg,&nbsp;Sarah E. Gerard,&nbsp;Joseph M. Reinhardt,&nbsp;Gabriel C. Motta Ribeiro,&nbsp;Azman Rashid,&nbsp;Tilo Winkler,&nbsp;Marcos F. Vidal Melo","doi":"10.1126/scitranslmed.ado1097","DOIUrl":"10.1126/scitranslmed.ado1097","url":null,"abstract":"<div >Mechanical ventilation exposes the lung to injurious stresses and strains that can negatively affect clinical outcomes in acute respiratory distress syndrome or cause pulmonary complications after general anesthesia. Excess global lung strain, estimated as increased respiratory system driving pressure, is associated with mortality related to mechanical ventilation. The role of small-dimension biomechanical factors underlying this association and their spatial heterogeneity within the lung are currently unknown. Using four-dimensional computed tomography with a voxel resolution of 2.4 cubic millimeters and a multiresolution convolutional neural network for whole-lung image segmentation, we dynamically measured voxel-wise lung inflation and tidal parenchymal strains. Healthy or injured ovine lungs were evaluated as the mechanical ventilation positive end-expiratory pressure (PEEP) was titrated from 20 to 2 centimeters of water. The PEEP of minimal driving pressure (PEEP_DP) optimized local lung biomechanics. We observed a greater rate of change in nonaerated lung mass with respect to PEEP below PEEP_DP compared with PEEP values above this threshold. PEEP_DP similarly characterized a breaking point in the relationships between PEEP and SD of local tidal parenchymal strain, the 95th percentile of local strains, and the magnitude of tidal overdistension. These findings advance the understanding of lung collapse, tidal overdistension, and strain heterogeneity as local triggers of ventilator-induced lung injury in large-animal lungs similar to those of humans and could inform the clinical management of mechanical ventilation to improve local lung biomechanics.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983130","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":"Development and preclinical validation of 2-deoxy 2-[18F]fluorocellobiose as an Aspergillus-specific PET tracer","authors":"Swati Shah,&nbsp;Jianhao Lai,&nbsp;Falguni Basuli,&nbsp;Neysha Martinez-Orengo,&nbsp;Reema Patel,&nbsp;Mitchell L. Turner,&nbsp;Benjamin Wang,&nbsp;Zhen-Dan Shi,&nbsp;Suman Sourabh,&nbsp;Morteza Peiravi,&nbsp;Anna Lyndaker,&nbsp;Sichen Liu,&nbsp;Seyedmojtaba Seyedmousavi,&nbsp;Peter R. Williamson,&nbsp;Rolf E. Swenson,&nbsp;Dima A. Hammoud","doi":"10.1126/scitranslmed.adl5934","DOIUrl":"10.1126/scitranslmed.adl5934","url":null,"abstract":"<div >The global incidence of invasive fungal infections (IFIs) has increased over the past few decades, mainly in immunocompromised patients, and is associated with high mortality and morbidity. <i>Aspergillus fumigatus</i> is one of the most common and deadliest IFI pathogens. Major hurdles to treating fungal infections remain the lack of rapid and definitive diagnosis, including the frequent need for invasive procedures to provide microbiological confirmation, and the lack of specificity of structural imaging methods. To develop an <i>Aspergillus</i>-specific positron emission tomography (PET) imaging agent, we focused on fungal-specific sugar metabolism. We radiolabeled cellobiose, a disaccharide known to be metabolized by <i>Aspergillus</i> species, and synthesized 2-deoxy-2-[¹⁸F]fluorocellobiose ([¹⁸F]FCB) by enzymatic conversion of 2-deoxy-2-[¹⁸F]fluoroglucose ([¹⁸F]FDG) with a radiochemical yield of 60 to 70%, a radiochemical purity of &gt;98%, and 1.5 hours of synthesis time. Two hours after [¹⁸F]FCB injection in <i>A. fumigatus</i> pneumonia as well as <i>A. fumigatus</i>, bacterial, and sterile inflammation myositis mouse models, retained radioactivity was only seen in foci with live <i>A. fumigatus</i> infection. In vitro testing confirmed production of β-glucosidase enzyme by <i>A. fumigatus</i> and not by bacteria, resulting in hydrolysis of [¹⁸F]FCB into glucose and [¹⁸F]FDG, the latter being retained by the live fungus. The parent molecule was otherwise promptly excreted through the kidneys, resulting in low background radioactivity and high target-to-nontarget ratios at <i>A. fumigatus</i> infectious sites. We conclude that [¹⁸F]FCB is a promising and clinically translatable <i>Aspergillus</i>-specific PET tracer.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983128","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":"Semisynthetic guanidino lipoglycopeptides with potent in vitro and in vivo antibacterial activity","authors":"Emma van Groesen,&nbsp;Elma Mons,&nbsp;Ioli Kotsogianni,&nbsp;Melina Arts,&nbsp;Kamaleddin H. M. E. Tehrani,&nbsp;Nicola Wade,&nbsp;Vladyslav Lysenko,&nbsp;Floor M. Stel,&nbsp;Jordy T. Zwerus,&nbsp;Stefania De Benedetti,&nbsp;Alexander Bakker,&nbsp;Parichita Chakraborty,&nbsp;Mario van der Stelt,&nbsp;Dirk-Jan Scheffers,&nbsp;Jairo Gooskens,&nbsp;Wiep Klaas Smits,&nbsp;Kirsty Holden,&nbsp;Peter S. Gilmour,&nbsp;Joost Willemse,&nbsp;Christopher A. Hitchcock,&nbsp;J. G. Coen van Hasselt,&nbsp;Tanja Schneider,&nbsp;Nathaniel I. Martin","doi":"10.1126/scitranslmed.abo4736","DOIUrl":"10.1126/scitranslmed.abo4736","url":null,"abstract":"<div >Gram-positive bacterial infections present a major clinical challenge, with methicillin- and vancomycin-resistant strains continuing to be a cause for concern. In recent years, semisynthetic vancomycin derivatives have been developed to overcome this problem as exemplified by the clinically used telavancin, which exhibits increased antibacterial potency but has also raised toxicity concerns. Thus, glycopeptide antibiotics with enhanced antibacterial activities and improved safety profiles are still necessary. We describe the development of a class of highly potent semisynthetic glycopeptide antibiotics, the guanidino lipoglycopeptides, which contain a positively charged guanidino moiety bearing a variable lipid group. These glycopeptides exhibited enhanced in vitro activity against a panel of Gram-positive bacteria including clinically relevant methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) and vancomycin-resistant strains, showed minimal toxicity toward eukaryotic cells, and had a low propensity for resistance selection. Mechanistically, guanidino lipoglycopeptides engaged with bacterial cell wall precursor lipid II with a higher binding affinity than vancomycin. Binding to both wild-type <span>d</span>-Ala-<span>d</span>-Ala lipid II and the vancomycin-resistant <span>d</span>-Ala-<span>d</span>-Lac variant was confirmed, providing insight into the enhanced activity of guanidino lipoglycopeptides against vancomycin-resistant isolates. The in vivo efficacy of guanidino lipoglycopeptide EVG7 was evaluated in a <i>S. aureus</i> murine thigh infection model and a 7-day sepsis survival study, both of which demonstrated superiority to vancomycin. Moreover, the minimal to mild kidney effects at supratherapeutic doses of EVG7 indicate an improved therapeutic safety profile compared with vancomycin. These findings position guanidino lipoglycopeptides as candidates for further development as antibacterial agents for the treatment of clinically relevant multidrug-resistant Gram-positive infections.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902814","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 self-amplifying RNA vaccine prevents enterovirus D68 infection and disease in preclinical models","authors":"Nikole L. Warner,&nbsp;Jacob Archer,&nbsp;Stephanie Park,&nbsp;Garima Singh,&nbsp;Kathryn M. McFadden,&nbsp;Taishi Kimura,&nbsp;Katrina Nicholes,&nbsp;Adrian Simpson,&nbsp;Jason T. Kaelber,&nbsp;David W. Hawman,&nbsp;Heinz Feldmann,&nbsp;Amit P. Khandhar,&nbsp;Peter Berglund,&nbsp;Matthew R. Vogt,&nbsp;Jesse H. Erasmus","doi":"10.1126/scitranslmed.adi1625","DOIUrl":"10.1126/scitranslmed.adi1625","url":null,"abstract":"<div >The recent emergence and rapid response to severe acute respiratory syndrome coronavirus 2 was enabled by prototype pathogen and vaccine platform approaches, driven by the preemptive application of RNA vaccine technology to the related Middle East respiratory syndrome coronavirus. Recently, the National Institutes of Allergy and Infectious Diseases identified nine virus families of concern, eight enveloped virus families and one nonenveloped virus family, for which vaccine generation is a priority. Although RNA vaccines have been described for a variety of enveloped viruses, a roadmap for their use against nonenveloped viruses is lacking. Enterovirus D68 was recently designated a prototype pathogen within the family Picornaviridae of nonenveloped viruses because of its rapid evolution and respiratory route of transmission, coupled with a lack of diverse anti-enterovirus vaccine approaches in development. Here, we describe a proof-of-concept approach using a clinical stage RNA vaccine platform that induced robust enterovirus D68–neutralizing antibody responses in mice and nonhuman primates and prevented upper and lower respiratory tract infections and neurological disease in mice. In addition, we used our platform to rapidly characterize the antigenic diversity within the six genotypes of enterovirus D68, providing the necessary data to inform multivalent vaccine compositions that can elicit optimal breadth of neutralizing responses. These results demonstrate that RNA vaccines can be used as tools in our pandemic-preparedness toolbox for nonenveloped viruses.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902810","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":"Piplartine attenuates aminoglycoside-induced TRPV1 activity and protects from hearing loss in mice","authors":"Marisa Zallocchi,&nbsp;Sarath Vijayakumar,&nbsp;Jonathan Fleegel,&nbsp;Lyudmila Batalkina,&nbsp;Katyarina E. Brunette,&nbsp;Dhaval Shukal,&nbsp;Zhiyong Chen,&nbsp;Olivier Devuyst,&nbsp;Huizhan Liu,&nbsp;David Z. Z. He,&nbsp;Ali Sajid Imami,&nbsp;Abdul-Rizaq Ali Hamoud,&nbsp;Robert McCullumsmith,&nbsp;Martin Conda-Sheridan,&nbsp;Luana Janaína De Campos,&nbsp;Jian Zuo","doi":"10.1126/scitranslmed.adn2140","DOIUrl":"10.1126/scitranslmed.adn2140","url":null,"abstract":"<div >Hearing loss is a major health concern in our society, affecting more than 400 million people worldwide. Among the causes, aminoglycoside therapy can result in permanent hearing loss in 40% to 60% of patients receiving treatment, and despite these high numbers, no drug for preventing or treating this type of hearing loss has yet been approved by the US Food and Drug Administration. We have previously conducted high-throughput screenings of bioactive compounds, using zebrafish as our discovery platform, and identified piplartine as a potential therapeutic molecule. In the present study, we expanded this work and characterized piplartine’s physicochemical and therapeutic properties. We showed that piplartine had a wide therapeutic window and neither induced nephrotoxicity in vivo in zebrafish nor interfered with aminoglycoside antibacterial activity. In addition, a fluorescence-based assay demonstrated that piplartine did not inhibit cytochrome C activity in microsomes. Coadministration of piplartine protected from kanamycin-induced hair cell loss in zebrafish and protected hearing function, outer hair cells, and presynaptic ribbons in a mouse model of kanamycin ototoxicity. Last, we investigated piplartine’s mechanism of action by phospho-omics, immunoblotting, immunohistochemistry, and molecular dynamics experiments. We found an up-regulation of AKT1 signaling in the cochleas of mice cotreated with piplartine. Piplartine treatment normalized kanamycin-induced up-regulation of TRPV1 expression and modulated the gating properties of this receptor. Because aminoglycoside entrance to the inner ear is, in part, mediated by TRPV1, these results suggested that by regulating TRPV1 expression, piplartine blocked aminoglycoside’s entrance, thereby preventing the long-term deleterious effects of aminoglycoside accumulation in the inner ear compartment.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902813","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 Bruton’s tyrosine kinase inhibition attenuates alcohol-associated liver disease by regulating CD84-mediated granulopoiesis","authors":"Prashanth Thevkar Nagesh,&nbsp;Yeonhee Cho,&nbsp;Yuan Zhuang,&nbsp;Mrigya Babuta,&nbsp;Marti Ortega-Ribera,&nbsp;Radhika Joshi,&nbsp;Veronika Brezani,&nbsp;Arman Patel,&nbsp;Aditi Ashish Datta,&nbsp;Viliam Brezani,&nbsp;Yun-Cheng Hsieh,&nbsp;Adriana Ramos,&nbsp;Jeeval Mehta,&nbsp;Christopher Copeland,&nbsp;Eleni Kanata,&nbsp;Zhenghui Gordon Jiang,&nbsp;Ioannis Vlachos,&nbsp;John Asara,&nbsp;AlcHepNet Consortium,&nbsp;Gyongyi Szabo","doi":"10.1126/scitranslmed.adg1915","DOIUrl":"10.1126/scitranslmed.adg1915","url":null,"abstract":"<div >Severe alcohol-associated hepatitis (AH) is a life-threatening form of alcohol-associated liver disease. Liver neutrophil infiltration is a hallmark of AH, yet the effects of alcohol on neutrophil functions remain elusive. Identifying therapeutic targets to reduce neutrophil-mediated liver damage is essential. Bruton’s tyrosine kinase (BTK) plays an important role in neutrophil development and function; however, the role of BTK in AH is unknown. Using RNA sequencing of circulating neutrophils, we found an increase in <i><i>Btk</i></i> expression (<i>P</i> = 0.05) and phosphorylated BTK (pBTK) in patients with AH compared with healthy controls. In vitro, physiologically relevant doses of alcohol resulted in a rapid, TLR4-mediated induction of pBTK in neutrophils. In a preclinical model of AH, administration of a small-molecule BTK inhibitor (evobrutinib) or myeloid-specific <i>Btk</i> knockout decreased proinflammatory cytokines and attenuated neutrophil-mediated liver damage. We found that pBTK was essential for alcohol-induced bone marrow granulopoiesis and liver neutrophil infiltration. In vivo, BTK inhibition or myeloid-specific <i>Btk</i> knockout reduced granulopoiesis, circulating neutrophils, liver neutrophil infiltration, and liver damage in a mouse model of AH. Mechanistically, using liquid chromatography–tandem mass spectrometry, we identified CD84 as a kinase target of BTK, which is involved in granulopoiesis. In vitro, CD84 promoted alcohol-induced interleukin-1β and tumor necrosis factor–α in primary human neutrophils, which was inhibited by CD84-blocking antibody treatment. Our findings define the role of BTK and CD84 in regulating neutrophil inflammation and granulopoiesis, with potential therapeutic implications in AH.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adg1915","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902812","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":"Engineered exosomes with a photoinducible protein delivery system enable CRISPR-Cas–based epigenome editing in Alzheimer’s disease","authors":"Jihoon Han,&nbsp;Jae Hoon Sul,&nbsp;Jeongmi Lee,&nbsp;Eunae Kim,&nbsp;Hark Kyun Kim,&nbsp;Minshik Chae,&nbsp;Jeein Lim,&nbsp;Jongho Kim,&nbsp;Chanhee Kim,&nbsp;Jun-Sik Kim,&nbsp;Yoonsuk Cho,&nbsp;Jae Hyung Park,&nbsp;Yong Woo Cho,&nbsp;Dong-Gyu Jo","doi":"10.1126/scitranslmed.adi4830","DOIUrl":"10.1126/scitranslmed.adi4830","url":null,"abstract":"<div >Effective intracellular delivery of therapeutic proteins can potentially treat a wide array of diseases. However, efficient delivery of functional proteins across the cell membrane remains challenging. Exosomes are nanosized vesicles naturally secreted by various types of cells and may serve as promising nanocarriers for therapeutic biomolecules. Here, we engineered exosomes equipped with a photoinducible cargo protein release system, termed mMaple3-mediated protein loading into and release from exosome (MAPLEX), in which cargo proteins can be loaded into the exosomes by fusing them with photocleavable protein (mMaple3)–conjugated exosomal membrane markers and subsequently released from the exosomal membrane by inducing photocleavage with blue light illumination. Using this system, we first induced transcriptional regulation by delivering octamer-binding transcription factor 4 and SRY-box transcription factor 2 to fibroblasts in vitro. Second, we induced in vivo gene recombination in Cre reporter mice by delivering Cre recombinase. Last, we achieved targeted epigenome editing in the brains of 5xFAD and 3xTg-AD mice, two models of Alzheimer’s disease. Administration of MAPLEXs loaded with β-site amyloid precursor protein cleaving enzyme 1 (<i>Bace1</i>)–targeting single guide RNA–incorporated dCas9 ribonucleoprotein complexes, coupled with the catalytic domain of DNA methyltransferase 3A, resulted in successful methylation of the targeted CpG sites within the <i>Bace1</i> promoter. This approach led to a significant reduction in <i>Bace1</i> expression, improved recognition memory impairment, and reduced amyloid pathology in 5xFAD and 3xTg-AD mice. These results suggest that MAPLEX is an efficient intracellular protein delivery system that can deliver diverse therapeutic proteins for multiple diseases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902811","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 prM mutation that attenuates dengue virus replication in human cells enhances midgut infection in mosquitoes","authors":"Allyson N. X. Choi,&nbsp;Tanamas Siriphanitchakorn,&nbsp;Milly M. Choy,&nbsp;Justin S. G. Ooi,&nbsp;Menchie Manuel,&nbsp;Hwee Cheng Tan,&nbsp;Lowell Z. Lin,&nbsp;Xin Yap,&nbsp;Duane J. Gubler,&nbsp;Eng Eong Ooi","doi":"10.1126/scitranslmed.adk4769","DOIUrl":"10.1126/scitranslmed.adk4769","url":null,"abstract":"<div >Dengue viruses (DENVs), like all viruses, evolve to perpetuate transmission of their species in their hosts. However, how DENV genetics influences dengue disease outbreaks remains poorly understood. Here, we examined isolates of the South Pacific dengue virus type 2 (DENV-2) that emerged in the 1970s and caused major dengue outbreaks in islands in this region until it reached Tonga, where only a few mild cases were reported. Phylogenetically, the DENV-2 strain isolated in Tonga segregated into a clade different from those clades infecting populations in other South Pacific islands. We found that this epidemiological observation could be explained by a single histidine-to-arginine substitution in position 86 of the premembrane (prM) protein of the Tonga DENV-2 strain. This mutation attenuated viral protein translation in mammalian cells but not in midgut cells of the mosquito vector <i>Aedes aegypti</i>. In mammalian cells, the prM mutation resulted in reduced translation of the viral genome and subsequent reduced virus replication. In contrast, in mosquito midgut cells, the prM mutation conferred a selective infection advantage, possibly because of the positively charged arginine residue introduced by the mutation. These findings provide molecular insights into the year-long silent transmission of attenuated DENV-2 in Tonga during the 1970s dengue outbreak in the South Pacific.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860759","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}