Science Translational Medicine最新文献

{"title":"Broadly neutralizing antibodies targeting pandemic GII.4 variants or seven GII genotypes of human norovirus","authors":"Juyeon Park,&nbsp;Lisa C. Lindesmith,&nbsp;Adam S. Olia,&nbsp;Veronica P. Costantini,&nbsp;Paul D. Brewer-Jensen,&nbsp;Michael L. Mallory,&nbsp;Cynthia E. Kelley,&nbsp;Ed Satterwhite,&nbsp;Victoria Longo,&nbsp;Yaroslav Tsybovsky,&nbsp;Tyler Stephens,&nbsp;Jeffrey Marchioni,&nbsp;Christina A. Martins,&nbsp;Yimin Huang,&nbsp;Ridhi Chaudhary,&nbsp;Mark Zweigart,&nbsp;Samantha R. May,&nbsp;Yaoska Reyes,&nbsp;Becca Flitter,&nbsp;Jan Vinjé,&nbsp;Sean N. Tucker,&nbsp;Gregory C. Ippolito,&nbsp;Jason J. Lavinder,&nbsp;Joost Snijder,&nbsp;Peter D. Kwong,&nbsp;George Georgiou,&nbsp;Ralph S. Baric","doi":"","DOIUrl":"","url":null,"abstract":"<div >Human norovirus causes more than 700 million illnesses annually. Extensive genetic diversity and a paucity of information on conserved neutralizing epitopes pose major obstacles to the design of broadly protective norovirus immunogens. Here, we used high-resolution liquid chromatography–tandem mass spectrometry (LC-MS/MS)–driven proteomics to quantitatively characterize the circulating serum IgG repertoire before and after immunization with an experimental monovalent norovirus GII.4 VP1 capsid–encoding adenoviral vaccine. Two participants were specifically selected on the basis of the breadth of serum neutralization responses either across GII.4 variants (participant A) or across GII genotypes (participant B). In participant A, vaccination back-boosted highly abundant serum antibody clonotypes targeting epitopes conserved among rapidly evolving GII.4 variants spanning from a strain identified in 1987 to a strain identified in 2019. In participant B, we identified a recall response consisting of broadly neutralizing monoclonal antibodies with remarkable cross-GII ligand-binding blockade (blocking ≥ seven GII genotypes) and virus neutralization breadth. The cocrystal structure of one of these antibodies, VX22, in complex with the VP1 capsid protruding (P) domain revealed a highly conserved epitope (residues 479 to 484 and 509 to 513) within two lateral loops of the P1 subdomain. Antibody evolutionary trajectory analysis further revealed that VX22 had originally evolved from an early heterologous infection, likely by a GII.12 strain. Together, our study demonstrates that norovirus human monoclonal antibodies with broad GII.4 potency and cross-GII breadth can be boosted in serum after immunization with an adenoviral vector–based vaccine, findings that may guide the design of immunogens for broadly protective norovirus vaccines.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 788","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565486","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 single-cell atlas of circulating immune cells over the first 2 months of age in extremely premature infants","authors":"Oluwabunmi Olaloye, Weihong Gu, Arne Gehlhaar, Burhanuddin Sabuwala, Chino K. Eke, Yujia Li, Tessa Kehoe, Rohit Farmer, Gisela Gabernet, Carrie L. Lucas, John S. Tsang, Saquib A. Lakhani, Sarah N. Taylor, George Tseng, Steven H. Kleinstein, Liza Konnikova","doi":"10.1126/scitranslmed.adr0942","DOIUrl":"https://doi.org/10.1126/scitranslmed.adr0942","url":null,"abstract":"Extremely premature infants (EPIs) who are born before 30 weeks of gestation are susceptible to infection; however, the trajectory of their peripheral immunity is poorly understood. Here, we undertook longitudinal analyses of immune cells from 250 μl of whole blood at 1 week, 1 month, and 2 months from 10 EPIs and compared these with samples from healthy adults and with preterm and full-term cord blood samples. Single-cell suspensions from individual samples were split to perform single-cell RNA sequencing, T and B cell receptor sequencing, and phosphoprotein mass cytometry. The trajectories of circulating T, B, myeloid, and natural killer cells in EPIs over the first 2 months of life were distinct from those of full-term infants. In EPIs, peripheral T cell development rapidly progressed over the first month of life, with an increase in the proportion of naïve CD4 <jats:sup>+</jats:sup> , regulatory, and cycling T cells, accompanied by greater STAT5 (signal transducer and activator of transcription 5) signaling. EPI memory CD4 <jats:sup>+</jats:sup> T cells showed a T helper 1 (T <jats:sub>H</jats:sub> 1) predominance compared with T <jats:sub>H</jats:sub> 2 skewing of central memory–like T cells in full-term infants, and B cells from 2-month-old EPIs exhibited increased signatures of activation and differentiation. Both B and T cells from 2-month-old EPIs displayed increased interferon signatures compared with cells from full-term infants. In conclusion, we demonstrated the feasibility of longitudinal multiomic analyses in EPIs using minute amounts of blood and developed a resource describing peripheral immune development in EPIs that suggested ongoing activation in early life.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"14 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143561353","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 tablet was safe and elicited mucosal immunity in older adults in a phase 1b clinical trial","authors":"Becca A. Flitter, Susan N. Greco, Colin A. Lester, Elena D. Neuhaus, Sarah N. Tedjakusuma, Mallory Shriver, Esmeralda Cuevas-Juárez, Samanta Gutierrez, Molly R. Braun, Marcela F. Pasetti, Sean N. Tucker, James F. Cummings","doi":"10.1126/scitranslmed.ads0556","DOIUrl":"https://doi.org/10.1126/scitranslmed.ads0556","url":null,"abstract":"Norovirus is a leading cause of acute gastroenteritis globally, with infections in older adults associated with heightened severity and increased risk of mortality. Currently, no licensed vaccines are available to prevent norovirus infection. We developed an orally administered vaccine tablet (VXA-G1.1-NN) that delivers a nonreplicating adenoviral vector expressing norovirus GI.1 major capsid protein VP1 to the small intestine. Here, we report safety and immunogenicity results of a randomized, double-blind, placebo-controlled clinical trial (NCT04854746) that investigated the oral administration of VXA-G1.1-NN in two groups of healthy older adults aged 55 to 65 and 66 to 80 years. VXA-G1.1-NN was administered orally at three dose levels by prime and boost, 28 days apart. Immunization was well tolerated regardless of dose, with mild to moderate reported solicited symptoms and no related serious or grade 3 adverse events. Oral delivery of VXA-G1.1-NN elicited VP1-specific serum immunoglobulin G (IgG) and IgA and functional antibodies in a dose-dependent manner 28 days postvaccination and remained above baseline for 210 days. Moreover, robust circulating VP1-specific IgA antibody-secreting cells were detected 1 week postvaccination along with IgA <jats:sup>+</jats:sup> plasmablasts expressing the mucosal-homing marker α4β7. VP1-specific IgA increased in saliva and nasal lining fluid 28 days postvaccination in both age groups and remained above baseline concentrations through 210 days, demonstrating durable mucosal responses. This clinical trial established that oral administration of VXA-G1.1-NN is safe, well tolerated, and induces robust systemic and mucosal immune responses in adults up to 80 years old.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"53 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143561352","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 tablet was safe and elicited mucosal immunity in older adults in a phase 1b clinical trial","authors":"Becca A. Flitter,&nbsp;Susan N. Greco,&nbsp;Colin A. Lester,&nbsp;Elena D. Neuhaus,&nbsp;Sarah N. Tedjakusuma,&nbsp;Mallory Shriver,&nbsp;Esmeralda Cuevas-Juárez,&nbsp;Samanta Gutierrez,&nbsp;Molly R. Braun,&nbsp;Marcela F. Pasetti,&nbsp;Sean N. Tucker,&nbsp;James F. Cummings","doi":"","DOIUrl":"","url":null,"abstract":"<div >Norovirus is a leading cause of acute gastroenteritis globally, with infections in older adults associated with heightened severity and increased risk of mortality. Currently, no licensed vaccines are available to prevent norovirus infection. We developed an orally administered vaccine tablet (VXA-G1.1-NN) that delivers a nonreplicating adenoviral vector expressing norovirus GI.1 major capsid protein VP1 to the small intestine. Here, we report safety and immunogenicity results of a randomized, double-blind, placebo-controlled clinical trial (NCT04854746) that investigated the oral administration of VXA-G1.1-NN in two groups of healthy older adults aged 55 to 65 and 66 to 80 years. VXA-G1.1-NN was administered orally at three dose levels by prime and boost, 28 days apart. Immunization was well tolerated regardless of dose, with mild to moderate reported solicited symptoms and no related serious or grade 3 adverse events. Oral delivery of VXA-G1.1-NN elicited VP1-specific serum immunoglobulin G (IgG) and IgA and functional antibodies in a dose-dependent manner 28 days postvaccination and remained above baseline for 210 days. Moreover, robust circulating VP1-specific IgA antibody-secreting cells were detected 1 week postvaccination along with IgA⁺ plasmablasts expressing the mucosal-homing marker α4β7. VP1-specific IgA increased in saliva and nasal lining fluid 28 days postvaccination in both age groups and remained above baseline concentrations through 210 days, demonstrating durable mucosal responses. This clinical trial established that oral administration of VXA-G1.1-NN is safe, well tolerated, and induces robust systemic and mucosal immune responses in adults up to 80 years old.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 788","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565464","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 single-cell atlas of circulating immune cells over the first 2 months of age in extremely premature infants","authors":"Oluwabunmi Olaloye,&nbsp;Weihong Gu,&nbsp;Arne Gehlhaar,&nbsp;Burhanuddin Sabuwala,&nbsp;Chino K. Eke,&nbsp;Yujia Li,&nbsp;Tessa Kehoe,&nbsp;Rohit Farmer,&nbsp;Gisela Gabernet,&nbsp;Carrie L. Lucas,&nbsp;John S. Tsang,&nbsp;Saquib A. Lakhani,&nbsp;Sarah N. Taylor,&nbsp;George Tseng,&nbsp;Steven H. Kleinstein,&nbsp;Liza Konnikova","doi":"","DOIUrl":"","url":null,"abstract":"<div >Extremely premature infants (EPIs) who are born before 30 weeks of gestation are susceptible to infection; however, the trajectory of their peripheral immunity is poorly understood. Here, we undertook longitudinal analyses of immune cells from 250 μl of whole blood at 1 week, 1 month, and 2 months from 10 EPIs and compared these with samples from healthy adults and with preterm and full-term cord blood samples. Single-cell suspensions from individual samples were split to perform single-cell RNA sequencing, T and B cell receptor sequencing, and phosphoprotein mass cytometry. The trajectories of circulating T, B, myeloid, and natural killer cells in EPIs over the first 2 months of life were distinct from those of full-term infants. In EPIs, peripheral T cell development rapidly progressed over the first month of life, with an increase in the proportion of naïve CD4⁺, regulatory, and cycling T cells, accompanied by greater STAT5 (signal transducer and activator of transcription 5) signaling. EPI memory CD4⁺ T cells showed a T helper 1 (T_H1) predominance compared with T_H2 skewing of central memory–like T cells in full-term infants, and B cells from 2-month-old EPIs exhibited increased signatures of activation and differentiation. Both B and T cells from 2-month-old EPIs displayed increased interferon signatures compared with cells from full-term infants. In conclusion, we demonstrated the feasibility of longitudinal multiomic analyses in EPIs using minute amounts of blood and developed a resource describing peripheral immune development in EPIs that suggested ongoing activation in early life.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 788","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565489","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":"Bispecific antibodies targeting the N-terminal and receptor binding domains potently neutralize SARS-CoV-2 variants of concern","authors":"Adonis A. Rubio, Viren A. Baharani, Bernadeta Dadonaite, Megan Parada, Morgan E. Abernathy, Zijun Wang, Yu E. Lee, Michael R. Eso, Jennie Phung, Israel Ramos, Teresia Chen, Gina El Nesr, Jesse D. Bloom, Paul D. Bieniasz, Michel C. Nussenzweig, Christopher O. Barnes","doi":"10.1126/scitranslmed.adq5720","DOIUrl":"https://doi.org/10.1126/scitranslmed.adq5720","url":null,"abstract":"The ongoing emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that reduce the effectiveness of antibody therapeutics necessitates development of next-generation antibody modalities that are resilient to viral evolution. Here, we characterized amino-terminal domain (NTD)– and receptor binding domain (RBD)–specific monoclonal antibodies previously isolated from coronavirus disease 2019 (COVID-19) convalescent donors for their activity against emergent SARS-CoV-2 VOCs. Among these, the NTD-specific antibody C1596 displayed the greatest breadth of binding to VOCs, with cryo–electron microscopy structural analysis revealing recognition of a distinct NTD epitope outside of the site i antigenic supersite. Given C1596’s favorable binding profile, we designed a series of bispecific antibodies (bsAbs), termed CoV2-biRNs, that featured both NTD and RBD specificities. Two of the C1596-inclusive bsAbs, CoV2-biRN5 and CoV2-biRN7, retained potent in vitro neutralization activity against all Omicron variants tested, including XBB.1.5, BA.2.86, and JN.1, contrasting the diminished potency of parental antibodies delivered as monotherapies or as a cocktail. Furthermore, prophylactic delivery of CoV2-biRN5 reduced the viral load within the lungs of K18-hACE2 mice after challenge with SARS-CoV-2 XBB.1.5. In conclusion, NTD-RBD bsAbs offer promising potential for the design of resilient, next-generation antibody therapeutics against SARS-CoV-2 VOCs.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"76 5 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143561350","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":"Reduced cerebellar rhythm by climbing fiber denervation is linked to motor rhythm deficits in mice and ataxia severity in patients","authors":"Chih-Chun Lin, Ke-Chu Fang, Ilaria Balbo, Ting-Yu Liang, Chia-Wei Liu, Wen-Chuan Liu, Yi-Mei Wang, Yen-Ling Hung, Kai-Chien Yang, Scott Kun Geng, Chun-Lun Ni, Christopher P. Driscoll, David S. Ruff, Ami Kumar, Nadia Amokrane, Natasha Desai, Phyllis L. Faust, Elan D. Louis, Sheng-Han Kuo, Ming-Kai Pan","doi":"10.1126/scitranslmed.adk3922","DOIUrl":"https://doi.org/10.1126/scitranslmed.adk3922","url":null,"abstract":"Cerebellar ataxia results from various genetic and nongenetic disorders and is characterized by involuntary movements that impair precision and motor rhythm. Here, we report that climbing fiber (CF) denervation is a common pathophysiology underlying motor rhythm loss in cerebellar ataxia. By examining cerebellar pathology in patients with spinocerebellar ataxia (SCA) types 1, 2, and 6 and multiple system atrophy, we identified CF degeneration with synaptic loss as a shared pathophysiology. Optogenetic silencing of CF synaptic activity in mice induced ataxia-like motor dysfunctions and loss of motor precision. In addition, CF silencing resulted in cerebellar and motor rhythm loss, another core feature of ataxia. This rhythm loss was predominantly CF dependent and resistant to Purkinje cell–specific lesioning by diphtheria toxin. Correspondingly, two patients with inferior olive pathology, the brain site that provides CFs to Purkinje cells, presented with ataxia and cerebellar rhythm loss. Patients with genetic or nongenetic cerebellar ataxia exhibited cerebellar rhythm loss that correlated with the Scale for the Assessment and Rating of Ataxia. Chemogenetic stimulation of CFs improved cerebellar and motor rhythms as well as motor performance in the SCA type 1 mouse model of ataxia. These results suggest that CF-dependent cerebellar rhythm loss occurs across different types of cerebellar ataxia, contributing to motor imprecision and motor rhythm loss, two defining features of ataxia.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"25 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506869","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 gut Eggerthella lenta –derived metabolite impairs neutrophil function to aggravate bacterial lung infection","authors":"Le-Le Wang, Xiyue Shen, Yingzhou Xie, Ai Ge, Haiwen Lu, Shuyi Gu, Lingxin Kong, Jayanth Kumar Narayana, Jochen Mattner, Sanjay H. Chotirmall, Jin-Fu Xu","doi":"10.1126/scitranslmed.adq4409","DOIUrl":"https://doi.org/10.1126/scitranslmed.adq4409","url":null,"abstract":"The composition of the gut microbiota in patients with bronchiectasis has been proven to be distinct from that of healthy individuals, and this disrupted gut microbiota can exacerbate lung infections. However, the responsible microbes and mechanisms in the “gut-lung” axis in bronchiectasis remain unknown. Here, we report that <jats:italic>Eggerthella lenta</jats:italic> was enriched in the gut, and taurine ursodeoxycholic acid (TUDCA) was enriched in both the guts and sera of patients with bronchiectasis, with both being associated with disease severity. Fecal microbiota transfer from patients with bronchiectasis as well as administration of <jats:italic>E. lenta</jats:italic> independently exacerbated pulmonary <jats:italic>Pseudomonas aeruginosa</jats:italic> infections in murine models. <jats:italic>E. lenta</jats:italic> –associated TUDCA bound adenosine monophosphate–activated protein kinase (AMPK) within neutrophils and interfered with the interaction between liver kinase B1 and AMPK, with a consequential decrease in AMPK phosphorylation. This ultimately reduced ATP production in neutrophils, inhibited their function, and compromised <jats:italic>P. aeruginosa</jats:italic> elimination from the lung, aggravating tissue injury. Metformin treatment improved disease severity and outcome in the mouse models. In sum, the gut bacterium <jats:italic>E. lenta</jats:italic> raises the stakes of bacterial lung infection because it causes dysfunction of neutrophils circulated from serum to lung via the metabolite TUDCA. Interventions targeting <jats:italic>E. lenta</jats:italic> or AMPK phosphorylation may serve as adjunctive strategies to complement existing approaches for managing chronic pulmonary infection in bronchiectasis and other chronic respiratory disease states.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"27 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507232","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 electroadhesive hydrogel interface prolongs porcine gastrointestinal mucosal theranostics","authors":"Binbin Ying,&nbsp;Kewang Nan,&nbsp;Qing Zhu,&nbsp;Tom Khuu,&nbsp;Hana Ro,&nbsp;Sophia Qin,&nbsp;Shubing Wang,&nbsp;Karen Jiang,&nbsp;Yonglin Chen,&nbsp;Guangyu Bao,&nbsp;Josh Jenkins,&nbsp;Andrew Pettinari,&nbsp;Johannes Kuosmanen,&nbsp;Keiko Ishida,&nbsp;Niora Fabian,&nbsp;Aaron Lopes,&nbsp;Flavia Codreanu,&nbsp;Joshua Morimoto,&nbsp;Jason Li,&nbsp;Alison Hayward,&nbsp;Robert Langer,&nbsp;Giovanni Traverso","doi":"","DOIUrl":"","url":null,"abstract":"<div >Establishing a robust and intimate mucosal interface that allows medical devices to remain within lumen-confined organs for extended periods has valuable applications, particularly for gastrointestinal theranostics. Here, we report the development of an electroadhesive hydrogel interface for robust and prolonged mucosal retention after electrical activation (e-GLUE). The e-GLUE device is composed of cationic polymers interpenetrated within a tough hydrogel matrix. An e-GLUE electrode design eliminated the need for invasive submucosal placement of ground electrodes for electrical stimulation during endoscopic delivery. With an electrical stimulation treatment of about 1 minute, the cationic polymers diffuse and interact with polyanionic proteins that have a relatively slow cellular turnover rate in the deep mucosal tissue. This mucosal adhesion mechanism increased the adhesion energy of hydrogels on the mucosa by up to 30-fold and enabled in vivo gastric retention of e-GLUE devices in a pig stomach for up to 30 days. The adhesion strength was modulated by polycationic chain length, electrical stimulation time, gel thickness, cross-linking density, voltage amplitude, polycation concentration, and perimeter-to-area ratio of the electrode assembly. In porcine studies, e-GLUE demonstrated rapid mucosal adhesion in the presence of luminal fluid and mucus exposure. In proof-of-concept studies, we demonstrated e-GLUE applications for mucosal hemostasis, sustained local delivery of therapeutics, and intimate biosensing in the gastrointestinal tract, which is an ongoing clinical challenge for commercially available alternatives, such as endoclips and mucoadhesive. The e-GLUE platform could enable theranostic applications across a range of digestive diseases, including recurrent gastrointestinal bleeding and inflammatory bowel disease.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 787","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143513962","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":"BCKDHA-BCKDHB digenic gene therapy restores metabolic homeostasis in two mouse models and a calf with classic maple syrup urine disease","authors":"Jiaming Wang, Laura E. Poskitt, Jillian Gallagher, Erik G. Puffenberger, R. Max Wynn, Gauri Shishodia, David T. Chuang, Jonathan Beever, Donald L. Hardin, Karlla W. Brigatti, William C. Baker, Rachael Gately, Stephanie Bertrand, Ashlin Rodrigues, Hector R Benatti, Toloo Taghian, Erin Hall, Rachel Prestigiacomo, Jialing Liang, Gong Chen, Xuntao Zhou, Lingzhi Ren, Nan Liu, Ran He, Qin Su, Jun Xie, Zhong Jiang, Alisha Gruntman, Heather Gray-Edwards, Guangping Gao, Kevin A. Strauss, Dan Wang","doi":"10.1126/scitranslmed.ads0539","DOIUrl":"https://doi.org/10.1126/scitranslmed.ads0539","url":null,"abstract":"Classic maple syrup urine disease (MSUD) results from biallelic mutations in genes that encode the <jats:italic>branched-chain α-ketoacid dehydrogenase E1</jats:italic> α ( <jats:italic>BCKDHA</jats:italic> ), <jats:italic>E1</jats:italic> β ( <jats:italic>BCKDHB</jats:italic> ), or <jats:italic>dihydrolipoamide branched-chain transacylase</jats:italic> ( <jats:italic>DBT</jats:italic> ) subunits, which interact to form the mitochondrial BCKDH complex that decarboxylates ketoacid derivatives of leucine, isoleucine, and valine. MSUD is an inborn error of metabolism characterized by recurrent life-threatening neurologic crises and progressive brain injury that can only be managed with an exacting prescription diet or allogeneic liver transplant. To develop a gene replacement therapy for MSUD, we designed a dual-function recombinant adeno-associated virus serotype 9 (rAAV9) vector to deliver codon-optimized <jats:italic>BCKDHA</jats:italic> and <jats:italic>BCKDHB</jats:italic> (rAAV9.h <jats:italic>A</jats:italic> -BiP-h <jats:italic>B</jats:italic> ) to the liver, muscle, heart, and brain. rAAV9.h <jats:italic>A</jats:italic> -BiP-h <jats:italic>B</jats:italic> restored coexpression of BCKDHA and BCKDHB as well as BCKDH holoenzyme activity in <jats:italic> BCKDHA <jats:sup>−/−</jats:sup> </jats:italic> HEK293T cells and did not perturb physiologic branched-chain amino acid homeostasis in wild-type mice at a systemic dose of 2.7 × 10 <jats:sup>14</jats:sup> vector genomes per kilogram. In two models of severe MSUD ( <jats:italic> Bckdha <jats:sup>−/−</jats:sup> </jats:italic> and <jats:italic> Bckdhb <jats:sup>−/−</jats:sup> </jats:italic> mice) and a newborn calf homozygous for <jats:italic>BCKDHA</jats:italic> c.248C&gt;T, one postnatal injection prevented perinatal death, normalized growth, restored coordinated expression of BCKDHA and BCKDHB in the skeletal muscle, liver, heart, and brain, and stabilized MSUD biomarkers in the face of high protein ingestion. In summary, we developed a one-time <jats:italic>BCKDHA-BCKDHB</jats:italic> systemic dual-gene replacement strategy that holds promise as a therapeutic alternative to prescription diet and liver transplant for treatment of MSUD types 1A and 1B, the two most common forms of MSUD in humans.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"28 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507013","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}