Pub Date : 2024-08-21DOI: 10.1126/scitranslmed.adl4222
Zhongcheng Mei, May A. Khalil, Yizhan Guo, Dongge Li, Anirban Banerjee, Mojtaba Taheri, Christina M. Kratzmeier, Kelly Chen, Christine L. Lau, Irina G. Luzina, Sergei P. Atamas, Sivaveera Kandasamy, Daniel Kreisel, Andrew E. Gelman, Elizabeth A. Jacobsen, Alexander Sasha Krupnick
Respiratory failure occurs more frequently after thoracic surgery than abdominal surgery. Although the etiology for this complication is frequently attributed to underlying lung disease present in patients undergoing thoracic surgery, this notion is often unfounded because many patients with normal preoperative pulmonary function often require prolonged oxygen supplementation even after minimal resection of lung tissue. Using a murine model of pulmonary resection and peripheral blood samples from patients undergoing resection of the lung or abdominal organs, we demonstrated that lung surgery initiates a proinflammatory loop that results in damage to the remaining lung tissue, noncardiogenic pulmonary edema, hypoxia, and even death. Specifically, we demonstrated that resection of murine lung tissue increased concentrations of the homeostatic cytokine interleukin-7, which led to local and systemic activation of type 2 innate lymphoid cells. This process activated lung-resident eosinophils and facilitated stress-induced eosinophil maturation in the bone marrow in a granulocyte-macrophage colony-stimulating factor–dependent manner, resulting in systemic eosinophilia in both mice and humans. Up-regulation of inducible nitric oxide synthase in lung-resident eosinophils led to tissue nitrosylation, pulmonary edema, hypoxia, and, at times, death. Disrupting this activation cascade at any stage ameliorated deleterious outcomes and improved survival after lung resection in the mouse model. Our data suggest that repurposing US Food and Drug Administration–approved eosinophil-targeting strategies may potentially offer a therapeutic intervention to improve outcomes for patients who require lung resection for benign or malignant etiology.
{"title":"Stress-induced eosinophil activation contributes to postoperative morbidity and mortality after lung resection","authors":"Zhongcheng Mei, May A. Khalil, Yizhan Guo, Dongge Li, Anirban Banerjee, Mojtaba Taheri, Christina M. Kratzmeier, Kelly Chen, Christine L. Lau, Irina G. Luzina, Sergei P. Atamas, Sivaveera Kandasamy, Daniel Kreisel, Andrew E. Gelman, Elizabeth A. Jacobsen, Alexander Sasha Krupnick","doi":"10.1126/scitranslmed.adl4222","DOIUrl":"10.1126/scitranslmed.adl4222","url":null,"abstract":"<div >Respiratory failure occurs more frequently after thoracic surgery than abdominal surgery. Although the etiology for this complication is frequently attributed to underlying lung disease present in patients undergoing thoracic surgery, this notion is often unfounded because many patients with normal preoperative pulmonary function often require prolonged oxygen supplementation even after minimal resection of lung tissue. Using a murine model of pulmonary resection and peripheral blood samples from patients undergoing resection of the lung or abdominal organs, we demonstrated that lung surgery initiates a proinflammatory loop that results in damage to the remaining lung tissue, noncardiogenic pulmonary edema, hypoxia, and even death. Specifically, we demonstrated that resection of murine lung tissue increased concentrations of the homeostatic cytokine interleukin-7, which led to local and systemic activation of type 2 innate lymphoid cells. This process activated lung-resident eosinophils and facilitated stress-induced eosinophil maturation in the bone marrow in a granulocyte-macrophage colony-stimulating factor–dependent manner, resulting in systemic eosinophilia in both mice and humans. Up-regulation of inducible nitric oxide synthase in lung-resident eosinophils led to tissue nitrosylation, pulmonary edema, hypoxia, and, at times, death. Disrupting this activation cascade at any stage ameliorated deleterious outcomes and improved survival after lung resection in the mouse model. Our data suggest that repurposing US Food and Drug Administration–approved eosinophil-targeting strategies may potentially offer a therapeutic intervention to improve outcomes for patients who require lung resection for benign or malignant etiology.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142018453","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}
Pub Date : 2024-08-21DOI: 10.1126/scitranslmed.adn0904
Zhen Lu, Ioannis Verginadis, Motofumi Kumazoe, Gerardo M. Castillo, Yao Yao, Rebecca E. Guerra, Sandra Bicher, Menghao You, George McClung, Rong Qiu, Zebin Xiao, Zhen Miao, Subin S. George, Daniel P. Beiting, Takashi Nojiri, Yasutake Tanaka, Yoshinori Fujimura, Hiroaki Onda, Yui Hatakeyama, Akiko Nishimoto-Ashfield, Katrina Bykova, Wei Guo, Yi Fan, Nikolay M. Buynov, J. Alan Diehl, Ben Z. Stanger, Hirofumi Tachibana, Terence P. Gade, Ellen Puré, Constantinos Koumenis, Elijah M. Bolotin, Serge Y. Fuchs
Deficit of oxygen and nutrients in the tumor microenvironment (TME) triggers abnormal angiogenesis that produces dysfunctional and leaky blood vessels, which fail to adequately perfuse tumor tissues. Resulting hypoxia, exacerbation of metabolic disturbances, and generation of an immunosuppressive TME undermine the efficacy of anticancer therapies. Use of carefully scheduled angiogenesis inhibitors has been suggested to overcome these problems and normalize the TME. Here, we propose an alternative agonist-based normalization approach using a derivative of the C-type natriuretic peptide (dCNP). Multiple gene expression signatures in tumor tissues were affected in mice treated with dCNP. In several mouse orthotopic and subcutaneous solid tumor models including colon and pancreatic adenocarcinomas, this well-tolerated agent stimulated formation of highly functional tumor blood vessels to reduce hypoxia. Administration of dCNP also inhibited stromagenesis and remodeling of the extracellular matrix and decreased tumor interstitial fluid pressure. In addition, treatment with dCNP reinvigorated the antitumor immune responses. Administration of dCNP decelerated growth of primary mouse tumors and suppressed their metastases. Moreover, inclusion of dCNP into the chemo-, radio-, or immune-therapeutic regimens increased their efficacy against solid tumors in immunocompetent mice. These results demonstrate the proof of principle for using vasculature normalizing agonists to improve therapies against solid tumors and characterize dCNP as the first in class among such agents.
{"title":"Modified C-type natriuretic peptide normalizes tumor vasculature, reinvigorates antitumor immunity, and improves solid tumor therapies","authors":"Zhen Lu, Ioannis Verginadis, Motofumi Kumazoe, Gerardo M. Castillo, Yao Yao, Rebecca E. Guerra, Sandra Bicher, Menghao You, George McClung, Rong Qiu, Zebin Xiao, Zhen Miao, Subin S. George, Daniel P. Beiting, Takashi Nojiri, Yasutake Tanaka, Yoshinori Fujimura, Hiroaki Onda, Yui Hatakeyama, Akiko Nishimoto-Ashfield, Katrina Bykova, Wei Guo, Yi Fan, Nikolay M. Buynov, J. Alan Diehl, Ben Z. Stanger, Hirofumi Tachibana, Terence P. Gade, Ellen Puré, Constantinos Koumenis, Elijah M. Bolotin, Serge Y. Fuchs","doi":"10.1126/scitranslmed.adn0904","DOIUrl":"10.1126/scitranslmed.adn0904","url":null,"abstract":"<div >Deficit of oxygen and nutrients in the tumor microenvironment (TME) triggers abnormal angiogenesis that produces dysfunctional and leaky blood vessels, which fail to adequately perfuse tumor tissues. Resulting hypoxia, exacerbation of metabolic disturbances, and generation of an immunosuppressive TME undermine the efficacy of anticancer therapies. Use of carefully scheduled angiogenesis inhibitors has been suggested to overcome these problems and normalize the TME. Here, we propose an alternative agonist-based normalization approach using a derivative of the C-type natriuretic peptide (dCNP). Multiple gene expression signatures in tumor tissues were affected in mice treated with dCNP. In several mouse orthotopic and subcutaneous solid tumor models including colon and pancreatic adenocarcinomas, this well-tolerated agent stimulated formation of highly functional tumor blood vessels to reduce hypoxia. Administration of dCNP also inhibited stromagenesis and remodeling of the extracellular matrix and decreased tumor interstitial fluid pressure. In addition, treatment with dCNP reinvigorated the antitumor immune responses. Administration of dCNP decelerated growth of primary mouse tumors and suppressed their metastases. Moreover, inclusion of dCNP into the chemo-, radio-, or immune-therapeutic regimens increased their efficacy against solid tumors in immunocompetent mice. These results demonstrate the proof of principle for using vasculature normalizing agonists to improve therapies against solid tumors and characterize dCNP as the first in class among such agents.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142018451","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}
Pub Date : 2024-08-14DOI: 10.1126/scitranslmed.adi6626
Xue Dong, Yinting Song, Yuming Liu, Xuejing Kou, Tianjing Yang, Samuel X. Shi, Kai He, Yiming Li, Ziqi Li, Xueming Yao, Ju Guo, Bohao Cui, Ziru Wu, Yi Lei, Mei Du, Mei Chen, Heping Xu, Qiang Liu, Fu-Dong Shi, Xiaohong Wang, Hua Yan
Neovascular age-related macular degeneration (nvAMD) is the leading cause of blindness in the elderly population. Although it is known that nvAMD is associated with focal inflammation, understanding of the precise immune components governing this process remains limited. Here, we identified natural killer (NK) cells as a prominent lymphocyte population infiltrating the perivascular space of choroidal neovascularization (CNV) lesions in patients with nvAMD and in mouse models. Olink proteomic analysis and single-cell RNA sequencing combined with knockout studies demonstrated the involvement of C-C chemokine receptor 5 (CCR5) in NK cell recruitment and extravasation at the CNV sites of mice. Depletion of NK cells or inhibition of activating receptor NK group 2, member D (NKG2D) inhibited the formation of neutrophil extracellular traps, increased vascular leakage, and exacerbated pathological angiogenesis, indicating that NK cells restrain pathogenesis in this mouse model. Age is the strongest risk factor for AMD, and we show that NK cells from aged human donors exhibited a less cytotoxic phenotype. NK cells from old mice exhibited compromised protective effects in the CNV mouse model. In addition, interleukin-2 complex–mediated expansion of NK cells improved CNV formation in mice. Collectively, our study highlights NK cells as a potential therapeutic target for patients with nvAMD.
新生血管性老年黄斑变性（nvAMD）是老年人失明的主要原因。尽管人们知道新生血管性老年黄斑变性与局灶性炎症有关，但对支配这一过程的精确免疫成分的了解仍然有限。在这里，我们发现自然杀伤（NK）细胞是渗入nvAMD患者和小鼠模型脉络膜新生血管（CNV）病变血管周围空间的主要淋巴细胞群。Olink蛋白组分析和单细胞RNA测序结合基因敲除研究证明，C-C趋化因子受体5（CCR5）参与了小鼠CNV部位的NK细胞招募和外渗。消耗NK细胞或抑制活化受体NK 2组D成员（NKG2D）可抑制中性粒细胞胞外捕获物的形成、增加血管渗漏并加剧病理性血管生成，这表明NK细胞抑制了该小鼠模型的发病机制。年龄是导致老年性视网膜病变的最大风险因素，而我们的研究表明，来自高龄人类供体的 NK 细胞表现出较低的细胞毒性表型。在 CNV 小鼠模型中，来自高龄小鼠的 NK 细胞表现出的保护作用也大打折扣。此外，白介素-2 复合物介导的 NK 细胞扩增改善了小鼠 CNV 的形成。总之，我们的研究强调了 NK 细胞是 nvAMD 患者的潜在治疗靶点。
{"title":"Natural killer cells promote neutrophil extracellular traps and restrain macular degeneration in mice","authors":"Xue Dong, Yinting Song, Yuming Liu, Xuejing Kou, Tianjing Yang, Samuel X. Shi, Kai He, Yiming Li, Ziqi Li, Xueming Yao, Ju Guo, Bohao Cui, Ziru Wu, Yi Lei, Mei Du, Mei Chen, Heping Xu, Qiang Liu, Fu-Dong Shi, Xiaohong Wang, Hua Yan","doi":"10.1126/scitranslmed.adi6626","DOIUrl":"10.1126/scitranslmed.adi6626","url":null,"abstract":"<div >Neovascular age-related macular degeneration (nvAMD) is the leading cause of blindness in the elderly population. Although it is known that nvAMD is associated with focal inflammation, understanding of the precise immune components governing this process remains limited. Here, we identified natural killer (NK) cells as a prominent lymphocyte population infiltrating the perivascular space of choroidal neovascularization (CNV) lesions in patients with nvAMD and in mouse models. Olink proteomic analysis and single-cell RNA sequencing combined with knockout studies demonstrated the involvement of C-C chemokine receptor 5 (CCR5) in NK cell recruitment and extravasation at the CNV sites of mice. Depletion of NK cells or inhibition of activating receptor NK group 2, member D (NKG2D) inhibited the formation of neutrophil extracellular traps, increased vascular leakage, and exacerbated pathological angiogenesis, indicating that NK cells restrain pathogenesis in this mouse model. Age is the strongest risk factor for AMD, and we show that NK cells from aged human donors exhibited a less cytotoxic phenotype. NK cells from old mice exhibited compromised protective effects in the CNV mouse model. In addition, interleukin-2 complex–mediated expansion of NK cells improved CNV formation in mice. Collectively, our study highlights NK cells as a potential therapeutic target for patients with nvAMD.</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":"141983131","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}
Pub Date : 2024-08-14DOI: 10.1126/scitranslmed.adl0715
Hui Chen, Stéphanie Moriceau, Adrien Joseph, Francois Mailliet, Sijing Li, Virginie Tolle, Philibert Duriez, Roland Dardennes, Sylvère Durand, Vincent Carbonnier, Gautier Stoll, Allan Sauvat, Sylvie Lachkar, Fanny Aprahamian, Carolina Alves Costa Silva, Hui Pan, Léa Montégut, Gerasimos Anagnostopoulos, Flavia Lambertucci, Omar Motiño, Uxía Nogueira-Recalde, Mélanie Bourgin, Misha Mao, Yuhong Pan, Alexandra Cerone, Erwan Boedec, Zelia L. Gouveia, Federica Marmorino, Chiara Cremolini, Lisa Derosa, Laurence Zitvogel, Oliver Kepp, Carlos López-Otín, Maria Chiara Maiuri, Franck Perez, Philip Gorwood, Nicolas Ramoz, Franck Oury, Isabelle Martins, Guido Kroemer
Extracellular acyl-coenzyme A binding protein [ACBP encoded by diazepam binding inhibitor (DBI)] is a phylogenetically ancient appetite stimulator that is secreted in a nonconventional, autophagy-dependent fashion. Here, we show that low ACBP/DBI plasma concentrations are associated with poor prognosis in patients with anorexia nervosa, a frequent and often intractable eating disorder. In mice, anorexia induced by chronic restraint stress (CRS) is accompanied by a reduction in circulating ACBP/DBI concentrations. We engineered a chemical-genetic system for the secretion of ACBP/DBI through a biotin-activatable, autophagy-independent pathway. In transgenic mice expressing this system in hepatocytes, biotin-induced elevations in plasma ACBP/DBI concentrations prevented anorexia induced by CRS or chemotherapeutic agents including cisplatin, doxorubicin, and paclitaxel. ACBP/DBI reversed the CRS or cisplatin-induced increase in plasma lipocalin-2 concentrations and the hypothalamic activation of anorexigenic melanocortin 4 receptors, for which lipocalin-2 is an agonist. Daily intravenous injections of recombinant ACBP/DBI protein or subcutaneous implantation of osmotic pumps releasing recombinant ACBP/DBI mimicked the orexigenic effects of the chemical-genetic system. In conclusion, the supplementation of extracellular and peripheral ACBP/DBI might constitute a viable strategy for treating anorexia.
{"title":"Acyl-CoA binding protein for the experimental treatment of anorexia","authors":"Hui Chen, Stéphanie Moriceau, Adrien Joseph, Francois Mailliet, Sijing Li, Virginie Tolle, Philibert Duriez, Roland Dardennes, Sylvère Durand, Vincent Carbonnier, Gautier Stoll, Allan Sauvat, Sylvie Lachkar, Fanny Aprahamian, Carolina Alves Costa Silva, Hui Pan, Léa Montégut, Gerasimos Anagnostopoulos, Flavia Lambertucci, Omar Motiño, Uxía Nogueira-Recalde, Mélanie Bourgin, Misha Mao, Yuhong Pan, Alexandra Cerone, Erwan Boedec, Zelia L. Gouveia, Federica Marmorino, Chiara Cremolini, Lisa Derosa, Laurence Zitvogel, Oliver Kepp, Carlos López-Otín, Maria Chiara Maiuri, Franck Perez, Philip Gorwood, Nicolas Ramoz, Franck Oury, Isabelle Martins, Guido Kroemer","doi":"10.1126/scitranslmed.adl0715","DOIUrl":"10.1126/scitranslmed.adl0715","url":null,"abstract":"<div >Extracellular acyl-coenzyme A binding protein [ACBP encoded by diazepam binding inhibitor (DBI)] is a phylogenetically ancient appetite stimulator that is secreted in a nonconventional, autophagy-dependent fashion. Here, we show that low ACBP/DBI plasma concentrations are associated with poor prognosis in patients with anorexia nervosa, a frequent and often intractable eating disorder. In mice, anorexia induced by chronic restraint stress (CRS) is accompanied by a reduction in circulating ACBP/DBI concentrations. We engineered a chemical-genetic system for the secretion of ACBP/DBI through a biotin-activatable, autophagy-independent pathway. In transgenic mice expressing this system in hepatocytes, biotin-induced elevations in plasma ACBP/DBI concentrations prevented anorexia induced by CRS or chemotherapeutic agents including cisplatin, doxorubicin, and paclitaxel. ACBP/DBI reversed the CRS or cisplatin-induced increase in plasma lipocalin-2 concentrations and the hypothalamic activation of anorexigenic melanocortin 4 receptors, for which lipocalin-2 is an agonist. Daily intravenous injections of recombinant ACBP/DBI protein or subcutaneous implantation of osmotic pumps releasing recombinant ACBP/DBI mimicked the orexigenic effects of the chemical-genetic system. In conclusion, the supplementation of extracellular and peripheral ACBP/DBI might constitute a viable strategy for treating anorexia.</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":"https://www.science.org/doi/reader/10.1126/scitranslmed.adl0715","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983126","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}
Pub Date : 2024-08-14DOI: 10.1126/scitranslmed.adr6878
{"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}
Pub Date : 2024-08-14DOI: 10.1126/scitranslmed.adi2245
Scarlett J. Barker, Mai B. Thayer, Chaeyoung Kim, David Tatarakis, Matthew J. Simon, Rebekah Dial, Lizanne Nilewski, Robert C. Wells, Yinhan Zhou, Megan Afetian, Padma Akkapeddi, Alfred Chappell, Kylie S. Chew, Johann Chow, Allisa Clemens, Claire B. Discenza, Jason C. Dugas, Chrissa Dwyer, Timothy Earr, Connie Ha, Yvonne S. Ho, David Huynh, Edwin I. Lozano, Srini Jayaraman, Wanda Kwan, Cathal Mahon, Michelle Pizzo, Yaneth Robles-Colmenares, Elysia Roche, Laura Sanders, Alexander Stergioulis, Raymond Tong, Hai Tran, Y. Joy Yu Zuchero, Anthony A. Estrada, Kapil Gadkar, Christopher M. M. Koth, Pascal E. Sanchez, Robert G. Thorne, Ryan J. Watts, Thomas Sandmann, Lesley A. Kane, Frank Rigo, Mark S. Dennis, Joseph W. Lewcock, Sarah L. DeVos
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 (TfRmu/hu KI) mice and nonhuman primates. Intravenous injection and systemic delivery of OTV to TfRmu/hu KI mice resulted in sustained knockdown of the ASO target RNA, Malat1, across multiple mouse CNS regions and cell types, including endothelial cells, neurons, astrocytes, microglia, and oligodendrocytes. In addition, systemic delivery of OTV enabled Malat1 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 TfRmu/hu KI mice and greater knockdown of Malat1 RNA compared with a bivalent, high-affinity TfR antibody. In cynomolgus macaques, an OTV directed against MALAT1 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.
{"title":"Targeting the transferrin receptor to transport antisense oligonucleotides across the mammalian blood-brain barrier","authors":"Scarlett J. Barker, Mai B. Thayer, Chaeyoung Kim, David Tatarakis, Matthew J. Simon, Rebekah Dial, Lizanne Nilewski, Robert C. Wells, Yinhan Zhou, Megan Afetian, Padma Akkapeddi, Alfred Chappell, Kylie S. Chew, Johann Chow, Allisa Clemens, Claire B. Discenza, Jason C. Dugas, Chrissa Dwyer, Timothy Earr, Connie Ha, Yvonne S. Ho, David Huynh, Edwin I. Lozano, Srini Jayaraman, Wanda Kwan, Cathal Mahon, Michelle Pizzo, Yaneth Robles-Colmenares, Elysia Roche, Laura Sanders, Alexander Stergioulis, Raymond Tong, Hai Tran, Y. Joy Yu Zuchero, Anthony A. Estrada, Kapil Gadkar, Christopher M. M. Koth, Pascal E. Sanchez, Robert G. Thorne, Ryan J. Watts, Thomas Sandmann, Lesley A. Kane, Frank Rigo, Mark S. Dennis, Joseph W. Lewcock, 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<sup>mu/hu</sup> KI) mice and nonhuman primates. Intravenous injection and systemic delivery of OTV to TfR<sup>mu/hu</sup> 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<sup>mu/hu</sup> 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}
Pub Date : 2024-08-14DOI: 10.1126/scitranslmed.ado1097
David Lagier, Congli Zeng, David W. Kaczka, Min Zhu, Kira Grogg, Sarah E. Gerard, Joseph M. Reinhardt, Gabriel C. Motta Ribeiro, Azman Rashid, Tilo Winkler, Marcos F. Vidal Melo
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 (PEEPDP) optimized local lung biomechanics. We observed a greater rate of change in nonaerated lung mass with respect to PEEP below PEEPDP compared with PEEP values above this threshold. PEEPDP 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.
机械通气会使肺部承受有害的压力和应变，从而对急性呼吸窘迫综合征的临床效果产生负面影响，或导致全身麻醉后的肺部并发症。根据呼吸系统驱动压力的增加估算，过大的整体肺应变与机械通气相关的死亡率有关。目前尚不清楚导致这种关联的小尺寸生物力学因素的作用及其在肺内的空间异质性。我们使用体素分辨率为 2.4 立方毫米的四维计算机断层扫描和用于全肺图像分割的多分辨率卷积神经网络，动态测量了体素范围内的肺充气和潮气实质应变。当机械通气呼气末正压（PEEP）从 20 厘米水滴调节到 2 厘米水滴时，我们对健康或受伤的绵羊肺进行了评估。最小驱动压力 PEEP（PEEPDP）优化了局部肺部生物力学。我们观察到，与高于 PEEPDP 的 PEEP 值相比，低于 PEEPDP 的 PEEP 值的非通气肺质量变化率更大。PEEPDP 同样也是 PEEP 与局部潮气实质应变 SD 值、局部应变第 95 百分位数和潮气过张程度之间关系的突破点。这些发现加深了人们对肺塌陷、潮气过张力和应变异质性作为呼吸机诱发肺损伤的局部触发因素的理解，这些因素在大动物肺中与人类肺相似，可为临床机械通气管理提供信息，以改善局部肺生物力学。
{"title":"Mechanical ventilation guided by driving pressure optimizes local pulmonary biomechanics in an ovine model","authors":"David Lagier, Congli Zeng, David W. Kaczka, Min Zhu, Kira Grogg, Sarah E. Gerard, Joseph M. Reinhardt, Gabriel C. Motta Ribeiro, Azman Rashid, Tilo Winkler, 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<sub>DP</sub>) optimized local lung biomechanics. We observed a greater rate of change in nonaerated lung mass with respect to PEEP below PEEP<sub>DP</sub> compared with PEEP values above this threshold. PEEP<sub>DP</sub> 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}
Pub Date : 2024-08-14DOI: 10.1126/scitranslmed.adl5934
Swati Shah, Jianhao Lai, Falguni Basuli, Neysha Martinez-Orengo, Reema Patel, Mitchell L. Turner, Benjamin Wang, Zhen-Dan Shi, Suman Sourabh, Morteza Peiravi, Anna Lyndaker, Sichen Liu, Seyedmojtaba Seyedmousavi, Peter R. Williamson, Rolf E. Swenson, Dima A. Hammoud
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. Aspergillus fumigatus 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 Aspergillus-specific positron emission tomography (PET) imaging agent, we focused on fungal-specific sugar metabolism. We radiolabeled cellobiose, a disaccharide known to be metabolized by Aspergillus 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 >98%, and 1.5 hours of synthesis time. Two hours after [18F]FCB injection in A. fumigatus pneumonia as well as A. fumigatus, bacterial, and sterile inflammation myositis mouse models, retained radioactivity was only seen in foci with live A. fumigatus infection. In vitro testing confirmed production of β-glucosidase enzyme by A. fumigatus 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 A. fumigatus infectious sites. We conclude that [18F]FCB is a promising and clinically translatable Aspergillus-specific PET tracer.
{"title":"Development and preclinical validation of 2-deoxy 2-[18F]fluorocellobiose as an Aspergillus-specific PET tracer","authors":"Swati Shah, Jianhao Lai, Falguni Basuli, Neysha Martinez-Orengo, Reema Patel, Mitchell L. Turner, Benjamin Wang, Zhen-Dan Shi, Suman Sourabh, Morteza Peiravi, Anna Lyndaker, Sichen Liu, Seyedmojtaba Seyedmousavi, Peter R. Williamson, Rolf E. Swenson, 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-[<sup>18</sup>F]fluorocellobiose ([<sup>18</sup>F]FCB) by enzymatic conversion of 2-deoxy-2-[<sup>18</sup>F]fluoroglucose ([<sup>18</sup>F]FDG) with a radiochemical yield of 60 to 70%, a radiochemical purity of >98%, and 1.5 hours of synthesis time. Two hours after [<sup>18</sup>F]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 [<sup>18</sup>F]FCB into glucose and [<sup>18</sup>F]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 [<sup>18</sup>F]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}
Pub Date : 2024-08-07DOI: 10.1126/scitranslmed.abo4736
Emma van Groesen, Elma Mons, Ioli Kotsogianni, Melina Arts, Kamaleddin H. M. E. Tehrani, Nicola Wade, Vladyslav Lysenko, Floor M. Stel, Jordy T. Zwerus, Stefania De Benedetti, Alexander Bakker, Parichita Chakraborty, Mario van der Stelt, Dirk-Jan Scheffers, Jairo Gooskens, Wiep Klaas Smits, Kirsty Holden, Peter S. Gilmour, Joost Willemse, Christopher A. Hitchcock, J. G. Coen van Hasselt, Tanja Schneider, Nathaniel I. Martin
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 Staphylococcus aureus (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 d-Ala-d-Ala lipid II and the vancomycin-resistant d-Ala-d-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 S. aureus 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.
革兰氏阳性细菌感染是一项重大的临床挑战，耐甲氧西林和耐万古霉素菌株一直是令人担忧的问题。近年来，人们开发了半合成万古霉素衍生物来解决这一问题，临床上使用的泰拉万星就是一例，它具有更强的抗菌效力，但也引发了毒性问题。因此，仍然需要抗菌活性更强、安全性更好的糖肽类抗生素。我们介绍了一类高效半合成糖肽抗生素--胍基脂甘肽的开发情况，这种抗生素含有一个带正电荷的胍基，并带有一个可变的脂基。这些糖肽对一系列革兰氏阳性细菌（包括临床相关的耐甲氧西林金黄色葡萄球菌（MRSA）和耐万古霉素菌株）具有更强的体外活性，对真核细胞的毒性极小，而且耐药性选择倾向低。从机理上讲，胍基脂甘肽与细菌细胞壁前体脂质 II 的结合亲和力高于万古霉素。与野生型 d-Ala-d-Ala 脂质 II 和对万古霉素耐药的 d-Ala-d-Lac 变体的结合均得到了证实，这为胍基聚糖肽增强对万古霉素耐药分离菌的活性提供了启示。在金黄色葡萄球菌小鼠大腿感染模型和 7 天败血症存活研究中评估了胍基脂多糖肽 EVG7 的体内疗效，结果均显示其优于万古霉素。此外，与万古霉素相比，EVG7 在超治疗剂量时对肾脏的影响极小至轻微，这表明其治疗安全性有所提高。这些研究结果表明，胍基脂甘肽可作为抗菌剂进一步开发，用于治疗临床相关的耐多药革兰氏阳性感染。
{"title":"Semisynthetic guanidino lipoglycopeptides with potent in vitro and in vivo antibacterial activity","authors":"Emma van Groesen, Elma Mons, Ioli Kotsogianni, Melina Arts, Kamaleddin H. M. E. Tehrani, Nicola Wade, Vladyslav Lysenko, Floor M. Stel, Jordy T. Zwerus, Stefania De Benedetti, Alexander Bakker, Parichita Chakraborty, Mario van der Stelt, Dirk-Jan Scheffers, Jairo Gooskens, Wiep Klaas Smits, Kirsty Holden, Peter S. Gilmour, Joost Willemse, Christopher A. Hitchcock, J. G. Coen van Hasselt, Tanja Schneider, 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}
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