Molecular Therapy最新文献_第9页

Clinical applications of oligonucleotides for cancer therapy.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-05 DOI: 10.1016/j.ymthe.2025.02.045

Vittorio DeFranciscis, Giovanni Amabile, Marcin Kortylewski

{"title":"Clinical applications of oligonucleotides for cancer therapy.","authors":"Vittorio DeFranciscis, Giovanni Amabile, Marcin Kortylewski","doi":"10.1016/j.ymthe.2025.02.045","DOIUrl":"10.1016/j.ymthe.2025.02.045","url":null,"abstract":"Oligonucleotide therapeutics (ONTs) represent a rapidly evolving modality for cancer treatment, capitalizing on their ability to modulate gene expression with high specificity. With more than 20 nucleic acid-based therapies that gained regulatory approval, advances in chemical modifications, sequence optimization, and novel delivery systems have propelled ONTs from research tools to clinical realities. ONTs, including siRNAs, antisense oligonucleotides, saRNA, miRNA, aptamers, and decoys, offer promising solutions for targeting previously \"undruggable\" molecules, such as transcription factors, and enhancing cancer immunotherapy by overcoming tumor immune evasion. The promise of ONT application in cancer treatment is exemplified by the recent FDA approval of the first oligonucleotide-based treatment to myeloproliferative disease. At the same time, there are challenges in delivering ONTs to specific tissues, mitigating off-target effects, and improving cellular uptake and endosomal release. This review provides a comprehensive overview of ONTs in clinical trials, emerging delivery strategies, and innovative therapeutic approaches, emphasizing the role of ONTs in immunotherapy and addressing hurdles that hinder their clinical translation. By examining advances and remaining challenges, we highlight opportunities for ONTs to revolutionize oncology and enhance patient outcomes.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567755","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}

引用次数: 0

Vitronectin regulates lung tissue remodeling and emphysema in chronic obstructive pulmonary disease. 玻璃体连接蛋白调节慢性阻塞性肺疾病的肺组织重塑和肺气肿。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-05 Epub Date: 2025-01-21 DOI: 10.1016/j.ymthe.2025.01.032

Gang Liu, Alan C Hsu, Silke Geirnaert, Christine Cong, Prema M Nair, Sj Shen, Jacqueline E Marshall, Tatt Jhong Haw, Michael Fricker, Ashleigh M Philp, Nicole G Hansbro, Stelios Pavlidis, Yike Guo, Janette K Burgess, Leandro Castellano, Antonio Ieni, Gaetano Caramori, Brain G G Oliver, K Fan Chung, Ian M Adcock, Darryl A Knight, Francesca Polverino, Ken Bracke, Peter A Wark, Philip M Hansbro

{"title":"Vitronectin regulates lung tissue remodeling and emphysema in chronic obstructive pulmonary disease.","authors":"Gang Liu, Alan C Hsu, Silke Geirnaert, Christine Cong, Prema M Nair, Sj Shen, Jacqueline E Marshall, Tatt Jhong Haw, Michael Fricker, Ashleigh M Philp, Nicole G Hansbro, Stelios Pavlidis, Yike Guo, Janette K Burgess, Leandro Castellano, Antonio Ieni, Gaetano Caramori, Brain G G Oliver, K Fan Chung, Ian M Adcock, Darryl A Knight, Francesca Polverino, Ken Bracke, Peter A Wark, Philip M Hansbro","doi":"10.1016/j.ymthe.2025.01.032","DOIUrl":"10.1016/j.ymthe.2025.01.032","url":null,"abstract":"Vitronectin (VTN) is an important extracellular matrix protein in tissue remodeling, but its role in chronic obstructive pulmonary disease (COPD) is unknown. We show that VTN regulates tissue remodeling through urokinase plasminogen activator (uPA) signaling pathway in COPD. In human COPD airways and bronchoepithelial cells and the airways of mice with cigarette smoke (CS)-induced experimental COPD, VTN protein was not changed, but downstream uPA signaling was altered (increased plasminogen activator inhibitor-1) that induced collagen and airway remodeling. In the parenchyma, VTN levels were decreased, uPA signaling pathway differentially altered and collagen reduced in lung fibroblasts from human and lung parenchyma in experimental COPD. Vtn inhibition with siRNA in mouse fibroblasts altered uPA signaling increased matrix metalloproteinase-12, and reduced collagen, whereas over-expression restored collagen production after CS extract challenge. Vtn-/- and Vtn small interfering RNA-treated mice had exaggerated inflammation, emphysema, and impaired lung function compared with controls with CS-induced COPD. Restoration of VTN in the parenchyma may be a therapeutic option for emphysema and COPD.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"917-932"},"PeriodicalIF":12.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11897773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007659","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}

引用次数: 0

Pharmacological blocking of microfibrillar-associated protein 4 reduces retinal neoangiogenesis and vascular leakage.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-05 Epub Date: 2025-01-25 DOI: 10.1016/j.ymthe.2025.01.038

Anders Schlosser, Bartosz Pilecki, Claire Allen, Andrew V Benest, Amy P Lynch, Jing Hua, Nikita Ved, Zoe Blackley, Thomas L Andersen, Dorle Hennig, Jonas H Graversen, Sören Möller, Sofie Skallerup, Maria Ormhøj, Clemens Lange, Hansjürgen T Agostini, Jakob Grauslund, Steffen Heegaard, Ivanka Dacheva, Michael Koss, Wenzheng Hu, Bibiana Iglesias, Matthew S Lawrence, Hans Christian Beck, Lasse Bach Steffensen, Nick S Laursen, Gregers R Andersen, Uffe Holmskov, David O Bates, Grith L Sorensen

{"title":"Pharmacological blocking of microfibrillar-associated protein 4 reduces retinal neoangiogenesis and vascular leakage.","authors":"Anders Schlosser, Bartosz Pilecki, Claire Allen, Andrew V Benest, Amy P Lynch, Jing Hua, Nikita Ved, Zoe Blackley, Thomas L Andersen, Dorle Hennig, Jonas H Graversen, Sören Möller, Sofie Skallerup, Maria Ormhøj, Clemens Lange, Hansjürgen T Agostini, Jakob Grauslund, Steffen Heegaard, Ivanka Dacheva, Michael Koss, Wenzheng Hu, Bibiana Iglesias, Matthew S Lawrence, Hans Christian Beck, Lasse Bach Steffensen, Nick S Laursen, Gregers R Andersen, Uffe Holmskov, David O Bates, Grith L Sorensen","doi":"10.1016/j.ymthe.2025.01.038","DOIUrl":"10.1016/j.ymthe.2025.01.038","url":null,"abstract":"Neovascular age-related macular degeneration and diabetic macular edema are leading causes of vision loss evoked by retinal neovascularization and vascular leakage. The glycoprotein microfibrillar-associated protein 4 (MFAP4) is an integrin αVβ3/5/6 ligand present in the extracellular matrix. Single-cell transcriptomics reveal MFAP4 expression in cell types in close proximity to vascular endothelial cells, including choroidal vascular mural cells, retinal astrocytes, and Müller cells. Binding of the anti-MFAP4 antibody, hAS0326, makes MFAP4 inaccessible for integrin receptor interaction, and thereby hAS0326 blocked endothelial cell motility in vitro. Intravitreal hAS0326 inhibited retinal vascular lesion area and neovessel volume in a laser-induced choroidal neovascularization mouse model, vascular permeability in streptozotocin-induced retinopathy, and vascular leakage area in a chronic non-human primate model of DL-2-aminoadipic acid-induced retinopathy. One dose of hAS0326 showed duration of efficacy of at least 12 weeks in the latter model. Moreover, hAS0326 treatment significantly enriched Gene Ontology terms involving reduction of integrin binding. Our data suggest that hAS0326 constitutes a promising treatment of neovascularization and vascular leakage in retinal diseases.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1048-1072"},"PeriodicalIF":12.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11897753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040292","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}

引用次数: 0

Virus-free CRISPR knockin of a chimeric antigen receptor into KLRC1 generates potent GD2-specific natural killer cells. 无病毒的CRISPR敲入嵌合抗原受体到KLRC1中，产生有效的gd2特异性自然杀伤细胞。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-05 Epub Date: 2025-01-14 DOI: 10.1016/j.ymthe.2025.01.024

Keerthana Shankar, Isabelle Zingler-Hoslet, Diana M Tabima, Seth Zima, Lei Shi, Kirstan Gimse, Matthew H Forsberg, Varun Katta, Sage Z Davis, Daniel Maldonado, Brittany E Russell, Muhammed Murtaza, Shengdar Q Tsai, Jose M Ayuso, Christian M Capitini, Krishanu Saha

{"title":"Virus-free CRISPR knockin of a chimeric antigen receptor into KLRC1 generates potent GD2-specific natural killer cells.","authors":"Keerthana Shankar, Isabelle Zingler-Hoslet, Diana M Tabima, Seth Zima, Lei Shi, Kirstan Gimse, Matthew H Forsberg, Varun Katta, Sage Z Davis, Daniel Maldonado, Brittany E Russell, Muhammed Murtaza, Shengdar Q Tsai, Jose M Ayuso, Christian M Capitini, Krishanu Saha","doi":"10.1016/j.ymthe.2025.01.024","DOIUrl":"10.1016/j.ymthe.2025.01.024","url":null,"abstract":"Natural killer (NK) cells are an appealing off-the-shelf, allogeneic cellular therapy due to their cytotoxic profile. However, their activity against solid tumors remains suboptimal in part due to the upregulation of NK-inhibitory ligands, such as HLA-E, within the tumor microenvironment. Here, we utilize CRISPR-Cas9 to disrupt the KLRC1 gene (encoding the HLA-E-binding NKG2A receptor) and perform non-viral insertion of a GD2-targeting chimeric antigen receptor (CAR) within NK cells isolated from human peripheral blood. Genome editing with CRISPR-Cas9 ribonucleoprotein complexes yields efficient genomic disruption of the KLRC1 gene with 98% knockout efficiency and specific knockin of the GD2 CAR transgene as high as 23%, with minimal off-target activity as shown by CHANGE-seq, in-out PCR, amplicon sequencing, and long-read whole-genome sequencing. KLRC1-GD2 CAR NK cells display high viability and proliferation, as well as precise cellular targeting and potency against GD2+ human tumor cells. Notably, KLRC1-GD2 CAR NK cells overcome HLA-E-based inhibition in vitro against HLA-E-expressing, GD2+ melanoma cells. Using a single-step, virus-free genome editing workflow, this study demonstrates the feasibility of precisely disrupting inhibitory signaling within NK cells via CRISPR-Cas9 while expressing a CAR to generate potent allogeneic cell therapies against HLA-E+ solid tumors.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1014-1030"},"PeriodicalIF":12.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11897758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008787","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}

引用次数: 0

Tissue nanotransfection-based endothelial PLCγ2-targeted epigenetic gene editing rescues perfusion and diabetic ischemic wound healing.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-05 Epub Date: 2025-01-25 DOI: 10.1016/j.ymthe.2025.01.034

Sumit S Verma, Chandan K Sen, Rajneesh Srivastava, Surya C Gnyawali, Parul Katiyar, Ajay K Sahi, Manishekhar Kumar, Yashika Rustagi, Sheng Liu, Diksha Pandey, Ahmed S Abouhashem, Leila N W Fehme, Sedat Kacar, Sujit K Mohanty, Julie Faden-McCormack, Michael P Murphy, Sashwati Roy, Jun Wan, Mervin C Yoder, Kanhaiya Singh

{"title":"Tissue nanotransfection-based endothelial PLCγ2-targeted epigenetic gene editing rescues perfusion and diabetic ischemic wound healing.","authors":"Sumit S Verma, Chandan K Sen, Rajneesh Srivastava, Surya C Gnyawali, Parul Katiyar, Ajay K Sahi, Manishekhar Kumar, Yashika Rustagi, Sheng Liu, Diksha Pandey, Ahmed S Abouhashem, Leila N W Fehme, Sedat Kacar, Sujit K Mohanty, Julie Faden-McCormack, Michael P Murphy, Sashwati Roy, Jun Wan, Mervin C Yoder, Kanhaiya Singh","doi":"10.1016/j.ymthe.2025.01.034","DOIUrl":"10.1016/j.ymthe.2025.01.034","url":null,"abstract":"Diabetic wounds are complicated by underlying peripheral vasculopathy. Reliance on vascular endothelial growth factor (VEGF) therapy to improve perfusion makes logical sense, yet clinical study outcomes on rescuing diabetic wound vascularization have yielded disappointing results. Our previous work has identified that low endothelial phospholipase Cγ2 (PLCγ2) expression hinders the therapeutic effect of VEGF on the diabetic ischemic limb. In this work, guided by single-cell RNA sequencing of human wound edge, we test the efficacy of gene-targeted therapeutic demethylation intending to improve VEGF-mediated neovascularization. PLCγ2 expression was diminished in all five identified diabetic wound-edge endothelial subclusters encompassing arterial, venous, and capillary cells. Such low expression was associated with hypermethylated PLCγ2 promoter. PLCγ2 promoter was also hypermethylated at murine diabetic ischemic wound edge. To specifically demethylate endothelial PLCγ2 promoter during VEGF therapy, a CRISPR-dCas9-based demethylation cocktail was delivered to the ischemic wound edge using tissue nanotransfection (TNT) technology. Demethylation-based upregulation of PLCγ2 during VEGF therapy improved wound tissue blood flow with an increased abundance of von Willebrand factor (vWF)+/PLCγ2+ vascular tissue elements by activating p44/p42-mitogen-activated protein kinase (MAPK) → hypoxia-inducible factor [HIF]-1α pathway. Taken together, TNT-based delivery of plasmids to demethylate the PLCγ2 gene promoter activity led to significant improvements in VEGF therapy for cutaneous diabetic wounds, resulting in better perfusion and accelerated wound closure.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"950-969"},"PeriodicalIF":12.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11897775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040295","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}

引用次数: 0

CDK1-loaded extracellular vesicles promote cell cycle to reverse impaired wound healing in diabetic obese mice.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-05 Epub Date: 2025-01-25 DOI: 10.1016/j.ymthe.2025.01.039

Wooil Choi, Dong Jun Park, Robert A Dorschner, Keita Nakatsutsumi, Michelle Yi, Brian P Eliceiri

{"title":"CDK1-loaded extracellular vesicles promote cell cycle to reverse impaired wound healing in diabetic obese mice.","authors":"Wooil Choi, Dong Jun Park, Robert A Dorschner, Keita Nakatsutsumi, Michelle Yi, Brian P Eliceiri","doi":"10.1016/j.ymthe.2025.01.039","DOIUrl":"10.1016/j.ymthe.2025.01.039","url":null,"abstract":"Small extracellular vesicles (sEVs) mediate intercellular signaling to coordinate the proliferation of cell types that promote re-epithelialization of skin following injury. Cyclin-dependent kinase 1 (CDK1) drives cell division and is a key regulator of entry to the cell cycle. To understand the potential of sEV-mediated delivery of CDK1 to reverse impaired wound healing, we generated CDK1-loaded sEVs (CDK1-sEVs) and evaluated their ability to mediate cell proliferation, re-epithelialization, and downstream signaling responses in the wound bed. We found that treatment of human keratinocytes with CDK1-sEVs increased phosphorylation of the CDK1 target, eukaryotic translation inhibition factor 4E-binding protein 1 (4E-BP1), and histone H3 within 24 h via AKT and ERK phosphorylation, driving increased proliferation and cell migration. Treatment of the wound bed of diabetic obese mice, a model of delayed wound healing, with a single dose of CDK1-sEVs accelerated wound closure, increased re-epithelialization, and promoted the proliferation of keratinocytes. These studies show that delivery of CDK1 by sEVs can stimulate selective and transient proliferation of cell types that increase re-epithelialization and promote proliferation of keratinocytes to accelerate wound healing.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1118-1133"},"PeriodicalIF":12.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11897770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046977","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}

引用次数: 0

Killing the killers: Natural killer cell therapy targeting glioma stem cells in high-grade glioma.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-03 DOI: 10.1016/j.ymthe.2025.02.043

Poorva Poorva, Jensen Mast, Bihui Cao, Mitesh V Shah, Karen E Pollok, Jia Shen

引用次数: 0

Targeting S100A8/A9-NCF1 axis in tumor microenvironment to prevent tumor metastasis by self-assembled peptide nanofibers.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-03 DOI: 10.1016/j.ymthe.2025.02.042

Yajing Guo, Zhifei Zhang, Hongxia Huang, Ye Wu, Lixin Yin, Yang Zhou, Feiqing Ding, Sheng Hong, Nicole F Steinmetz, Hui Cai

{"title":"Targeting S100A8/A9-NCF1 axis in tumor microenvironment to prevent tumor metastasis by self-assembled peptide nanofibers.","authors":"Yajing Guo, Zhifei Zhang, Hongxia Huang, Ye Wu, Lixin Yin, Yang Zhou, Feiqing Ding, Sheng Hong, Nicole F Steinmetz, Hui Cai","doi":"10.1016/j.ymthe.2025.02.042","DOIUrl":"10.1016/j.ymthe.2025.02.042","url":null,"abstract":"The immunosuppressive microenvironment plays a crucial role in driving and accelerating tumor metastasis. S100A8/A9, produced by myeloid-derived suppressor cells, is a potential therapeutic target for metastatic cancer due to its role in promoting premetastatic niche formation. Previous studies have revealed that the S100A9-targeted peptide (H6, MEWSLEKGYTIK) fused to the Fc region of mouse IgG2b antibodies exhibits antitumor effects; however, the mechanism remains unclear. Here, dual-function peptide nanofibers (H6-Q11) were constructed, consisting of peptide H6 and self-assembly peptide (Q11, QQKFQFQFEQQ), which achieved high avidity for S100A9. In vivo studies showed that H6-Q11 nanofibers significantly prolonged lung retention and inhibited pulmonary metastasis from melanoma and breast cancer without obvious toxicity. Immunological analyses indicated that treatment with H6-Q11 nanofibers decreased the infiltration of immunosuppressive cells while promoting the recruitment of immune effector cells to the lungs, potentially correlated with disturbances of S100A8/A9-NCF1 signaling in the tumor microenvironment. Our findings support a potential clinical application of S100A9-targeted peptide nanofibers as candidate nanomedicine for inhibiting tumor metastasis.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557497","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}

引用次数: 0

Nasal delivery of secretory IgA confers enhanced neutralizing activity against Omicron variants compared to its IgG counterpart.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-01 DOI: 10.1016/j.ymthe.2025.02.041

Guanying Zhang, Ping Huang, Hongyu Yuan, Entao Li, Xiangyang Chi, Hancong Sun, Jin Han, Ting Fang, Yunzhu Dong, Jie Li, Yaoxing Wang, Jianmin Li, Sandra Chiu, Changming Yu

{"title":"Nasal delivery of secretory IgA confers enhanced neutralizing activity against Omicron variants compared to its IgG counterpart.","authors":"Guanying Zhang, Ping Huang, Hongyu Yuan, Entao Li, Xiangyang Chi, Hancong Sun, Jin Han, Ting Fang, Yunzhu Dong, Jie Li, Yaoxing Wang, Jianmin Li, Sandra Chiu, Changming Yu","doi":"10.1016/j.ymthe.2025.02.041","DOIUrl":"10.1016/j.ymthe.2025.02.041","url":null,"abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its multiple variants continue to spread worldwide, causing respiratory symptoms primarily through mucosal infection. The mucosa serves as the primary barrier against viral entry, in which secretory immunoglobulin A (sIgA) plays a critical role in preventing infection. Here, we engineered and characterized a neutralizing monoclonal antibody, ZW2G10, in IgG, monomeric, dimeric, secretory IgA1, and IgA2 formats. All seven forms of the ZW2G10 antibody showed similar thermal stability. sIgA, especially sIgA1, displayed enhanced neutralizing activity against Omicron-lineage BA.2.75, BA.2.76 and BA.4/5 pseudoviruses compared to IgG. Nasal administration of sIgA1 conferred robust protection against the BA.2.76 pseudovirus in ACE2 transgenic mice, and its protective efficacy was superior to that of IgG. The crystal structure of Omicron receptor binding domain (RBD) and ZW2G10 antibody fragment (Fab) complex revealed that ZW2G10 had no clashes with ACE2. Thus, nasal administration of sIgA may serve as a promising tool for the prevention and treatment of Omicron infection.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537446","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}

引用次数: 0

Viral and cellular insulators promote sustained HSV vector-mediated transgene expression in brain. 病毒和细胞绝缘体可促进 HSV 载体介导的转基因在大脑中的持续表达

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-02-28 DOI: 10.1016/j.ymthe.2025.02.039

Selene Ingusci, Justus B Cohen, Joseph C Glorioso

{"title":"Viral and cellular insulators promote sustained HSV vector-mediated transgene expression in brain.","authors":"Selene Ingusci, Justus B Cohen, Joseph C Glorioso","doi":"10.1016/j.ymthe.2025.02.039","DOIUrl":"10.1016/j.ymthe.2025.02.039","url":null,"abstract":"We have developed a gene therapy platform based on non-toxic, high-capacity replication-defective (rd) herpes simplex virus type 1 (HSV-1) vectors. We previously determined that transgene expression from rdHSV-1 vectors requires strategic placement of insulators-small DNA elements that overcome the host's epigenetic silencing of foreign DNA-to maintain transgenes in euchromatin regions. Transgene expression was rescued by replacing either the latency associated transcript (LAT) or the the infected cell protein 4 (ICP4) gene with the transgene cassette close to naturally occurring viral insulators. The ICP4 locus was more permissive for transgene expression than the LAT locus in neurons in vitro. Following in vivo brain delivery, transgene expression from both loci lasted for at least 4 months. However, the level of expression tended to decline over time. To enhance transgene expression, we designed a novel insulator environment by combining cellular insulators with the resident viral insulators. In combination, these elements provided significantly higher levels of transgene expression in the brain than the viral insulators alone, lasting for at least 11.7 months. This new cassette design extends transgene activity in neurons compared with previous designs and holds promise for gene therapy applications in treating brain disorders.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531681","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}

引用次数: 0