Molecular Therapy最新文献_第9页

mRNA-LNPs induce immune activation and cytokine release in human whole blood assays across diverse health conditions. mRNA-LNPs 可在人体全血检测中诱导免疫激活和细胞因子释放，适用于各种健康状况。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-06-04 Epub Date: 2024-12-12 DOI: 10.1016/j.ymthe.2024.12.019

Hong-My Nguyen, Kristin E Alexander, Mark Collinge, James C Hickey, Thomas A Lanz, Jin Li, Mark J Sheehan, Leah C Newman, Mitchell Thorn

{"title":"mRNA-LNPs induce immune activation and cytokine release in human whole blood assays across diverse health conditions.","authors":"Hong-My Nguyen, Kristin E Alexander, Mark Collinge, James C Hickey, Thomas A Lanz, Jin Li, Mark J Sheehan, Leah C Newman, Mitchell Thorn","doi":"10.1016/j.ymthe.2024.12.019","DOIUrl":"10.1016/j.ymthe.2024.12.019","url":null,"abstract":"RNA medicines have become a promising platform for therapeutic use in recent years. Understanding the immunomodulatory effects of novel mRNA-lipid nanoparticles (LNPs) is crucial for future therapeutic development. An in vitro whole blood assay was developed to assess the impact of mRNA-LNPs on immune cell function, cytokine release, and complement activation. mRNA-LNPs significantly increased CD69 expression on T cells and natural killer cells, and CD80/CD86 on myeloid subsets, in a dose-dependent fashion. Furthermore, mRNA-LNPs elicited a robust release of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, monocyte chemoattractant protein-1, IL-6, and IP-10, indicating a potent immune response. Notably, mRNA-LNPs stimulate early cytokine production prior to triggering immune cell activation, suggesting a temporal and biological relationship. Moreover, mRNA-LNPs induce complement activation via the alternative pathway, as evidenced by increased serum sC5b-9, C3a, and Bb, which can amplify the inflammatory response and potentially impact safety. In vitro effects of mRNA-LNPs in whole blood of healthy human donors were compared with those from disease cohorts including systemic lupus erythematosus, type 2 diabetes mellitus, and cancer donors. The differences in mRNA-LNP effects on samples from healthy and diseased populations may impact therapeutic efficacy or toxicity, indicating a need for tailoring LNPs for specific target populations.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2872-2885"},"PeriodicalIF":12.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12172169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823944","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

Cancer-derived extracellular vesicles in natural killer cell immune evasion: Molecular mechanisms and therapeutic insights. 自然杀伤细胞免疫逃避中的癌源性细胞外囊泡：分子机制和治疗见解。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-31 DOI: 10.1016/j.ymthe.2025.05.038

Elaina Coleborn, Raluca Ghebosu, Joy Wolfram, Fernando Souza-Fonseca-Guimaraes

{"title":"Cancer-derived extracellular vesicles in natural killer cell immune evasion: Molecular mechanisms and therapeutic insights.","authors":"Elaina Coleborn, Raluca Ghebosu, Joy Wolfram, Fernando Souza-Fonseca-Guimaraes","doi":"10.1016/j.ymthe.2025.05.038","DOIUrl":"10.1016/j.ymthe.2025.05.038","url":null,"abstract":"Natural killer cells are innate lymphocytes equipped with the ability to rapidly identify and eliminate cancer cells. However, cancer cells release nanosized extracellular vesicles that can induce an immunosuppressive tumor microenvironment, subsequently hindering natural killer cell immunosurveillance. Studies have reported that extracellular vesicles derived from different cancers, such as acute myeloid leukemia, melanoma, mesothelioma, head and neck squamous carcinoma, lung carcinoma, breast cancer, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma, can induce natural killer cell dysfunction by suppressing cytolytic proteins and downregulating expression of receptors involved in the recognition of oncogenic cells. Additionally, cancer-derived extracellular vesicles can interfere with natural killer cell survival, proliferation, cell migration, and metabolic functions. Therefore, extracellular vesicle-induced natural killer cell suppression has emerged as a key target for research and new therapeutic approaches to recover and enhance the tumoricidal potential of these immune cells. Here, we summarize the current knowledge regarding cancer-derived extracellular vesicles and natural killer cell interactions, their role in immunosuppression, implications for developing efficient cellular immunotherapies and outstanding questions in this field.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199577","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

Quantifying the mutational landscape of retroviral and lentiviral vectors in gene therapy patients. 定量基因治疗患者逆转录病毒和慢病毒载体的突变景观。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-30 DOI: 10.1016/j.ymthe.2025.05.034

Kevyn L Hart, Ralph Valentine Crisostomo, Annika Mittelhauser, Lingyu Zhan, Nika Kononov, Kathryn Bradford, Donald B Kohn

{"title":"Quantifying the mutational landscape of retroviral and lentiviral vectors in gene therapy patients.","authors":"Kevyn L Hart, Ralph Valentine Crisostomo, Annika Mittelhauser, Lingyu Zhan, Nika Kononov, Kathryn Bradford, Donald B Kohn","doi":"10.1016/j.ymthe.2025.05.034","DOIUrl":"10.1016/j.ymthe.2025.05.034","url":null,"abstract":"Adenosine deaminase severe combined immunodeficiency (ADA-SCID) is a monogenic disorder caused by mutations in the ADA gene. Gene therapy using γ-retroviral and lentiviral vector gene addition approaches have shown curative results. We sequenced the ADA transgene in transduced CD3+ T cells, and in peripheral blood cells from patients treated with autologous CD34+ cells transduced with either a γ-retroviral or lentiviral ADA gene vector to assess transgene mutational profiles. In both CD3+ T cells and ADA-SCID patients' cells treated with the lentiviral vector, we observed significantly higher occurrences of guanine (G)-to-adenosine (A) base substitutions than with the γ-retroviral vector. We hypothesized that this G-to-A mutational signature was due to the APOBEC3 cytosine deaminase protein family. By knocking out APOBEC3 genes in HEK239T packaging cells, APOBEC3-mediated mutagenesis decreased by 91.2% along the transgene in CD34+ transduced cells in comparison to CD34+ cells transduced with lentiviral supernatant packaged in parental HEK293T cells.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226040","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

Multi-engineered T cell vaccine boosting TCR-T cell therapy enhances anti-tumor function and eradicates heterogeneous solid tumors. 多工程T细胞疫苗增强TCR-T细胞治疗，增强抗肿瘤功能，根除异质实体瘤。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-30 DOI: 10.1016/j.ymthe.2025.05.036

Xuan Che, Shen Zheng, Yuan Sun, Xiya Wang, Pengchong Zhang, Jixiang Cao, Yun Bai

{"title":"Multi-engineered T cell vaccine boosting TCR-T cell therapy enhances anti-tumor function and eradicates heterogeneous solid tumors.","authors":"Xuan Che, Shen Zheng, Yuan Sun, Xiya Wang, Pengchong Zhang, Jixiang Cao, Yun Bai","doi":"10.1016/j.ymthe.2025.05.036","DOIUrl":"10.1016/j.ymthe.2025.05.036","url":null,"abstract":"T cell receptor (TCR)-engineered T cell therapy holds great promise for treating solid tumors, but the overall clinical efficacy remains limited. The vital challenge lies in the loss of TCR-targeted antigens and poor T cell persistence. Here, we demonstrate a novel approach to enhance TCR-T cell therapy and reject antigen-heterogeneous tumors through a multi-engineered T cell vaccine (Multi-Tvac). Multi-Tvac is composed of a TCR-targeted cognate peptide, tumor neoantigens, and an LAG-3Ig adjuvant signal, which significantly boosts dendritic cell (DC) maturation, enhances TCR-T cell anti-tumor function, and alleviates exhaustion phenotype. When combined with TCR-T cell therapy, Multi-Tvac induced long-lasting responses in established solid tumors resistant to TCR-T cell monotherapy. Notably, Multi-Tvac prevented antigen-loss tumor escape and achieved complete responses in an antigen-heterogeneous solid tumor model. Mechanistically, Multi-Tvac enhanced antigen presentation in secondary lymphoid organs (SLOs), orchestrating a strong endogenous immune response that primes T cells. As a proof-of-concept, our study extended T cell engineering beyond TCR-directed killing, which could perform as a therapeutic vaccination platform to empower TCR-T cells with new capabilities and overcome major barriers in the clinical treatment of solid tumors.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226038","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

Podocyte FFAR4 deficiency aggravated glomerular diseases and aging. 足细胞FFAR4缺乏加重肾小球疾病和衰老。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-30 DOI: 10.1016/j.ymthe.2025.05.035

Ting Yin, Letian Yang, Lei Tang, Jian Li, Dekai Liu, Fan Guo, Yingsong Mu, Qimei Wu, Yuying Feng, Zhouke Tan, Ping Fu, Xiaoniao Chen, Liang Ma

{"title":"Podocyte FFAR4 deficiency aggravated glomerular diseases and aging.","authors":"Ting Yin, Letian Yang, Lei Tang, Jian Li, Dekai Liu, Fan Guo, Yingsong Mu, Qimei Wu, Yuying Feng, Zhouke Tan, Ping Fu, Xiaoniao Chen, Liang Ma","doi":"10.1016/j.ymthe.2025.05.035","DOIUrl":"10.1016/j.ymthe.2025.05.035","url":null,"abstract":"Podocyte injury contributes to the progression of glomerular disease and aging; however, causative molecular/physiological pathways are poorly defined, and there are few therapies to improve kidney outcomes. We previously reported that free fatty acid receptor 4 (FFAR4) agonist TUG891 improved podocyte injury to alleviate renal inflammation and fibrosis in diabetic nephropathy. However, the role of podocyte FFAR4 as a promising drug target has not been explored in glomerular diseases and aging. Here, we found that glomerular FFAR4 expression was abnormally decreased in patients and highly correlated with kidney function decline of glomerular diseases. Similarly, podocyte FFAR4 decreased in experimental focal segmental glomerulosclerosis and diabetic kidney disease mice. Both systemic and podocyte-specific FFAR4 deletion aggravated glomerular damage, whereas administration of FFAR4 agonist TUG891 and fish oil alleviated the severity of disease in adriamycin-induced nephropathy, diabetic, and aging mice, respectively. Mechanistically, FFAR4 reduction triggered cellular senescence and lipid metabolism disorder in injured podocytes and glomerulus. FFAR4 agonism exerted anti-senescent and anti-lipotoxic effects via activating CaMKKβ-AMPK signaling to protect against podocyte damage. These findings provide insight into signaling pathways involved in podocyte injury and enhance the understanding of the mechanistic functions of FFAR4 to reveal promising therapeutic opportunities against glomerular diseases and aging.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226039","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

Dual blockade of TNFR2 and CD47 reshape tumor immune microenvironment and improve antitumor effects in colorectal cancer. 双重阻断TNFR2和CD47重塑肿瘤免疫微环境，提高结直肠癌的抗肿瘤作用。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-30 DOI: 10.1016/j.ymthe.2025.05.032

Xiaozhen Kang, Yuxin Li, Yifeng Han, Mengdi Wu, Peng Qian, Jie Dong, Jiwu Wei

{"title":"Dual blockade of TNFR2 and CD47 reshape tumor immune microenvironment and improve antitumor effects in colorectal cancer.","authors":"Xiaozhen Kang, Yuxin Li, Yifeng Han, Mengdi Wu, Peng Qian, Jie Dong, Jiwu Wei","doi":"10.1016/j.ymthe.2025.05.032","DOIUrl":"10.1016/j.ymthe.2025.05.032","url":null,"abstract":"Colorectal cancer (CRC) is a major cause of cancer deaths, with poor outcomes in advanced stages. CD47, overexpressed in CRC, helps tumors evade immune detection by blocking macrophage phagocytosis, while CD47 blockade has shown limited efficacy in CRC. Our study showed that dual blockade of CD47 and TNFR2 demonstrated synergistic antitumor effects in murine CRC models. Since TNFR2 was highly expressed on Tregs and M-MDSCs, combination therapy targeting both CD47 and TNFR2 was tested, resulting in improved tumor control, prolonged survival, and enhanced immune responses by reducing Tregs and M-MDSCs, further increasing CD8+ T cell activation and macrophage function. A bispecific antibody fusion protein targeting both CD47 and TNFR2, called ATA47, demonstrated comparable efficacy to the combination therapy. Incorporating ATA47 into an oncolytic adenovirus (AdV-ATA47) also enhanced tumor control and immune activation with minimal systemic effects. AdV-ATA47 demonstrated significant antitumor effects in both murine and human tumor models, supporting its potential as a therapeutic strategy, particularly in combination with approved CRC therapies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226035","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

Inhibition of NAD-GPx4 axis and MEK triggers ferroptosis to suppress pancreatic ductal adenocarcinoma. 抑制NAD-GPx4轴和MEK触发铁下垂抑制胰腺导管腺癌。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-30 DOI: 10.1016/j.ymthe.2025.05.037

Hui Jiang, Yusuke Satoh, Ryodai Yamamura, Takako Ooshio, Yang Luo, Han Hai, Takuya Otsuka, Soichiro Hata, Reo Sato, Taiga Hirata, Tsuyoshi Osawa, Keisuke Goda, Masahiro Sonoshita

{"title":"Inhibition of NAD-GPx4 axis and MEK triggers ferroptosis to suppress pancreatic ductal adenocarcinoma.","authors":"Hui Jiang, Yusuke Satoh, Ryodai Yamamura, Takako Ooshio, Yang Luo, Han Hai, Takuya Otsuka, Soichiro Hata, Reo Sato, Taiga Hirata, Tsuyoshi Osawa, Keisuke Goda, Masahiro Sonoshita","doi":"10.1016/j.ymthe.2025.05.037","DOIUrl":"10.1016/j.ymthe.2025.05.037","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) ranks among the most lethal malignancies, highlighting the critical need for innovative therapeutic strategies. In this study, we examined the roles of nicotinamide adenine dinucleotide (NAD) synthesis pathway in PDAC. Targeting the NAD synthesis pathway significantly mitigated lethality in a Drosophila model that recapitulated the PDAC genotype. Within this pathway, we identified Glutathione peroxidase 4 (GPx4) as a critical effector responsible for scavenging reactive oxygen species (ROS). The combined application of GPx4 and Mitogen-activated protein kinase kinase (MEK) inhibitors, namely ML210 and trametinib, respectively, reduced lethality and tumor-like phenotypes in these flies. Notably, this combination treatment synergistically suppressed the proliferation of human PDAC cells and their corresponding xenografts in mice by inducing ROS accumulation, which triggered ferroptosis. These results suggest that inducing ferroptosis could represent a promising therapeutic strategy for PDAC.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226037","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

Targeting CD117 on hematopoietic stem and progenitor cells impairs CAR T cell activity. 将CD117靶向造血干细胞和祖细胞会损害CAR - T细胞的活性。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-30 DOI: 10.1016/j.ymthe.2025.05.033

Rubina Thomas, Julie K Ritchey, John F DiPersio, Miriam Y Kim

{"title":"Targeting CD117 on hematopoietic stem and progenitor cells impairs CAR T cell activity.","authors":"Rubina Thomas, Julie K Ritchey, John F DiPersio, Miriam Y Kim","doi":"10.1016/j.ymthe.2025.05.033","DOIUrl":"10.1016/j.ymthe.2025.05.033","url":null,"abstract":"CD117 is a cell-surface receptor expressed on hematopoietic stem and progenitor cells and acute myeloid leukemia (AML), and thus CD117-targeting chimeric antigen receptor T cells (CART117) can function as both conditioning for hematopoietic stem cell transplantation and a therapy for AML. We developed human and mouse CART117 to evaluate the safety and feasibility of targeting CD117 in preclinical mouse models. Human CART117 had potent anti-tumor activity while also mediating significant hematopoietic toxicity in a humanized mouse model. Murine CART117 (mCART117) led to systemic and hematopoietic toxicity without anti-leukemic benefit in immunocompetent C57BL/6 mice. Intriguingly, mCART117 was able to eliminate CD117+ cells in the spleen but not in the bone marrow (BM). Of note, proliferation of BM CD117+ cells in response to lymphodepleting chemotherapy amplified mCART117-mediated systemic toxicity. Alternative lymphodepletion with radiation ameliorated the systemic toxicity of mCART117 but did not improve anti-leukemic efficacy. Immunodeficient mice given mCART117 in the absence of lymphodepletion died from severe pancytopenia, and this effect was recapitulated by regulatory T cell depletion in immunocompetent mice. Increasing CD117 expression on AML improved the anti-leukemic efficacy and toxicity profile of mCART117. In conclusion, mCART117 anti-leukemic activity is impaired in immunocompetent mice when CD117 is expressed at physiological levels on AML.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226041","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

Essential role of CD56^dimNKG2C⁺ NK cells trained by SARS-CoV-2 vaccines in protecting against COVID-19. SARS-CoV-2疫苗培养的CD56dimNKG2C+ NK细胞在预防COVID-19中的重要作用

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-30 DOI: 10.1016/j.ymthe.2025.05.031

Huiwen Zheng, Yanli Chen, Jing Li, Yifan Zhang, Heng Li, Xin Zhao, Zhanlong He, Yun Liao, Zihan Zhang, Haijing Shi, Fengmei Yang, Yunguang Hu, Yadong Li, Jiali Li, Yuping Zhao, Xinglong Zhang, Jingsi Yang, Qihan Li, Longding Liu

{"title":"Essential role of CD56dimNKG2C+ NK cells trained by SARS-CoV-2 vaccines in protecting against COVID-19.","authors":"Huiwen Zheng, Yanli Chen, Jing Li, Yifan Zhang, Heng Li, Xin Zhao, Zhanlong He, Yun Liao, Zihan Zhang, Haijing Shi, Fengmei Yang, Yunguang Hu, Yadong Li, Jiali Li, Yuping Zhao, Xinglong Zhang, Jingsi Yang, Qihan Li, Longding Liu","doi":"10.1016/j.ymthe.2025.05.031","DOIUrl":"10.1016/j.ymthe.2025.05.031","url":null,"abstract":"The adaptive immune protection elicited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination has been proven to control the severity of novel coronavirus disease 2019 (COVID-19). However, the contributions of innate lymphoid cells formed from immunization are poorly defined in vaccine evaluation. Here, we highlight how the natural killer (NK) and macrophage (Mϕ) cells' response, primed by the inactivated COVID-19 vaccine, is crucial to preventing lung injury. We propose that a specific subset of NK cells, marked CD56dimCD16+NKG2C+, along with M2-like Mϕ, CD8+ T cells, are important in defending against SARS-CoV-2. Our studies using a rhesus macaque model showed that this orchestration of protection was depicted as a trajectory of adaptive NK and Mϕ cell responses from circulating peripheral blood mononuclear cells to the lungs. Through single-cell RNA sequencing and mass cytometry (cytometry by time-of-flight) analysis, we also identified the significance of adaptive CD56dimCD16+CD57+NKG2C+ NK cells and classical monocytes with chemotaxis traits in orchestrating T cell immunity in humans. Interestingly, our findings show a deficiency of these adaptive cells in older participants post-booster vaccination, leading to potentially inadequate protection. This study discusses the evaluation of vaccines at the innate immune level, which can contribute to the development of successful vaccines.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226036","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

Biosafety and efficacy of Kv7 activating rdHSV-CA8∗ analgesic gene therapy for chronic pain via the intra-articular route in mice. Kv7激活rdHSV-CA8*镇痛基因通过关节内途径治疗小鼠慢性疼痛的生物安全性和有效性

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-28 DOI: 10.1016/j.ymthe.2025.05.029

Roy C Levitt, Munal B Kandel, Gerald Z Zhuang, William F Goins, Konstantinos D Sarantopoulos, Joseph C Glorioso

{"title":"Biosafety and efficacy of Kv7 activating rdHSV-CA8∗ analgesic gene therapy for chronic pain via the intra-articular route in mice.","authors":"Roy C Levitt, Munal B Kandel, Gerald Z Zhuang, William F Goins, Konstantinos D Sarantopoulos, Joseph C Glorioso","doi":"10.1016/j.ymthe.2025.05.029","DOIUrl":"10.1016/j.ymthe.2025.05.029","url":null,"abstract":"Chronic pain remains a global health challenge, often resistant to available treatments with socioeconomic and psychological burdens. All chronic pain is believed due to neuronal signaling imbalances, resulting in increased excitability. Gene therapy represents a promising molecular therapy targeting molecular pain processing pathways, by offering precise, localized, long-lasting neuromodulation while minimizing systemic exposure and side effects. In model systems, replication-defective, disease-free, herpes simplex virus (rdHSV) gene therapy expressing an analgesic carbonic anhydrase-8 (CA8∗) peptide variant corrects somatosensory hyperexcitability by activating Kv7 voltage-gated potassium channels, produces profound, long-lasting analgesia and treats chronic pain from knee osteoarthritis (OA). In these studies, we provide the first non-glucagon-like peptide (GLP) biosafety, efficacy, biodistribution, shedding, and histopathology examination of this rdHSV-CA8∗. Naive mice were examined for clinical safety, biodistribution across all major tissues, knee histopathology, and analgesic efficacy via the intra-articular knee route of administration. We observed no signs of persistent toxicity, viral genomes remained where they were injected, and there was no evidence of shedding. Profound analgesia persisted for 6 months without functional impairments. These initial biosafety and efficacy data support further development of rdHSV-CA8∗ for treating chronic knee pain due to moderate to severe OA.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174192","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