Molecular Therapy最新文献_第10页

Antisense-mediated exon skipping targeting EZH2 suppresses tumor growth in a xenograft mouse model of hepatocellular carcinoma. 靶向EZH2的反义介导外显子跳变抑制肝癌小鼠异种移植模型的肿瘤生长

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2025-02-22 DOI: 10.1016/j.ymthe.2025.02.032

Jialin Bai, Bolin Zhao, Yongkun Ma, Li Wang, Pengchao Feng, Yimin Hua

{"title":"Antisense-mediated exon skipping targeting EZH2 suppresses tumor growth in a xenograft mouse model of hepatocellular carcinoma.","authors":"Jialin Bai, Bolin Zhao, Yongkun Ma, Li Wang, Pengchao Feng, Yimin Hua","doi":"10.1016/j.ymthe.2025.02.032","DOIUrl":"10.1016/j.ymthe.2025.02.032","url":null,"abstract":"Enhancer of zeste homolog 2 (EZH2) catalyzes trimethylation of histone H3 at lysine 27 (H3K27me3), which promotes heterochromatin formation and gene silencing. Expression of EZH2 is frequently elevated in various malignancies, including hepatocellular carcinoma (HCC). Silencing of EZH2 has been pursued as a promising strategy to halt cancer progression. Here, we identified antisense oligonucleotides (ASOs) that efficiently silence EZH2 through promoting skipping of its exon 14, an exon encoding part of the essential CXC domain, increasing production of an internally shortened isoform that exerts dominant negative effect on the full-length EZH2. A lead ASO, hybridizing to an exonic splicing enhancer element bound by SRSF3, robustly promoted exon 14 skipping not only in cultured human HCC cell lines but also in mouse peripheral tissues after systemic administration, leading to dramatic reduction of EZH2 and H3K27me3 levels. The lead ASO potently inhibited HCC cell proliferation through multiple mechanisms including enhanced apoptosis, cell-cycle arrest, and reversed epithelial-mesenchymal transition, which is likely attributable to the suppression of diverse cancer-related pathways. In an orthotopic xenograft HCC mouse model, ASO treatment repressed tumor growth, improved tissue phenotype, and extended the median survival. Our data highlight therapeutic potential of the lead exon-skipping ASO in treating HCC.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1485-1501"},"PeriodicalIF":12.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483709","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

Dasatinib-resistant universal CAR-T cells proliferate in the presence of host immune cells and exhibit antitumor activity. 抗达沙替尼通用CAR-T细胞在宿主免疫细胞存在下增殖并表现出抗肿瘤活性

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2025-02-11 DOI: 10.1016/j.ymthe.2025.02.012

Yuhang Cheng, Jiayuan Zhang, Wei Mu, Shanwei Ye, Jiali Cheng, Li Zhu, Gaoxiang Wang, Yang Cao, Dengju Li, Guang Hu, Liang Huang, Jue Wang, Jianfeng Zhou

{"title":"Dasatinib-resistant universal CAR-T cells proliferate in the presence of host immune cells and exhibit antitumor activity.","authors":"Yuhang Cheng, Jiayuan Zhang, Wei Mu, Shanwei Ye, Jiali Cheng, Li Zhu, Gaoxiang Wang, Yang Cao, Dengju Li, Guang Hu, Liang Huang, Jue Wang, Jianfeng Zhou","doi":"10.1016/j.ymthe.2025.02.012","DOIUrl":"10.1016/j.ymthe.2025.02.012","url":null,"abstract":"The universal chimeric antigen receptor T cell (UCAR-T) immunotherapy derived from healthy donors holds great promise in pan-cancer treatment. However, UCAR-T cell therapy faces a challenge in the rapid elimination of allogeneic cells by the host immune system. To address this, we introduced a T316I mutation in the leukocyte-specific protein tyrosine kinase (LCK) locus in CAR-T cells using the cytosine base editor (CBE) system. Concurrently, we disrupted endogenous T cell receptor alpha chain (TRAC) and beta-2 microglobulin (B2M) with the CRISPR-Cas9 system, along with dasatinib to overcome host immune rejection, an Src family kinase (SFK) inhibitor. The resulting LCK mutated UCAR-T (KM UCAR-T) cells exhibited normal phenotypes in activation, proliferation, differentiation, and tumor cytotoxicity in vitro. Moreover, KM UCAR-T cells demonstrated sustained expansion in mixed lymphocyte reactions (MLR) when incubated with T cells or peripheral blood mononuclear cells (PBMCs) from HLA-mismatched donors upon dasatinib treatment. Additionally, we illustrated that KM UCAR-T cells displayed antitumor activity in a xenograft murine model and verified the expansion and cytotoxicity of KM UCAR-T over traditional UCAR-T in the presence of allogeneic PBMCs when treated with dasatinib in vivo. These findings offer a novel strategy for UCAR-T cells to resist host immune rejection and achieve sustained expansion.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1535-1551"},"PeriodicalIF":12.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399698","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

A differentiated β-globin gene replacement strategy uses heterologous introns to restore physiological expression. 利用异源内含子恢复生理表达的分化β-球蛋白基因替换策略。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2025-02-28 DOI: 10.1016/j.ymthe.2025.02.036

Kirby A Wallace, Trevor L Gerstenberg, Craig L Ennis, Juan A Perez-Bermejo, James R Partridge, Christopher Bandoro, William M Matern, Gaia Andreoletti, Kristina Krassovsky, Shaheen Kabir, Cassandra D Lalisan, Aishwarya R Churi, Glen M Chew, Lana Corbo, Jon E Vincelette, Timothy D Klasson, Brian J Silva, Yuri G Strukov, B Joy Quejarro, Kaisle A Hill, Sebastian Treusch, Jane L Grogan, Daniel P Dever, Matthew H Porteus, Beeke Wienert

{"title":"A differentiated β-globin gene replacement strategy uses heterologous introns to restore physiological expression.","authors":"Kirby A Wallace, Trevor L Gerstenberg, Craig L Ennis, Juan A Perez-Bermejo, James R Partridge, Christopher Bandoro, William M Matern, Gaia Andreoletti, Kristina Krassovsky, Shaheen Kabir, Cassandra D Lalisan, Aishwarya R Churi, Glen M Chew, Lana Corbo, Jon E Vincelette, Timothy D Klasson, Brian J Silva, Yuri G Strukov, B Joy Quejarro, Kaisle A Hill, Sebastian Treusch, Jane L Grogan, Daniel P Dever, Matthew H Porteus, Beeke Wienert","doi":"10.1016/j.ymthe.2025.02.036","DOIUrl":"10.1016/j.ymthe.2025.02.036","url":null,"abstract":"β-Hemoglobinopathies are common monogenic disorders. In sickle cell disease (SCD), a single mutation in the β-globin (HBB) gene results in dysfunctional hemoglobin protein, while in β-thalassemia, over 300 mutations distributed across the gene reduce β-globin levels and cause severe anemia. Genetic engineering replacing the whole HBB gene through homology-directed repair (HDR) is an ideal strategy to restore a benign genotype and rescue HBB expression for most genotypes. However, this is technically challenging because (1) the insert must not be homologous to the endogenous gene and (2) synonymous codon-optimized, intron-less sequences may not reconstitute adequate β-globin levels. Here, we developed an HBB gene replacement strategy using CRISPR-Cas9 that successfully addresses these challenges. We determined that a DNA donor containing a diverged HBB coding sequence and heterologous introns to avoid sequence homology provides proper physiological expression. We identified a DNA donor that uses truncated γ-globin introns, results in 34% HDR, and rescues β-globin expression in in vitro models of SCD and β-thalassemia in hematopoietic stem and progenitor cells (HSPCs). Furthermore, while HDR allele frequency dropped in vivo, it was maintained at ∼15%, demonstrating editing of long-term repopulating HSPCs. In summary, our HBB gene replacement strategy offers a differentiated approach by restoring naturally regulated adult hemoglobin expression.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1407-1419"},"PeriodicalIF":12.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531697","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

Turning "trashed" genomic loci into treasurable sites for integrating chimeric antigen receptors in T and NK cells. 将“废弃”的基因组位点转化为整合T细胞和NK细胞中的嵌合抗原受体的宝贵位点。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2025-02-20 DOI: 10.1016/j.ymthe.2025.02.028

Yajie Wang, Jie Jiang, Kai Shang, Xiaobao Xu, Jie Sun

{"title":"Turning \"trashed\" genomic loci into treasurable sites for integrating chimeric antigen receptors in T and NK cells.","authors":"Yajie Wang, Jie Jiang, Kai Shang, Xiaobao Xu, Jie Sun","doi":"10.1016/j.ymthe.2025.02.028","DOIUrl":"10.1016/j.ymthe.2025.02.028","url":null,"abstract":"Chimeric antigen receptor (CAR)-based immune cell therapy involves genetically engineering immune cells, such as T cells and natural killer (NK) cells, to express CARs that can specifically recognize target antigens. This modification enables T/NK cells to selectively eliminate tumor cells following adoptive transfer. One common approach to stably integrate CARs into the genome of T/NK cells is through retroviral or lentiviral vectors. However, these vectors mediate semi-random gene integration, posing risks such as oncogenic mutations, gene silencing, and variable CAR expression levels. Targeted integration of CAR genes into the specific genomic locus could overcome these limitations, but identifying the optimal integration sites to maximize the safety and efficacy of CAR-T/NK cell products remains a critical question. Improper integration sites may disturb the endogenous genes surrounding the integration sites, raising safety concerns. Additionally, regulatory elements at the integration sites, such as promoters, can influence the expression level of CAR genes, thus affecting the efficacy of CAR-T/NK cells. In this review, we summarized current strategies for selecting integration sites and promoters in the engineering of CAR-T/NK cells to achieve potent anti-tumor efficacy in preclinical studies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1368-1379"},"PeriodicalIF":12.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468414","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

A BPTF-specific PROTAC degrader enhances NK cell-based cancer immunotherapy. 一种bptf特异性的PROTAC降解物增强了基于NK细胞的癌症免疫治疗。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2025-02-11 DOI: 10.1016/j.ymthe.2025.02.013

Yunjia Li, Lin Bai, Hao Liang, Peidong Yan, Hao Chen, Zhuoxian Cao, Yiqing Shen, Zhongyv Wang, Mei Huang, Bin He, Quan Hao, Yide Mei, Haiming Wei, Chen Ding, Jing Jin, Yi Wang

{"title":"A BPTF-specific PROTAC degrader enhances NK cell-based cancer immunotherapy.","authors":"Yunjia Li, Lin Bai, Hao Liang, Peidong Yan, Hao Chen, Zhuoxian Cao, Yiqing Shen, Zhongyv Wang, Mei Huang, Bin He, Quan Hao, Yide Mei, Haiming Wei, Chen Ding, Jing Jin, Yi Wang","doi":"10.1016/j.ymthe.2025.02.013","DOIUrl":"10.1016/j.ymthe.2025.02.013","url":null,"abstract":"Natural killer (NK) cell-based immunotherapy shows promise in cancer treatment, but its efficacy remains limited, necessitating the development of novel strategies. In this study, we demonstrate that the epigenetic factor bromodomain PHD-finger containing transcription factor (BPTF) hinders hepatocellular carcinoma (HCC) recognition by NK cells through its PHD finger's interpretation of H3K4me3. We have generated a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degrades human and murine BPTF. The degradation of BPTF using PROTACs directly enhances the abundance of natural cytotoxicity receptor ligands on HCC cells, facilitating their recognition by NK cells and thereby augmenting NK cell cytotoxicity against HCC both in vitro and in vivo. Through multidisciplinary techniques, our findings establish targeting BPTF with PROTACs as a promising approach to overcome immune evasion of HCC from NK cells and provide a new strategy to enhance NK cell-based cancer immunotherapy.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1566-1583"},"PeriodicalIF":12.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399696","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

RESET: A TCR-coupled antigen receptor with superior targeting sensitivity and reversible drug-regulated anti-tumor activity. RESET：一种可逆的tcr偶联抗原受体，具有优越的靶向敏感性和药理学控制的抗肿瘤活性。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2025-02-20 DOI: 10.1016/j.ymthe.2025.02.026

Jardin Leleux, Jillian Rosenberg, Olmo Sonzogni, Rebecca L Walker, Anita Venkitaraman, Sarah M Garrison, Nan Jin, Philip D Gregory, Jordan Jarjour

{"title":"RESET: A TCR-coupled antigen receptor with superior targeting sensitivity and reversible drug-regulated anti-tumor activity.","authors":"Jardin Leleux, Jillian Rosenberg, Olmo Sonzogni, Rebecca L Walker, Anita Venkitaraman, Sarah M Garrison, Nan Jin, Philip D Gregory, Jordan Jarjour","doi":"10.1016/j.ymthe.2025.02.026","DOIUrl":"10.1016/j.ymthe.2025.02.026","url":null,"abstract":"Chimeric antigen receptor (CAR) T cells are effective cancer therapies, particularly in indications with high, stable, and tumor-specific antigen expression. Other settings may require improved targeting sensitivity, controllable targeting selectivity, and/or additional potency enhancements to achieve robust efficacy. Here, we describe a novel receptor architecture called RESET (rapamycin-enabled, switchable endogenous T cell receptor) that combines (1) cell surface antigen targeting, (2) small-molecule regulation, and (3) the signaling proficiency and inherent sensitivity of native T cell receptors. RESET-T cells outperformed both constitutive and drug-regulated CAR-T cells and show hallmarks of TCR activation that suggest improved fidelity to native T cell responses. Pharmacological control then increases safety through toggling T cell activation between active and resting states and may mitigate T cell exhaustion caused by continuous antigen exposure. This convergence of drug-regulated targeting and natural immune receptor signal transduction may better replicate the kinetics and physiology of a classical T cell response and potentiate more successful and safer immunotherapies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1608-1620"},"PeriodicalIF":12.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468069","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

Understanding the interplay between oHSV and the host immune system: Implications for therapeutic oncolytic virus development. 了解oHSV与宿主免疫系统之间的相互作用：对溶瘤病毒治疗发展的影响。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2024-12-30 DOI: 10.1016/j.ymthe.2024.12.054

Kalkidan Ayele, Hiroaki Wakimoto, Hans J Nauwynck, Howard L Kaufman, Samuel D Rabkin, Dipongkor Saha

{"title":"Understanding the interplay between oHSV and the host immune system: Implications for therapeutic oncolytic virus development.","authors":"Kalkidan Ayele, Hiroaki Wakimoto, Hans J Nauwynck, Howard L Kaufman, Samuel D Rabkin, Dipongkor Saha","doi":"10.1016/j.ymthe.2024.12.054","DOIUrl":"10.1016/j.ymthe.2024.12.054","url":null,"abstract":"Oncolytic herpes simplex viruses (oHSV) preferentially replicate in cancer cells while inducing antitumor immunity, and thus, they are often referred to as in situ cancer vaccines. OHSV infection of tumors elicits diverse host immune responses comprising both innate and adaptive components. Although the innate and adaptive immune responses primarily target the tumor, they also contribute to antiviral immunity, limiting viral replication/oncolysis. OHSV-encoded proteins use various mechanisms to evade host antiviral pathways and immune recognition, favoring oHSV replication, oncolysis, and spread. In general, oHSV infection and replication within tumors results in a series of sequential events, such as oncolysis and release of tumor and viral antigens, dendritic cell-mediated antigen presentation, T cell priming and activation, T cell trafficking and infiltration to tumors, and T cell recognition of cancer cells, leading to tumor (and viral) clearance. These sequential events align with all steps of the cancer-immunity cycle. However, a comprehensive understanding of the interplay between oHSV and host immune responses is crucial to optimize oHSV-induced antitumor immunity and efficacy. Therefore, this review aims to elucidate oHSV's communication with innate and adaptive immune systems and use such interactions to improve oHSV's potential as a potent immunovirotherapeutic agent against cancer.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1327-1343"},"PeriodicalIF":12.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915331","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

Gene therapy rescues brain edema and motor function in a mouse model of megalencephalic leukoencephalopathy with subcortical cysts. 基因疗法拯救了巨脑白质脑病伴皮层下囊肿小鼠模型的脑水肿和运动功能。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2025-03-05 DOI: 10.1016/j.ymthe.2025.02.046

Alejandro Brao, Ángela Sánchez, Irina Rodríguez, Javier Del Rey, Silvia Lope-Piedrafita, Esther Prat, Virginia Nunes, Miguel Chillón, Raúl Estévez, Assumpció Bosch

{"title":"Gene therapy rescues brain edema and motor function in a mouse model of megalencephalic leukoencephalopathy with subcortical cysts.","authors":"Alejandro Brao, Ángela Sánchez, Irina Rodríguez, Javier Del Rey, Silvia Lope-Piedrafita, Esther Prat, Virginia Nunes, Miguel Chillón, Raúl Estévez, Assumpció Bosch","doi":"10.1016/j.ymthe.2025.02.046","DOIUrl":"10.1016/j.ymthe.2025.02.046","url":null,"abstract":"Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an ultrarare, infantile-onset leukodystrophy characterized by white matter edema for which there is no treatment. More than 75% of diagnosed cases result from biallelic loss-of-function mutations in the astrocyte-specific gene MLC1, leading to early-onset macrocephaly, cerebellar ataxia, epilepsy, and mild cognitive decline. To develop a gene therapy for MLC, we administered an adeno-associated viral vector capable of crossing the murine blood-brain barrier, delivering the human MLC1 cDNA under the control of a human astrocyte-specific promoter, to 10-month-old Mlc1-/- mice. We observed long-term astrocyte-driven expression of MLC1 up to 1 year after viral vector administration in all brain areas analyzed. Despite the late-stage intervention, in vivo magnetic resonance imaging revealed normalization of water accumulation. Notably, our therapy successfully reversed locomotor deficits in Mlc1-/- mice, as evidenced by improved performance in motor tests assessing cerebellar ataxia-like behaviors. Collectively, these findings not only demonstrate the sustained efficacy of our gene therapy but also highlight the reversibility of vacuolation and motor impairments in Mlc1-/- mice, suggesting that MLC patients could benefit from treatment even after symptom onset.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1434-1448"},"PeriodicalIF":12.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573497","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

Y4 RNA fragment alleviates myocardial injury in heart transplantation via SNRNP200 to enhance IL-10 mRNA splicing. Y4 RNA片段通过snrnp200介导的IL-10 pre-mRNA剪接增强减轻心脏移植心肌缺血-再灌注损伤。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2025-02-11 DOI: 10.1016/j.ymthe.2025.02.014

Chuanghong Lu, Zhongyuan Meng, Senhu Tang, Heng Wei, Yaoshi Hu, Dexin Chen, Dezhao Liu, Hong Wen, Kun Dong, Na Na, Feng Huang, Zhiyu Zeng

{"title":"Y4 RNA fragment alleviates myocardial injury in heart transplantation via SNRNP200 to enhance IL-10 mRNA splicing.","authors":"Chuanghong Lu, Zhongyuan Meng, Senhu Tang, Heng Wei, Yaoshi Hu, Dexin Chen, Dezhao Liu, Hong Wen, Kun Dong, Na Na, Feng Huang, Zhiyu Zeng","doi":"10.1016/j.ymthe.2025.02.014","DOIUrl":"10.1016/j.ymthe.2025.02.014","url":null,"abstract":"Myocardial ischemia-reperfusion injury (MIRI) inevitably occurs during heart transplantation, highlighting the imperative for effective therapeutic interventions. A Y4 RNA fragment (YF1) was applied to treat a syngeneic mouse model of heart transplantation, with the heart subjected to cold ischemia-reperfusion (CIR). Cardiomyocytes and macrophages were treated with YF1, and a cellular cold hypoxia-reoxygenation (CHR) model was established. We found that YF1 alleviated CIR-induced inflammatory macrophage infiltration and cardiomyocytes injury in the graft heart. YF1 had no direct effects on cardiomyocytes in vitro, while YF1 inhibited macrophage polarization to the pro-inflammatory phenotype with increased expression of anti-inflammatory factors. Moreover, YF1 attenuated CHR-induced cardiomyocyte injury by regulating the interleukin-10 (IL-10) expression in macrophages. Mechanistically, YF1 increased the mRNA expression ratio of IL-10/pre-IL-10 by binding to SNRNP200, a spliceosome-specific protein for pre-mRNA splicing, with reduced SNRNP200 ubiquitination. It was reversed by Brr2-IN-3, a specific SNRNP200 inhibitor. Collectively, we hold that YF1 might alleviate MIRI in heart transplantation via binding to SNRNP200 and regulating its ubiquitination to enhance IL-10 pre-mRNA splicing. These findings further clarify the effects and mechanism of YF1 on MIRI and suggest a potential cardioprotective therapy in heart transplantation.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1735-1748"},"PeriodicalIF":12.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997478/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399700","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

ZP4: A novel target for CAR-T cell therapy in triple negative breast cancer. ZP4: CAR - T细胞治疗三阴性乳腺癌的新靶点

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2025-02-20 DOI: 10.1016/j.ymthe.2025.02.029

Lauren K Somes, Jonathan T Lei, Xinpei Yi, Diego F Chamorro, Paul Shafer, Ahmed Z Gad, Lacey E Dobrolecki, Emily Madaras, Nabil Ahmed, Michael T Lewis, Bing Zhang, Valentina Hoyos

{"title":"ZP4: A novel target for CAR-T cell therapy in triple negative breast cancer.","authors":"Lauren K Somes, Jonathan T Lei, Xinpei Yi, Diego F Chamorro, Paul Shafer, Ahmed Z Gad, Lacey E Dobrolecki, Emily Madaras, Nabil Ahmed, Michael T Lewis, Bing Zhang, Valentina Hoyos","doi":"10.1016/j.ymthe.2025.02.029","DOIUrl":"10.1016/j.ymthe.2025.02.029","url":null,"abstract":"Triple-negative breast cancer (TNBC) remains one of the most challenging subtypes of breast cancer to treat due to a lack of effective targeted therapies. Chimeric antigen receptor (CAR)-T cells hold promise, but their efficacy in solid tumors is often limited by on-target/off-tumor toxicities. Through comprehensive bioinformatic analysis of public RNA and proteomic data, we identified zona pellucida glycoprotein 4 (ZP4) as a novel target for TNBC. ZP4 RNA and protein were detected in a subset of TNBC patient samples and patient-derived xenograft (PDX) models, with expression otherwise restricted to oocytes. We generated 89 ZP4-specific novel monoclonal antibodies and used the single-chain variable fragment (scFv) antigen binding domains from the top three candidates to engineer CAR constructs. ZP4 CAR-T cells demonstrated efficacy against ZP4-expressing TNBC cells and PDX models. Additionally, we found that variations in the scFv antigen binding domain significantly influence CAR-T cell function.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1621-1641"},"PeriodicalIF":12.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11997509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468434","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