Molecular TherapyPub Date : 2025-02-04DOI: 10.1016/j.ymthe.2025.01.026
Brian Spencer, Sarah Michael, Jay Shen, Kori Kosberg, Edward Rockenstein, Christina Patrick, Anthony Adame, Eliezer Masliah
{"title":"Retraction Notice to: Lentivirus Mediated Delivery of Neurosin Promotes Clearance of Wild-type α-Synuclein and Reduces the Pathology in an α-Synuclein Model of LBD.","authors":"Brian Spencer, Sarah Michael, Jay Shen, Kori Kosberg, Edward Rockenstein, Christina Patrick, Anthony Adame, Eliezer Masliah","doi":"10.1016/j.ymthe.2025.01.026","DOIUrl":"10.1016/j.ymthe.2025.01.026","url":null,"abstract":"","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255951","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}
Molecular TherapyPub Date : 2025-02-04DOI: 10.1016/j.ymthe.2025.01.048
Cuifeng Li, Shuqi Wei, Donglin Sun, Zhuo Yang, Qi Wang, Han Lin, Haohao Zhang, Yiming Hu, Dandan Liu, Deji Ye, Yu Tao, Zhanjie Liu, Zhijian Xu, Bo Li, Lingling Li, Jie Zhang, Xi Chen, Ningxia Xie, Yufang Shi, Sanhong Liu, Yongzhong Liu, Yuhang Jiang, Weiliang Zhu, Xiaoren Zhang
{"title":"Development of RelB-targeting small-molecule inhibitors of non-canonical NF-κB signaling with antitumor efficacy.","authors":"Cuifeng Li, Shuqi Wei, Donglin Sun, Zhuo Yang, Qi Wang, Han Lin, Haohao Zhang, Yiming Hu, Dandan Liu, Deji Ye, Yu Tao, Zhanjie Liu, Zhijian Xu, Bo Li, Lingling Li, Jie Zhang, Xi Chen, Ningxia Xie, Yufang Shi, Sanhong Liu, Yongzhong Liu, Yuhang Jiang, Weiliang Zhu, Xiaoren Zhang","doi":"10.1016/j.ymthe.2025.01.048","DOIUrl":"10.1016/j.ymthe.2025.01.048","url":null,"abstract":"<p><p>Dysfunction of the non-canonical nuclear factor κB (NF-κB) signaling pathway has been causally associated with numbers of cancers and autoimmune diseases. However, specific inhibitors for this signaling pathway remain to be developed. Here, we showed that structure-based cell-based screening yielded a potent and specific small molecule targeting RelB to inhibit the non-canonical NF-κB signaling pathway, while it had no inhibitory effect on the canonical NF-κB signaling pathway. Mechanistically, the inhibitor directly interacted with RelB protein and disrupted RelB binding to its target DNA, thus repressing RelB transactivity on target genes. Through blocking oncogenic activity of the non-canonical NF-κB signaling pathway in colorectal cancer or B lymphoma, the inhibitor efficiently exerted a potent antitumor effect in vitro and in vivo. Thus, our study provided a new RelB-targeting inhibitor that inhibited the non-canonical NF-κB signaling pathway and facilitated precise therapeutic applications in cancers and possibly other diseases.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Targeting the TRIM21-PD-1 axis potentiates immune checkpoint blockade and CAR-T cell therapy.","authors":"Jie Shi, Zijian Zhang, Hsin-Yi Chen, Yingmeng Yao, Shanwen Ke, Kechun Yu, Jiangzhou Shi, Xiangling Xiao, Chuan He, Bolin Xiang, Yishuang Sun, Minling Gao, Xixin Xing, Haisheng Yu, Xiyong Wang, Wei-Chien Yuan, Bugi Ratno Budiarto, Shih-Yu Chen, Tongcun Zhang, Yu-Ru Lee, Haichuan Zhu, Jinfang Zhang","doi":"10.1016/j.ymthe.2025.01.047","DOIUrl":"10.1016/j.ymthe.2025.01.047","url":null,"abstract":"<p><p>Dysregulation of T cells is a major limitation for the clinical success of T cell-based cancer immunotherapies, such as immune checkpoint blockade and chimeric antigen receptor (CAR)-T cell therapy. Understanding the underlying mechanisms for regulating T cell functions can facilitate designing therapeutic strategies to improve immunotherapies. Here, we report that TRIM21 impairs CD8<sup>+</sup> T cell activation and anti-tumor immunity. Mechanistically, TRIM21 catalyzes the K63-linked ubiquitination on programmed cell death-1 (PD-1) at K233, leading to stabilization of PD-1 through antagonizing its K48-linked ubiquitination and degradation. Thus, Trim21 knockout (KO) significantly decreases PD-1 expression and enhances the activation of cytotoxic CD8<sup>+</sup> T cells, which sensitizes tumors to anti-CTLA-4 immunotherapy. Notably, Trim21 KO anti-CD19 CAR-T cells exhibit improved anti-tumor efficacy. These results reveal the molecular mechanism by which TRIM21-mediated K63-linked ubiquitination on PD-1 restrains the activation of CD8<sup>+</sup> T cells, highlighting that targeting the TRIM21-PD-1 axis as a potential therapeutic strategy to potentiate cancer immunotherapy.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190044","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}
Molecular TherapyPub Date : 2025-02-03DOI: 10.1016/j.ymthe.2025.01.049
Marta Garcia-Gomara, Naroa Legarra-Marcos, Maria Serena, Elvira Rojas-de-Miguel, Maria Espelosin, Irene Marcilla, Alberto Perez-Mediavilla, Maria Rosario Luquin, Jose Luis Lanciego, Maria Angeles Burrell, Mar Cuadrado-Tejedor, Ana Garcia-Osta
{"title":"FKBP51 inhibition ameliorates neurodegeneration and motor dysfunction in the neuromelanin-SNCA mouse model of Parkinson's disease.","authors":"Marta Garcia-Gomara, Naroa Legarra-Marcos, Maria Serena, Elvira Rojas-de-Miguel, Maria Espelosin, Irene Marcilla, Alberto Perez-Mediavilla, Maria Rosario Luquin, Jose Luis Lanciego, Maria Angeles Burrell, Mar Cuadrado-Tejedor, Ana Garcia-Osta","doi":"10.1016/j.ymthe.2025.01.049","DOIUrl":"10.1016/j.ymthe.2025.01.049","url":null,"abstract":"<p><p>Parkinson's disease (PD) is characterized by the loss of neuromelanin (NM)-containing dopaminergic (DA) neurons in the substantia nigra (SN) pars compacta (SNpc) and the buildup of α-synuclein (α-syn) inclusions, called Lewy bodies. To investigate the roles of NM and α-syn in DA neuron degeneration, we modeled PD by inducing NM accumulation in a humanized α-syn mouse model (Snca<sup>-</sup>; PAC-Tg(SNCA<sup>WT</sup>)) via the expression of human tyrosinase in the SN. We found that this mouse strain develops naturally progressive motor dysfunction and dopaminergic neuronal loss in the SN with aging. Upon tyrosinase injection, NM-containing neurons developed p62 and ubiquitin inclusions. Furthermore, the upregulation of genes associated with microglial activation in the midbrain indicated a role of pro-inflammatory factors in neurodegeneration. Midbrain RNA sequencing confirmed the microglial response and identified Fkbp5 as one of the more dysregulated genes. Next, we showed that FKBP51(51 kDa) was significantly upregulated with aging and in PD human brains. Pharmacological treatment with SAFit2, a potent FKBP51 inhibitor, led to a reduction in ubiquitin-positive inclusions, prevention of neurodegeneration in the SNpc, and improved motor function in NM-SNCAWT mice. These results highlight the critical role of FKBP51 in PD and propose SAFit2 as a promising therapeutic candidate for reducing neurodegeneration in PD.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190038","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}
Molecular TherapyPub Date : 2025-02-03DOI: 10.1016/j.ymthe.2025.01.045
Weijie Du, Fatih Noyan, Oliver McCallion, Vanessa Drosdek, Jonas Kath, Viktor Glaser, Carla Fuster-Garcia, Mingxing Yang, Maik Stein, Clemens Franke, Yaolin Pu, Olaf Weber, Julia K Polansky, Toni Cathomen, Elmar Jaeckel, Joanna Hester, Fadi Issa, Hans-Dieter Volk, Michael Schmueck-Henneresse, Petra Reinke, Dimitrios L Wagner
{"title":"Gene editing of CD3 epsilon to redirect regulatory T cells for adoptive T cell transfer.","authors":"Weijie Du, Fatih Noyan, Oliver McCallion, Vanessa Drosdek, Jonas Kath, Viktor Glaser, Carla Fuster-Garcia, Mingxing Yang, Maik Stein, Clemens Franke, Yaolin Pu, Olaf Weber, Julia K Polansky, Toni Cathomen, Elmar Jaeckel, Joanna Hester, Fadi Issa, Hans-Dieter Volk, Michael Schmueck-Henneresse, Petra Reinke, Dimitrios L Wagner","doi":"10.1016/j.ymthe.2025.01.045","DOIUrl":"10.1016/j.ymthe.2025.01.045","url":null,"abstract":"<p><p>Adoptive transfer of antigen-specific regulatory T cells (Tregs) is a promising strategy to combat immunopathologies in transplantation and autoimmune diseases. However, their low frequency in peripheral blood poses challenges for both manufacturing and clinical application. Chimeric antigen receptors have been used to redirect the specificity of Tregs, using retroviral vectors. However, retroviral gene transfer is costly, time consuming, and raises safety issues. Here, we explored non-viral CRISPR-Cas12a gene editing to redirect Tregs, using human leukocyte antigen (HLA)-A2-specific constructs for proof-of-concept studies in transplantation models. Knock-in of an antigen-binding domain into the N terminus of CD3 epsilon (CD3ε) gene generates Tregs expressing a chimeric CD3ε-T cell receptor fusion construct (TRuC) protein that integrates into the endogenous TCR/CD3 complex. These CD3ε-TRuC Tregs exhibit potent antigen-dependent activation while maintaining responsiveness to TCR/CD3 stimulation. This enables preferential enrichment of TRuC-redirected Tregs over CD3ε knockout Tregs via repetitive CD3/CD28 stimulation in a good manufacturing practice-compatible expansion system. CD3ε-TRuC Tregs retained their phenotypic, epigenetic, and functional identity. In a humanized mouse model, HLA-A2-specific CD3ε-TRuC Tregs demonstrate superior protection of allogeneic HLA-A2<sup>+</sup> skin grafts from rejection compared with polyclonal Tregs. This approach provides a pathway for developing clinical-grade CD3ε-TRuC-based Treg cell products for transplantation immunotherapy and other immunopathologies.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The deubiquitinase USP28 maintains the expression of PPARγ and its inactivation protects mice from diet-induced MASH and hepatocarcinoma.","authors":"Changzhou Cai, Hangqi Luo, Jin Peng, Xinghua Zhen, Xiang Shen, Xiaomei Xi, Jianrong Zhu, Yanfei Fang, Xiaoli Chen, Jiewei Wang, Chaohui Yu, Pumin Zhang, Chengfu Xu","doi":"10.1016/j.ymthe.2025.01.046","DOIUrl":"10.1016/j.ymthe.2025.01.046","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of metabolic dysfunction-associated fatty liver disease (MAFLD), is a leading cause of liver disease worldwide and can progress to cirrhosis and cancer. Despite its prevalence, the pathogenesis of MASH remains poorly understood, and there is only one U.S. Food and Drug Administration-approved treatment, highlighting the need for new therapeutic strategies. Peroxisome proliferator-activated receptor (PPAR)γ is activated in the liver under high-fat or obese conditions, promoting lipid storage and contributing to MASH progression. We found that USP28 expression is elevated in the livers of MAFLD/MASH patients. Through dietary induction, including a methionine-choline deficient (MCD) diet and a western diet (WD) combined with carbon tetrachloride (CCl<sub>4</sub>) injections, we established two severe mouse models of MASH to explore the role of USP28. Mechanistically, the hepatic deubiquitinase (DUB) USP28 directly binds to PPARγ, preventing its ubiquitination and subsequent degradation, thereby maintaining the integrity of the PPARγ signaling pathway. In the absence of Usp28 or if the DUB is inhibited, PPARγ is downregulated, and the PPAR signaling pathway is inhibited, enhancing cellular defenses against excess fat. Both genetic and pharmacological inactivation of Usp28 significantly reduced MASH severity induced by the MCD diet or WD-CCl<sub>4</sub> regimen, as well as WD-CCl<sub>4</sub>-induced hepatocellular carcinoma in mice.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190046","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}
Molecular TherapyPub Date : 2025-02-02DOI: 10.1016/j.ymthe.2025.01.027
Brian Spencer, Sharareh Emadi, Paula Desplats, Simona Eleuteri, Sarah Michael, Kori Kosberg, Jay Shen, Edward Rockenstein, Christina Patrick, Anthony Adame, Tania Gonzalez, Michael Sierks, Eliezer Masliah
{"title":"Retraction Notice to: ESCRT-mediated Uptake and Degradation of Brain-targeted α-synuclein Single Chain Antibody Attenuates Neuronal Degeneration In Vivo.","authors":"Brian Spencer, Sharareh Emadi, Paula Desplats, Simona Eleuteri, Sarah Michael, Kori Kosberg, Jay Shen, Edward Rockenstein, Christina Patrick, Anthony Adame, Tania Gonzalez, Michael Sierks, Eliezer Masliah","doi":"10.1016/j.ymthe.2025.01.027","DOIUrl":"10.1016/j.ymthe.2025.01.027","url":null,"abstract":"","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123149","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}
Molecular TherapyPub Date : 2025-01-28DOI: 10.1016/j.ymthe.2025.01.043
Qingmei Zhang,Wing-Lim Chan,Sin-Yee Fung,Li Pang,Tao Ding,Jia Ming Nickolas Teo,Yuan Zhou,Chung Ming Alex Wu,Kam-Leung Siu,Jiacheng Bi,Guang Sheng Ling,Dong-Yan Jin,Kwan Man,Yick Pang Ching
{"title":"Centrosome protein TAX1BP mediates STING-dependent immune response and potentiates anti-PD-1 efficacy in Hepatocellular Carcinoma.","authors":"Qingmei Zhang,Wing-Lim Chan,Sin-Yee Fung,Li Pang,Tao Ding,Jia Ming Nickolas Teo,Yuan Zhou,Chung Ming Alex Wu,Kam-Leung Siu,Jiacheng Bi,Guang Sheng Ling,Dong-Yan Jin,Kwan Man,Yick Pang Ching","doi":"10.1016/j.ymthe.2025.01.043","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.01.043","url":null,"abstract":"Centrosome aberrations are a common feature in human cancer cells. Our previous studies demonstrated that the centrosomal protein Tax1 binding protein 2 (TAX1BP2) inhibits centrosome overduplication and is underexpressed in hepatocellular carcinoma (HCC). Here, we report that Intratumoral TAX1BP2 promotes tumor lymphocyte infiltration and enhances the efficacy of anti-PD-1 therapy. Clinically, we discovered that a hallmark of low TAX1BP2 expression in HCC tumors is T-cell exclusion, whereas re-depression of TAX1BP2 in preclinical models restores antitumor immunity and potentiates anti-PD-1 efficacy. Mechanistically, we identified that reconstitution of intratumor TAX1BP2 triggers the type 1 interferon (IFN-I) response and subsequent facilitation of a subtype of CD27+CD8+ T cell recruitment. Furthermore, we demonstrated that Intratumor TAX1BP2 upregulates STING by inhibiting the hyperactivation of DNMT1, and EZH2 is linked to endogenous LKB1 activity.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"54 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062063","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}
Molecular TherapyPub Date : 2025-01-28DOI: 10.1016/j.ymthe.2025.01.042
Yuki Tachida, Kannan V Manian, Rossano Butcher, Jonathan M Levy, Nachiket Pendse, Erin Hennessey, David R Liu, Eric A Pierce, Qin Liu, Jason Comander
{"title":"Systematic empirical evaluation of individual base editing targets: validating therapeutic targets in USH2A and comparison of methods.","authors":"Yuki Tachida, Kannan V Manian, Rossano Butcher, Jonathan M Levy, Nachiket Pendse, Erin Hennessey, David R Liu, Eric A Pierce, Qin Liu, Jason Comander","doi":"10.1016/j.ymthe.2025.01.042","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.01.042","url":null,"abstract":"<p><p>Base editing shows promise for the correction of human mutations at a higher efficiency than other repair methods and is especially attractive for mutations in large genes that are not amenable to gene augmentation therapy. Here, we demonstrate a comprehensive workflow for in vitro screening of potential therapeutic base editing targets for the USH2A gene and empirically validate the efficiency of adenine and cytosine base editor/guide combinations for correcting 35 USH2A mutations. Editing efficiency and bystander edits are compared between different target templates (plasmids versus transgenes) and assays (Next generation sequencing versus Sanger), as well as comparisons between unbiased empirical results and computational predictions. Based on these observations, practical assay recommendations are discussed. Finally, a humanized knock-in mouse model was created with the best-performing target, the nonsense mutation c.11864G>A p.(Trp3955*). Split-intein AAV9 delivery of editing reagents resulted in the restoration of USH2A protein and a correction rate of 65 ± 3% at the mutant base pair and of 52 ± 3% excluding bystander amino acid changes. This efficiency is higher than that seen in a retinal gene editing program testing in a clinical trial. These results demonstrate the effectiveness of this overall strategy to identify and test base editing reagents with the potential for human therapeutic applications.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066852","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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