Pub Date : 2025-12-20DOI: 10.1016/j.ymthe.2025.12.020
Julie M. Crudele
{"title":"Safety and efficacy of commercially administered elevidys (delandistrogene moxeparvovec-rokl)","authors":"Julie M. Crudele","doi":"10.1016/j.ymthe.2025.12.020","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.12.020","url":null,"abstract":"","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"26 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1016/j.ymthe.2025.12.014
Jeffrey A. Medin
{"title":"Tissue accessibility and thresholds in gene therapy for a lysosomal storage disorder","authors":"Jeffrey A. Medin","doi":"10.1016/j.ymthe.2025.12.014","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.12.014","url":null,"abstract":"","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"7 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784477","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}
Chimeric antigen receptor (CAR)-T cell therapy has shown success in hematologic malignancies but remains limited in solid tumors due to poor persistence, migration, and TME-induced exhaustion. In an investigator-initiated trial in relapsed/refractory ovarian cancer, mesothelin-targeted CAR-T cells demonstrated a 75% partial response rate and good safety. To enhance efficacy, we combined CAR-T therapy with sodium valproate (VPA), a clinically approved histone deacetylase inhibitor (HDACi). VPA-treated CAR-T cells (CAR-T+VPA) showed improved cytotoxicity, reduced exhaustion, and enhanced tumor infiltration. Mechanistically, VPA induced histone propionylation, particularly H3K56pr, leading to transcriptional activation of key genes. LOX promoted migration and adhesion, while GUCY1B3 enhanced metabolic fitness. CUT&Tag and RNA-seq analyses confirmed VPA-driven epigenetic remodeling of pathways linked to T cell persistence and effector function. CAR-T+VPA cells exhibited elevated oxidative phosphorylation and glycolysis, supporting sustained activity in hostile tumor environments. In xenograft models of ovarian and triple-negative breast cancer, VPA significantly improved tumor control and survival without added toxicity. These findings support metabolic-epigenetic modulation as a strategy to improve CAR-T therapy in solid tumors.
{"title":"Sodium Valproate Drives Propionylation-Mediated Epigenetic Reprogramming to Enhance Mesothelin CAR-T Cell Therapy in Solid Tumors.","authors":"Jiannan Chen,Wenying Li,Shuai Wang,Jiayi Li,Lianfeng Zhao,Xudong Ao,Wenyu Wang,Li Zhu,Haipeng Rao,Shichu Xu,Mengru Wen,Zhigang Hu,Feiyan Pan,Lingfeng He,Lili Gu,Weijia Fang,Shengjing Xu,Junqing Liang,Peng Zhao,Haoyan Chen,Zhigang Guo","doi":"10.1016/j.ymthe.2025.12.021","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.12.021","url":null,"abstract":"Chimeric antigen receptor (CAR)-T cell therapy has shown success in hematologic malignancies but remains limited in solid tumors due to poor persistence, migration, and TME-induced exhaustion. In an investigator-initiated trial in relapsed/refractory ovarian cancer, mesothelin-targeted CAR-T cells demonstrated a 75% partial response rate and good safety. To enhance efficacy, we combined CAR-T therapy with sodium valproate (VPA), a clinically approved histone deacetylase inhibitor (HDACi). VPA-treated CAR-T cells (CAR-T+VPA) showed improved cytotoxicity, reduced exhaustion, and enhanced tumor infiltration. Mechanistically, VPA induced histone propionylation, particularly H3K56pr, leading to transcriptional activation of key genes. LOX promoted migration and adhesion, while GUCY1B3 enhanced metabolic fitness. CUT&Tag and RNA-seq analyses confirmed VPA-driven epigenetic remodeling of pathways linked to T cell persistence and effector function. CAR-T+VPA cells exhibited elevated oxidative phosphorylation and glycolysis, supporting sustained activity in hostile tumor environments. In xenograft models of ovarian and triple-negative breast cancer, VPA significantly improved tumor control and survival without added toxicity. These findings support metabolic-epigenetic modulation as a strategy to improve CAR-T therapy in solid tumors.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"29 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1016/j.ymthe.2025.12.022
Yan-Ruide Li,Yuning Chen,Lili Yang
Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system characterized by aberrant immune responses against myelin and neuronal antigens, resulting in demyelination, axonal injury, and progressive neurological impairment. Although current immunomodulatory therapies can reduce relapse frequency and slow disease progression, they rarely induce durable remission or reverse established pathology. Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy, initially developed for cancer treatment, has recently emerged as a promising strategy for autoimmune diseases. By engineering T cells to selectively eliminate autoreactive B cells or other pathogenic immune populations, CAR-T therapy holds the potential to achieve long-lasting disease control and even immune system reset. Preclinical studies and early-phase clinical trials targeting CD19+ B cells have shown encouraging efficacy in autoimmunity, including MS. Nonetheless, significant challenges remain, such as optimizing antigen targets, minimizing treatment-associated toxicities, sustaining therapeutic benefit, and advancing scalable, safe, and cost-effective clinical applications. In this review, we summarize recent advances in applying CAR-T cell therapy to MS, outline key lessons learned from oncology and other autoimmune diseases, and discuss future directions for establishing CAR-T cells as a transformative approach in neuroimmunology.
{"title":"Redefining Multiple Sclerosis with CAR-T Cell Therapy.","authors":"Yan-Ruide Li,Yuning Chen,Lili Yang","doi":"10.1016/j.ymthe.2025.12.022","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.12.022","url":null,"abstract":"Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system characterized by aberrant immune responses against myelin and neuronal antigens, resulting in demyelination, axonal injury, and progressive neurological impairment. Although current immunomodulatory therapies can reduce relapse frequency and slow disease progression, they rarely induce durable remission or reverse established pathology. Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy, initially developed for cancer treatment, has recently emerged as a promising strategy for autoimmune diseases. By engineering T cells to selectively eliminate autoreactive B cells or other pathogenic immune populations, CAR-T therapy holds the potential to achieve long-lasting disease control and even immune system reset. Preclinical studies and early-phase clinical trials targeting CD19+ B cells have shown encouraging efficacy in autoimmunity, including MS. Nonetheless, significant challenges remain, such as optimizing antigen targets, minimizing treatment-associated toxicities, sustaining therapeutic benefit, and advancing scalable, safe, and cost-effective clinical applications. In this review, we summarize recent advances in applying CAR-T cell therapy to MS, outline key lessons learned from oncology and other autoimmune diseases, and discuss future directions for establishing CAR-T cells as a transformative approach in neuroimmunology.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"93 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728455","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}
Human adenovirus type 55, 11 and 14 (HAdV-55, -11 and -14) are pathogenic respiratory viruses for which no drugs or vaccines are currently available. We report the generation of a replication-incompetent rAd55-5E4 with deleted E1 and E3 genes, which only replicates in cells that provide E1 proteins in trans. In mice and non-human primates, vaccination with live non-replicating rAd55-5E4 elicited robust and durable neutralizing antibody (nAb) and cell-mediated immune (CMI) responses against HAdV-55, as well as cross-reactivity against HAdV-11 and HAdV-14. Furthermore, vaccination with the live non-replicating rAd55-5E4 elicited much stronger immune responses than inactivated rAd55-5E4. In transgenic mice that express human desmoglein-2, the cellular receptor for HAdV-55, -11 and -14, vaccination with rAd55-5E4 or passive transfer of macaque immune sera collected at 66 weeks post-vaccination effectively protected against challenges with HAdV-55, HAdV-11, and HAdV-14. Epitope profiling revealed that nAbs mainly recognize epitopes on hexon hypervariable regions 1, 2, 5, and 7, as well as the fiber knob. This study supports the feasibility of developing replication-incompetent HAdVs as vaccines against pathogenic HAdVs.
{"title":"A replication-incompetent adenovirus type 55 vaccine induces broad and durable protective immunity against pathogenic adenoviruses.","authors":"Ying Feng,Tao Shu,Liang Li,Xinxin Sun,Changfa Yu,Wenming Liu,Lingling Hong,Jiashun Li,Shutao Zhao,Weikai Zeng,Chenchen Yang,Chunhua Wang,Xuehua Zheng,Xianmiao Ye,Xikui Sun,Yichu Liu,Zhixia Li,Si Chen,Xuefeng Niu,Rong Zhou,Pingchao Li,Liqiang Feng,Ling Chen","doi":"10.1016/j.ymthe.2025.12.027","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.12.027","url":null,"abstract":"Human adenovirus type 55, 11 and 14 (HAdV-55, -11 and -14) are pathogenic respiratory viruses for which no drugs or vaccines are currently available. We report the generation of a replication-incompetent rAd55-5E4 with deleted E1 and E3 genes, which only replicates in cells that provide E1 proteins in trans. In mice and non-human primates, vaccination with live non-replicating rAd55-5E4 elicited robust and durable neutralizing antibody (nAb) and cell-mediated immune (CMI) responses against HAdV-55, as well as cross-reactivity against HAdV-11 and HAdV-14. Furthermore, vaccination with the live non-replicating rAd55-5E4 elicited much stronger immune responses than inactivated rAd55-5E4. In transgenic mice that express human desmoglein-2, the cellular receptor for HAdV-55, -11 and -14, vaccination with rAd55-5E4 or passive transfer of macaque immune sera collected at 66 weeks post-vaccination effectively protected against challenges with HAdV-55, HAdV-11, and HAdV-14. Epitope profiling revealed that nAbs mainly recognize epitopes on hexon hypervariable regions 1, 2, 5, and 7, as well as the fiber knob. This study supports the feasibility of developing replication-incompetent HAdVs as vaccines against pathogenic HAdVs.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"146 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1016/j.ymthe.2025.12.026
Jin-Hui Hor,Jin Rong Ow,Winanto Ng,Boominathan Ramasamy,Tommaso Tabaglio,Kimberly Ngee Hui Lim,Muhammad Ikhsan Bin Muzakar,Valerie Jing Wen Lim,Rajasekhar Reddy Gurrampati,Ravisankar Rajarethinam,Shyuan T Ngo,Venkataramanan Ramadass,Shuo-Chien Ling,Manikandan Lakshmanan,Keng Boon Wee,Shi-Yan Ng
Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressing and debilitating neurodegenerative disease, yet the mechanisms underlying disease onset and progression remain poorly understood, particularly in sporadic ALS. Emerging evidence suggests that mitochondrial dysfunction and metabolic dysregulation are central to ALS pathophysiology. A key feature of ALS motor neurons (MNs) is hyper-acetylation of mitochondrial proteins, which disrupt mitochondrial respiration and energy homeostasis. In this study, we identify BLOC1S1 (also known as GCN5L1) as a novel regulator of mitochondrial acetylation in ALS. We demonstrate that BLOC1S1 is significantly upregulated in ALS patient-derived MNs, post-mortem motor cortices, and spinal cords of ALS mouse models. Functional studies in induced pluripotent stem cell (iPSC)-derived MNs reveal that BLOC1S1 depletion rescues key disease phenotypes. Therefore, we develop an efficacious splice-switching antisense oligonucleotide (SSO) that induces nonsense-mediated decay of BLOC1S1 transcripts as a potential therapeutic candidate. Besides mitigating ALS-relevant cellular deficits in MN cultures from diverse genetic backgrounds, it was validated to extend disease-free and overall survival that is associated with improved rotarod performance in an ALS mouse model. These findings establish BLOC1S1 as a critical modifier of disease progression in ALS and highlight its potential as a novel therapeutic target.
{"title":"Depletion of BLOC1S1 with splice-switching oligonucleotides in ALS motor neurons improves mitochondrial respiration and rescues disease phenotypes.","authors":"Jin-Hui Hor,Jin Rong Ow,Winanto Ng,Boominathan Ramasamy,Tommaso Tabaglio,Kimberly Ngee Hui Lim,Muhammad Ikhsan Bin Muzakar,Valerie Jing Wen Lim,Rajasekhar Reddy Gurrampati,Ravisankar Rajarethinam,Shyuan T Ngo,Venkataramanan Ramadass,Shuo-Chien Ling,Manikandan Lakshmanan,Keng Boon Wee,Shi-Yan Ng","doi":"10.1016/j.ymthe.2025.12.026","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.12.026","url":null,"abstract":"Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressing and debilitating neurodegenerative disease, yet the mechanisms underlying disease onset and progression remain poorly understood, particularly in sporadic ALS. Emerging evidence suggests that mitochondrial dysfunction and metabolic dysregulation are central to ALS pathophysiology. A key feature of ALS motor neurons (MNs) is hyper-acetylation of mitochondrial proteins, which disrupt mitochondrial respiration and energy homeostasis. In this study, we identify BLOC1S1 (also known as GCN5L1) as a novel regulator of mitochondrial acetylation in ALS. We demonstrate that BLOC1S1 is significantly upregulated in ALS patient-derived MNs, post-mortem motor cortices, and spinal cords of ALS mouse models. Functional studies in induced pluripotent stem cell (iPSC)-derived MNs reveal that BLOC1S1 depletion rescues key disease phenotypes. Therefore, we develop an efficacious splice-switching antisense oligonucleotide (SSO) that induces nonsense-mediated decay of BLOC1S1 transcripts as a potential therapeutic candidate. Besides mitigating ALS-relevant cellular deficits in MN cultures from diverse genetic backgrounds, it was validated to extend disease-free and overall survival that is associated with improved rotarod performance in an ALS mouse model. These findings establish BLOC1S1 as a critical modifier of disease progression in ALS and highlight its potential as a novel therapeutic target.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"49 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728427","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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