Pub Date : 2026-01-06DOI: 10.1016/j.ymthe.2025.12.067
Dongsheng Duan, Roland W Herzog
Duchenne muscular dystrophy (DMD) is a fatal muscle degenerating disease caused by dystrophin deficiency. Adeno-associated virus (AAV)-based gene therapy holds promise for restoring missing dystrophin and improving quality of life. Many clinical trials have been conducted or are ongoing. Despite compelling preclinical data, the full potential of AAV gene therapy remains to be established in DMD patients. Importantly, high-dose intravenous AAV administration has resulted in hospitalizations and several deaths in patients afflicted by DMD and other inherited diseases due to innate and adaptive immune responses to the vectors. Although fatal outcomes are rare, a critical analysis of these cases may provide insights to refine systemic AAV gene therapy for DMD and other inherited diseases. Here, we review the clinical findings of the reported deaths and related cases in AAV gene therapy for DMD and other diseases. We also evaluate the underlying mechanisms and discuss mitigating strategies and future directions.
{"title":"Deaths in gene therapy of Duchenne muscular dystrophy and other diseases: Underlying mechanisms and mitigating strategies.","authors":"Dongsheng Duan, Roland W Herzog","doi":"10.1016/j.ymthe.2025.12.067","DOIUrl":"10.1016/j.ymthe.2025.12.067","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is a fatal muscle degenerating disease caused by dystrophin deficiency. Adeno-associated virus (AAV)-based gene therapy holds promise for restoring missing dystrophin and improving quality of life. Many clinical trials have been conducted or are ongoing. Despite compelling preclinical data, the full potential of AAV gene therapy remains to be established in DMD patients. Importantly, high-dose intravenous AAV administration has resulted in hospitalizations and several deaths in patients afflicted by DMD and other inherited diseases due to innate and adaptive immune responses to the vectors. Although fatal outcomes are rare, a critical analysis of these cases may provide insights to refine systemic AAV gene therapy for DMD and other inherited diseases. Here, we review the clinical findings of the reported deaths and related cases in AAV gene therapy for DMD and other diseases. We also evaluate the underlying mechanisms and discuss mitigating strategies and future directions.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12882805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918100","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}
Pub Date : 2026-01-06DOI: 10.1016/j.ymthe.2025.12.052
Chiara Martinello, Els Verhoeyen
{"title":"Combining conventional and adapter CAR T cells: An elegant solution to erase current CAR T cell limitations","authors":"Chiara Martinello, Els Verhoeyen","doi":"10.1016/j.ymthe.2025.12.052","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.12.052","url":null,"abstract":"","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"40 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902496","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 : 2026-01-05DOI: 10.1016/j.ymthe.2025.12.053
Shi Yan, Yan Dong
{"title":"Restoring chloride homeostasis in depression through EV-enabled drug delivery","authors":"Shi Yan, Yan Dong","doi":"10.1016/j.ymthe.2025.12.053","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.12.053","url":null,"abstract":"","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"2 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903327","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 : 2026-01-03DOI: 10.1016/j.ymthe.2025.12.001
Florian Kühnel, Engin Gürlevik, Thomas C. Wirth, Nina Strüver, Nisar P. Malek, Martina Müller-Schilling, Michael P. Manns, Amancio Carnero, Lars Zender, Stefan Kubicka
{"title":"Targeting of p53-Transcriptional Dysfunction by Conditionally Replicating Adenovirus Is Not Limited by p53-Homologues","authors":"Florian Kühnel, Engin Gürlevik, Thomas C. Wirth, Nina Strüver, Nisar P. Malek, Martina Müller-Schilling, Michael P. Manns, Amancio Carnero, Lars Zender, Stefan Kubicka","doi":"10.1016/j.ymthe.2025.12.001","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.12.001","url":null,"abstract":"","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"27 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893924","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 : 2026-01-03DOI: 10.1016/j.ymthe.2025.12.046
Luke J. Laffin, Steven E. Nissen
{"title":"In vivo gene editing for lipid management: An early perspective from ANGPTL3-targeted CRISPR-Cas9 therapy","authors":"Luke J. Laffin, Steven E. Nissen","doi":"10.1016/j.ymthe.2025.12.046","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.12.046","url":null,"abstract":"","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"13 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893922","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 : 2026-01-02DOI: 10.1016/j.ymthe.2025.12.059
Yuan Zhang, Shuai Deng, Yanlun Zhu, Xu Li, Jiani Deng, Chengdong Wang, Jianmin Sun, Feixiang Bao, Shibing Tang, Haifeng Ye, Hon Fai Chan, Hui Zhao
Synthetic gene circuits can be programmed to produce therapeutic proteins in response to the presence of disease biomarkers. Here, we established a hyperglycemia-sensing gene circuit to enhance blood glucose homeostasis in diabetic mouse models. To achieve such a sensing mechanism, we functionally linked the O-GlcNAcylation-mediated nuclear translocation of Yes-associated protein (YAP), a universally existing cellular pathway, to a prokaryotic Tet-Off transcription regulatory system. This linkage involved engineering two chimeric transcription factors that promote intense transcription activity in response to supraphysiological glucose levels to induce the expression of therapeutic proteins from the Tet-inducible promoter. In vivo application of the gene circuit enhanced blood glucose homeostasis in diabetic mouse models via coordinating hyperglycemia-triggered insulin or glucagon-like peptide-1 (GLP-1) expression and ameliorated hyperglycemia-induced tissue damage in type 1 and type 2 diabetic mice. Besides its antidiabetic therapeutic potential, the hyperglycemia-sensing gene circuit demonstrates the generalized possibility of repurposing widely-evolved sensors from various organisms for customized therapeutics.
{"title":"A synthetic hyperglycemia–sensing gene circuit enhances blood glucose homeostasis in diabetic mice","authors":"Yuan Zhang, Shuai Deng, Yanlun Zhu, Xu Li, Jiani Deng, Chengdong Wang, Jianmin Sun, Feixiang Bao, Shibing Tang, Haifeng Ye, Hon Fai Chan, Hui Zhao","doi":"10.1016/j.ymthe.2025.12.059","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.12.059","url":null,"abstract":"Synthetic gene circuits can be programmed to produce therapeutic proteins in response to the presence of disease biomarkers. Here, we established a hyperglycemia-sensing gene circuit to enhance blood glucose homeostasis in diabetic mouse models. To achieve such a sensing mechanism, we functionally linked the O-GlcNAcylation-mediated nuclear translocation of Yes-associated protein (YAP), a universally existing cellular pathway, to a prokaryotic Tet-Off transcription regulatory system. This linkage involved engineering two chimeric transcription factors that promote intense transcription activity in response to supraphysiological glucose levels to induce the expression of therapeutic proteins from the Tet-inducible promoter. In vivo application of the gene circuit enhanced blood glucose homeostasis in diabetic mouse models via coordinating hyperglycemia-triggered insulin or glucagon-like peptide-1 (GLP-1) expression and ameliorated hyperglycemia-induced tissue damage in type 1 and type 2 diabetic mice. Besides its antidiabetic therapeutic potential, the hyperglycemia-sensing gene circuit demonstrates the generalized possibility of repurposing widely-evolved sensors from various organisms for customized therapeutics.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"42 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893928","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 : 2026-01-02DOI: 10.1016/j.ymthe.2025.12.058
Xiaotong Gao, Hailing Liu, Guokun Li, Yali Zhou, Yan Dong, Xiao Chen, Wen Fan, Erbing Li, Sanmei Wang, Qinyao Luan, Jing Zhang, Hui Jin, Hui Liao, Yizhou Luo, Li Liu, Weiwei Qin, Jiangtao Ren, Jianyong Li, Lei Fan
Therapies leveraging chimeric antigen receptor (CAR) T cells for acute myeloid leukemia (AML) are limited by the scarcity of leukemia stem cell (LSC)-specific antigens. Here, we found that CD96 is expressed in 48.3% of AML patients, with higher expression on LSCs than blasts, and is absent on normal hematopoietic stem/progenitor cells (HSPCs). We developed a panel of CD96-CAR T cells using single-chain variable fragments derived from various monoclonal antibodies, incorporating distinct transmembrane and costimulatory domains. Treatment with CD96-CAR T cells confers specific anti-leukemic activity correlated with CD96 expression. Notably, CAR T cells featuring a CD28 transmembrane and costimulatory domain (CD96-28z) exhibit enhanced proliferation and cytotoxic capabilities in vitro. In vivo, CD96-28z potently eliminated AML cells and prolonged survival in mice bearing CD96-high, but not CD96-low, AML. To address CD96-low AML, we combined CD96-28z with a CD33-targeted chimeric costimulatory receptor (CCR), thereby increasing cytotoxic efficacy. Importantly, CD96-CAR T cells did not inhibit colony formation by HSPCs during manufacturing. These findings indicate that CD96 is a promising target for AML immunotherapy, and the combination of CD96-CAR and CD33-CCR may represent a potent strategy for patients with CD96-positive AML while preserving normal hematopoiesis.
{"title":"CD96 as a Therapeutic Target for CAR T-Cell Therapy in Acute Myeloid Leukemia","authors":"Xiaotong Gao, Hailing Liu, Guokun Li, Yali Zhou, Yan Dong, Xiao Chen, Wen Fan, Erbing Li, Sanmei Wang, Qinyao Luan, Jing Zhang, Hui Jin, Hui Liao, Yizhou Luo, Li Liu, Weiwei Qin, Jiangtao Ren, Jianyong Li, Lei Fan","doi":"10.1016/j.ymthe.2025.12.058","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.12.058","url":null,"abstract":"Therapies leveraging chimeric antigen receptor (CAR) T cells for acute myeloid leukemia (AML) are limited by the scarcity of leukemia stem cell (LSC)-specific antigens. Here, we found that CD96 is expressed in 48.3% of AML patients, with higher expression on LSCs than blasts, and is absent on normal hematopoietic stem/progenitor cells (HSPCs). We developed a panel of CD96-CAR T cells using single-chain variable fragments derived from various monoclonal antibodies, incorporating distinct transmembrane and costimulatory domains. Treatment with CD96-CAR T cells confers specific anti-leukemic activity correlated with CD96 expression. Notably, CAR T cells featuring a CD28 transmembrane and costimulatory domain (CD96-28z) exhibit enhanced proliferation and cytotoxic capabilities in vitro. In vivo, CD96-28z potently eliminated AML cells and prolonged survival in mice bearing CD96-high, but not CD96-low, AML. To address CD96-low AML, we combined CD96-28z with a CD33-targeted chimeric costimulatory receptor (CCR), thereby increasing cytotoxic efficacy. Importantly, CD96-CAR T cells did not inhibit colony formation by HSPCs during manufacturing. These findings indicate that CD96 is a promising target for AML immunotherapy, and the combination of CD96-CAR and CD33-CCR may represent a potent strategy for patients with CD96-positive AML while preserving normal hematopoiesis.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"13 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893929","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}
Counteracting XIAP (X-Linked Inhibitor of Apoptosis) and IAP with mimicking SMAC (Second Mitochondria-derived Activator of Caspase) function is a clinically validated therapeutic option against solid tumors. Anti-tumor efficacy of currently available SMAC mimetics is limited due to its dependence on TNF-α. Utilizing medicinal chemistry approach, here, we report the identification and preclinical characterization of SMAC mimetic compound S-016-1348 that can even promote cancer cell death independent of TNF-α. Its potent capability to upregulate functional DR5 expression is the key differentiator for its monotherapy application against diverse tumor types. S-016-1348 demonstrates marked antitumor efficacy in colon, head & neck cancer and TNBC patient-derived xenograft (PDX) models. S-016-1348 holds drug like properties for its excellent oral bioavailability across species, promising pharmacokinetic properties, and well tolerated in preclinical safety evaluations with high safety margins. These findings highlight the translational potential of SMAC mimetic S-016-1348 as a monotherapy against solid tumors.
通过模拟SMAC （Second Mitochondria-derived Activator of Caspase）功能来对抗XIAP （X-Linked Inhibitor of Apoptosis）和IAP是一种临床验证的治疗实体瘤的选择。目前可用的SMAC模拟物的抗肿瘤效果有限，因为它依赖于TNF-α。利用药物化学方法，我们报告了SMAC模拟化合物S-016-1348的鉴定和临床前表征，该化合物甚至可以独立于TNF-α促进癌细胞死亡。其上调功能性DR5表达的强大能力是其单药治疗不同肿瘤类型的关键区别。S-016-1348在结肠癌、头颈癌和TNBC患者来源的异种移植瘤（PDX）模型中显示出显著的抗肿瘤疗效。S-016-1348具有良好的跨物种口服生物利用度，具有良好的药代动力学特性，在临床前安全性评估中具有良好的耐受性和高安全边际，具有类似药物的特性。这些发现突出了SMAC模拟物S-016-1348作为单一疗法治疗实体肿瘤的转化潜力。
{"title":"Discovery, preclinical safety, and efficacy characterization of SMAC mimetic S-016-1348 as a potential cancer therapeutic","authors":"Abhipsa Sinha, Mushtaq Ahmad Nengroo, Rafat Ali, Afsar Ali Khan, Himangsu Sekhar Dutta, Akhilesh Singh, Krishan Kumar Saini, Kiran Tripathi, Roshan Katekar, Shivam Rathaur, Jayanti Vaishnav, Gajendra Singh, Mohammad Afsar, Sanjeev Meena, Anjna Sahu, Abhishek Kumar Shaw, Kulranjan Singh, Ravishankar Ramachandran, Manish Kumar Chourasia, Manoj Barthwal, Prem Narayan Yadav, Aravind Singh Kshatri, Radha Rangarajan, Aamir Nazir, Ravi Sankar Ampapathi, Jiaur Rahaman Gayen, Dipankar Koley, Wahajul Haq, Dipak Datta","doi":"10.1016/j.ymthe.2025.12.056","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.12.056","url":null,"abstract":"Counteracting XIAP (X-Linked Inhibitor of Apoptosis) and IAP with mimicking SMAC (Second Mitochondria-derived Activator of Caspase) function is a clinically validated therapeutic option against solid tumors. Anti-tumor efficacy of currently available SMAC mimetics is limited due to its dependence on TNF-α. Utilizing medicinal chemistry approach, here, we report the identification and preclinical characterization of SMAC mimetic compound S-016-1348 that can even promote cancer cell death independent of TNF-α. Its potent capability to upregulate functional DR5 expression is the key differentiator for its monotherapy application against diverse tumor types. S-016-1348 demonstrates marked antitumor efficacy in colon, head & neck cancer and TNBC patient-derived xenograft (PDX) models. S-016-1348 holds drug like properties for its excellent oral bioavailability across species, promising pharmacokinetic properties, and well tolerated in preclinical safety evaluations with high safety margins. These findings highlight the translational potential of SMAC mimetic S-016-1348 as a monotherapy against solid tumors.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"53 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893947","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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