Pub Date : 2026-01-07Epub Date: 2025-09-23DOI: 10.1016/j.ymthe.2025.09.037
Jorge L Cueva Vargas, Nicolas Belforte, Isaac A Vidal-Paredes, Florence Dotigny, Christine Vande Velde, Heberto Quintero, Adriana Di Polo
Increased vascular leakage and endothelial cell (EC) dysfunction are major features of neurodegenerative diseases. Here, we investigated the mechanisms leading to EC dysregulation and asked whether altered mitochondrial dynamics in ECs impinge on vascular barrier integrity and neurodegeneration. We show that ocular hypertension, a major risk factor for developing glaucoma, induced mitochondrial fragmentation in retinal capillary ECs, accompanied by increased oxidative stress and ultrastructural defects. Analysis of EC mitochondrial components revealed overactivation of dynamin-related protein 1 (DRP1), a central regulator of mitochondrial fission, during glaucomatous damage. Pharmacological DRP1 inhibition or EC-specific in vivo gene delivery of a dominant-negative DRP1 mutant was sufficient to rescue mitochondrial volume, reduce vascular leakage, and increase expression of the tight junction claudin-5 (CLDN5). We further demonstrate that EC-targeted CLDN5 gene augmentation restored blood-retinal barrier integrity, promoted neuronal survival, and improved light-evoked visual behaviors in glaucomatous mice. Our findings reveal that preserving mitochondrial homeostasis and EC function are valuable strategies to enhance neuroprotection and improve vision in glaucoma.
{"title":"Stress-induced mitochondrial fragmentation in endothelial cells disrupts blood-retinal barrier integrity causing neurodegeneration.","authors":"Jorge L Cueva Vargas, Nicolas Belforte, Isaac A Vidal-Paredes, Florence Dotigny, Christine Vande Velde, Heberto Quintero, Adriana Di Polo","doi":"10.1016/j.ymthe.2025.09.037","DOIUrl":"10.1016/j.ymthe.2025.09.037","url":null,"abstract":"<p><p>Increased vascular leakage and endothelial cell (EC) dysfunction are major features of neurodegenerative diseases. Here, we investigated the mechanisms leading to EC dysregulation and asked whether altered mitochondrial dynamics in ECs impinge on vascular barrier integrity and neurodegeneration. We show that ocular hypertension, a major risk factor for developing glaucoma, induced mitochondrial fragmentation in retinal capillary ECs, accompanied by increased oxidative stress and ultrastructural defects. Analysis of EC mitochondrial components revealed overactivation of dynamin-related protein 1 (DRP1), a central regulator of mitochondrial fission, during glaucomatous damage. Pharmacological DRP1 inhibition or EC-specific in vivo gene delivery of a dominant-negative DRP1 mutant was sufficient to rescue mitochondrial volume, reduce vascular leakage, and increase expression of the tight junction claudin-5 (CLDN5). We further demonstrate that EC-targeted CLDN5 gene augmentation restored blood-retinal barrier integrity, promoted neuronal survival, and improved light-evoked visual behaviors in glaucomatous mice. Our findings reveal that preserving mitochondrial homeostasis and EC function are valuable strategies to enhance neuroprotection and improve vision in glaucoma.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"562-581"},"PeriodicalIF":12.0,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138036","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 : 2026-01-06DOI: 10.1016/j.ymthe.2025.12.054
Sagi Ravid, Inbal Hazan-Halevy, Dan Peer
{"title":"cSMRTS for cancer therapeutics","authors":"Sagi Ravid, Inbal Hazan-Halevy, Dan Peer","doi":"10.1016/j.ymthe.2025.12.054","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.12.054","url":null,"abstract":"","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"14 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902497","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 : 2026-01-06DOI: 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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号