Molecular Therapy最新文献

{"title":"Memory matters: T cell phenotype shapes CAR T cell fate.","authors":"Francesco Di Meo","doi":"10.1016/j.ymthe.2025.06.011","DOIUrl":"10.1016/j.ymthe.2025.06.011","url":null,"abstract":"","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2975-2976"},"PeriodicalIF":12.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144506877","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":"Peeling back the layers of immunogenicity in CRISPR/Cas9-based genomic medicine.","authors":"Virpi Stigzelius,Anna Lina Cavallo,Rakesh Kantilal Chandode,Roberto Nitsch","doi":"10.1016/j.ymthe.2025.06.045","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.045","url":null,"abstract":"The CRISPR/Cas9 system is rewriting the treatment of genetic diseases, offering unprecedented potential for detrimental and previously untreatable diseases. As this technology advances towards wider utilization in clinical applications, the immunogenicity of Cas9 nuclease has emerged as a potential challenge for in vivo therapies. Immune recognition of CRISPR/Cas9 components can trigger both innate and adaptive responses. The complex interactions between Cas9, delivery vectors, and host immune responses play a crucial role in determining the safety and efficacy of CRISPR-based treatments. Recent advances in mitigating Cas9 immunogenicity include epitope engineering, optimized delivery systems, and nucleic acid modifications. These strategies, explored across various tissue contexts and delivery methods, show promise in enhancing the tolerability of CRISPR-based therapies. However, pre-existing immunity to Cas9 and the potential for long-term adaptive immune responses remain important considerations. Addressing these immunological challenges requires an integrated approach, combining insights from immunology with innovative engineering solutions. As the field progresses, overcoming Cas9 immunogenicity will be crucial for realizing the full therapeutic potential of the CRISPR/Cas9 system in diverse clinical applications.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"104 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547774","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":"Recovery of Cone-Mediated Vision in Lebercilin-Associated Severe Retinal Ciliopathy (LCA5) after Gene Therapy: One Year Results of a Phase Ib/IIa Trial.","authors":"Tomas S Aleman,Katherine E Uyhazi,Alejandro J Roman,Mariejel L Weber,Erin C O'Neil,Malgorzata Swider,Alexander Sumaroka,Katherine H Maguire,Elena M Aleman,Arlene J Santos,Rebecca J Kim,Kelsey M Parchinski,Andrew Billek,Makayla Fradin,William Chung,Paris Margaritis,Junwei Sun,Drew H Scoles,Vivian Wu,Alexandra V Garafalo,Ashwath Jayagopal,Ben Yerxa,Sarah Tuller,Albert M Maguire,Jean Bennett,Artur V Cideciyan","doi":"10.1016/j.ymthe.2025.06.035","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.035","url":null,"abstract":"We assessed the preliminary safety of a recombinant adeno-associated virus serotype 8 vector carrying the native human LCA5 cDNA (OPGx-001) in LCA5-associated Leber congenital amaurosis (LCA5-LCA), a congenital blindness. The phase 1b/2a trial (NCT05616793) is a nonrandomized, single ascending, dose-escalation study. Three subjects with LCA5-LCA (ages 19, 26 and 34 years old) received uniocular subretinal injections of 1E10 vector genome per eye of OPGx-001. There were no serious adverse events related to OPGx-001 or the procedure. Retinal microstructure by SD-OCT showed no major changes in retinal lamination of the treated central retina compared to the contralateral control. Efficacy was detectable in these severely affected patients by subjective and objective methods at one-month post-treatment and persisted for at least 12 months. Chromatic full-field stimulus testing showed improvements in cone-mediated vision averaging ∼1 log10 unit. Objective pupillometry confirmed perceptual results. Improvements were associated with better performance on a virtual reality orientation and mobility test. Visual acuity returned to baseline or improved in the treated eyes of all participants. The favorable safety profile and efficacy outcomes pave the path for enrolling milder phenotypes with careful dose escalation.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"26 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533476","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":"Galectin-4 potentiates CD8+ T cell immunity by enhancing MHC-I expression on dendritic cells: Therapeutic implications for cancer and viral infection.","authors":"In-Gu Lee,Jeonghyeon Lee,Hyeong-Rae Kim,Younghyun Lim,Hye-Won Yu,Tae-Hyung Kim,Bumsuk Hahm,Hyun Ah Kang,So-Hee Hong,Young-Jin Seo","doi":"10.1016/j.ymthe.2025.06.040","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.040","url":null,"abstract":"Galectin-4 (Gal-4), a member of the β-galactoside-binding galectin family, plays a role in various physiological processes, including tumor progression and intestinal disorders. However, its contribution to adaptive immunity remains poorly understood. In this study, Gal-4 is identified as a critical factor for effective generation of CD8+ T cell responses against tumors and viral infections. Gal-4-deficient mice exhibit significantly enhanced tumor growth in syngeneic mouse cancer models, attributed to impaired CD8+ T cell responses. Similarly, antiviral CD8+ T cell responses against lymphocytic choriomeningitis virus (LCMV) are profoundly diminished in Gal-4-deficient mice. This is not due to CD8+ T cell-intrinsic defects but instead linked to decreased surface expression of antigen-MHC-I complexes on dendritic cells. Building on these findings, the therapeutic potential of Gal-4 is investigated. Administration of Gal-4 enhances the efficacy of cancer vaccines and PD-1 blockade cancer therapy to improve outcomes in tumor-bearing mice. Additionally, systemic administration of Gal-4 markedly amplifies antiviral CD8+ T cell responses against LCMV. Collectively, these results underscore the pivotal role of Gal-4 in modulating CD8+ T cell immunity and highlight its promise as a therapeutic target for the development of novel immunotherapeutics against cancer and viral diseases.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"7 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144521335","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":"miR-375 protects against acetaminophen-induced acute liver failure by orchestrating pharmacogene expression.","authors":"Yi Wang,Jinghua Liu,Sha Zhu,Shiliang Hu,Xiupeng Chen,Elisabet Mandon,Ngoc Tam Tran,Songbo Zhang,Yangran Qi,Hong Ma,Ran He,Yu Cao,Qin Su,Thomas L Gallagher,Zixiu Ii,Chan Zhou,Philip W L Tai,Guangping Gao,Jun Xie","doi":"10.1016/j.ymthe.2025.06.038","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.038","url":null,"abstract":"Acetaminophen (APAP) overdose is a leading cause of acute liver failure (ALF), primarily through the excessive production of N-acetyl-p-benzoquinone imine (NAPQI). N-acetylcysteine (NAC) is the FDA-approved treatment for APAP overdose, but there is a growing interest in microRNAs as potential therapeutic agents. We delivered miR-375 ectopically via a liver-tropic adeno-associated virus serotype 8 (AAV8) and demonstrated its potent protection in a murine model of APAP overdose-induced ALF. Slc16a2, Cyb5b, and Acsl5 were identified as critical targets acting synergistically to mitigate toxicity. Liver transcriptome revealed that miR-375 overexpression or silencing of the targets of miR-375 increased Gstm3 expression in mice. AAV8-mediated Gstm3 expression protects against APAP-ALF, and the protection was further enhanced by disrupting the expression of Cyp2e1. Additionally, CYP2E1 and GSS, which contribute to APAP detoxification, were down- and upregulated by miR-375, respectively. These findings suggest that miR-375 prevents APAP-ALF by orchestrating the expression of pharmacogenes and enhancing glutathione synthesis. We conclude that miR-375 and its targets are promising therapeutic targets for APAP-ALF.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"467 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533477","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":"Circulating urobilinogen contributes to Inflammation, Intestinal Permeability and corticosteroid non-response in Severe Alcohol-associated Hepatitis.","authors":"Manisha Yadav,Abhishak Gupta,Babu Mathew,Gaurav Tripathi,Nishu Dalal,Neha Sharma,Pushpa Yadav,Gaurav Yadav,Rita Singh,Vasundhra Bindal,Rimsha Saif,Sanju Yadav,Nupur Sharma,Sushmita Pandey,Sadam H Bhat,Ravinder Singh,Jitender Kumar,Manish Kushwaha,Tahseen Khan,Narendra Kumar Sharma,Ashima Bhaskar,Ved Prakash Dwivedi,Anil Kumar,Niraj Kumar,Dinesh Mani Tripathi,Nirupama Trehanpati,Anupama Kumara,Shvetank Sharma,Shiv Kumar Sarin,Jaswinder Singh Maras","doi":"10.1016/j.ymthe.2025.06.041","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.041","url":null,"abstract":"Severe alcohol-associated hepatitis (SAH) is a life-threatening condition with high mortality rates and poor response to prednisolone therapy. Identifying reliable early predictors of therapy response and survival is critical. Plasma metabolomics was conducted on 70 SAH patients (50 responders, 20 non-responders) to identify biomarkers for non-response and early mortality. These findings were validated in a cohort of 153 patients and an independent cohort of 245 using high resolution mass spectrometry, machine learning, and severity indices. Temporal metabolic changes indicated interactions between the host and microbiome, with a focus on inflammation and intestinal permeability. Plasma metabolomics revealed that non-responders had significantly higher urobilinogen levels (3.6-fold change). Additionally, a decrease in alpha/beta diversity and temporal metabolic inactivity characterized non-responders. Plasma urobilinogen levels predicted non-response (AUC>0.97) and identified non-survivors (AUC=0.94) with a threshold of >0.07 mg/ml. Urobilinogen levels correlated with bacterial peptides belonging to Firmicutes and Proteobacteria, neutrophil activation, oxidative stress, and pro-inflammatory cytokine production. These changes contributed to non-response by increasing glucocorticoid receptor β expression and compromising intestinal permeability. Fecal microbiota transplantation decreased urobilinogen levels by reducing bilirubin reductase gene-containing microbiota. Plasma urobilinogen >0.07 mg/ml could predict early mortality, and modulation of the gut microbiome may improve outcomes in SAH patients.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"65 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144521363","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":"Epigen-Mediated Mechanisms to Alleviate Glucose Homeostasis Disruptions in Diet-Induced Obese and STZ-Induced Diabetic Mice.","authors":"Ka-Ying Chan,Chu-Jun Deng,Dilun Chen,Tak-Ho Lo,Shiqi Jia,Pauline Po Yee Lui,Chi-Ming Wong","doi":"10.1016/j.ymthe.2025.06.044","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.044","url":null,"abstract":"Epidermal growth factor receptor (EGFR) plays a crucial role in cellular processes such as development and tissue repair, with dysregulation linked to various diseases, including those affecting energy metabolism. Previous studies have reported that EGFR ligands enhance glucose homeostasis through various mechanisms across different tissues. However, epigen, the latest EGFR ligand, has not been thoroughly investigated regarding its impact on energy metabolism. In this study, we employed both in vivo gain-of-function and loss-of-function approaches to investigate the role of epigen in metabolic regulation using diet-induced obesity (DIO) and streptozotocin (STZ)-induced diabetic mice. Our findings, which align with previous research on other EGFR ligands, provide the first evidence that epigen is crucial for glucose homeostasis. It promotes the release of endogenous insulin, enhances glucose uptake in adipocytes and muscle, improves glycolysis and respiration utilization in adipose tissues of DIO mice, and increases pancreatic beta cell mass in STZ-induced diabetic mice. Overall, our findings suggest that epigen could be a potential therapeutic target for managing both type 2 and type 1 diabetes, warranting further exploration in clinical settings.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"19 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533495","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":"Cardiac safety of fordadistrogene movaparvovec gene therapy in Duchenne muscular dystrophy: Initial observations from a phase 1b trial","authors":"Sarah P. Sherlock, Daniel I. Levy, Avery McIntosh, Perry B. Shieh, Edward C. Smith, Tara G. McDonnell, Kelly A. Ryan, Marielle Delnomdedieu, Michael Binks, Ashwin K. Lal, Russell J. Butterfield","doi":"10.1016/j.ymthe.2025.06.031","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.031","url":null,"abstract":"Fordadistrogene movaparvovec (FM; PF-06939926) is a recombinant adeno-associated virus serotype-9 gene-replacement construct containing a mini-dystrophin transgene, in development for Duchenne muscular dystrophy (DMD). We present findings of cardiac safety assessments in DMD participants during a 1-year follow-up from an ongoing, phase 1b, multicenter, single-arm, open-label trial of low- and high-dose FM. Cardiac troponin-I (cTn-I) levels and cardiac magnetic resonance imaging (cMRI) measures were obtained from 19 ambulatory participants (n=3, low-dose; n=16, high-dose; median age 8.8 years), and three non-ambulatory participants (high-dose; median age 15.1 years). Six ambulatory and three non-ambulatory participants had cTn-I levels above the upper limit of normal (ULN) at baseline. Of these, one ambulatory participant and two non-ambulatory participants had cTn-I levels >3x the baseline level during the first year following infusion. At 1-year post-infusion, mean (±SD) change from baseline in left ventricular ejection fraction (LVEF) was -0.9%±4.0% in ambulatory participants, and −3.1%±1.8% in non-ambulatory participants. One 16-year-old non-ambulatory DMD participant experienced fatal cardiogenic shock 6 days after high-dose of FM. With the exception of participants with DMD with advanced cardiac fibrosis, assessments of cTn-I, LVEF by cMRI, and progression of late gadolinium enhancement suggest low cardiac toxicity from FM in ambulatory DMD participants in this study.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"36 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516037","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 NLRP3/caspase-1/GSDMD to treat inner ear injury from labyrinthine hemorrhage","authors":"Qiong Wu, Minwei Xu, Yuan Yao, Tianyu Gong, Qin Zhang, Yulian Jin, Jun Yang, Qing Zhang","doi":"10.1016/j.ymthe.2025.06.034","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.034","url":null,"abstract":"Sudden sensorineural hearing loss (SSNHL) is a prevalent condition in otolaryngology with poorly understood mechanisms. Inner ear labyrinthine hemorrhage (IELH) is a potentially significant cause. Our study focused on the NLR family pyrin domain containing 3 (NLRP3) inflammasome activation following IELH and the protective role of the NLRP3 inhibitor CY-09. In mice with IELH, significant increases in hearing thresholds and vestibular dysfunction were observed compared to control groups. The activation of the NLRP3 inflammasome and other pro-inflammatory factors were markedly elevated, leading to potential damage in cochlear and vestibular hair cells via the Gasdermin D (GSDMD)-mediated pyroptosis pathway. Treatment with CY-09 significantly ameliorated hearing loss and vestibular dysfunction via inhibition of the NLRP3 inflammasome and associated cell pyroptosis. These results highlight the critical roles of the NLRP3 inflammasome and pyroptosis in IELH-induced SSNHL and suggest the NLRP3/caspase-1/GSDMD pathway as a therapeutic target for managing this condition. This study offers a new theoretical basis for the potential clinical management of SSNHL.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"10 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516045","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":"Complement Activation in a Phase Ib Study of Fordadistrogene Movaparvovec for Duchenne Muscular Dystrophy","authors":"Barry J. Byrne, Russell J. Butterfield, Perry B. Shieh, Edward C. Smith, Christoph Licht, Michael Binks, Sandra Casinghino, Marielle Delnomdedieu, Kodihalli C. Ravindra, Tara McDonnell, Kelly Ryan, Martin Schulz, Qi Shen, Heliang Shi, Madhu P. Sirivelu, Vishal S. Vaidya, Laurence Whiteley, Daniel I. Levy","doi":"10.1016/j.ymthe.2025.06.032","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.032","url":null,"abstract":"Thrombotic microangiopathy (TMA) has been reported as an uncommon but severe adverse effect of recombinant adeno-associated virus (rAAV)-based gene therapy. Here, we describe in detail the occurrences of clinically evident TMA following infusion of the rAAV9-based therapy fordadistrogene movaparvovec (1 or 3 x 10<ce:sup loc=\"post\">14</ce:sup> vg/kg) in 22 participants with Duchenne muscular dystrophy (DMD). Three participants experienced clinical evidence of TMA. Platelet levels rapidly decreased 7-10 days post-infusion, together with C3 and C4 depletion and elevated C5b-9 after ∼7 days. Peak vector blood concentration was observed for 4-7 days, and Type 1 interferon cytokine levels increased within 2-7 days. Each affected participant was hospitalized, received supportive care and anti-complement therapy. Anti-AAV9 IgM and IgG were detected within days post-infusion, and participants with TMA demonstrated a particularly rapid rise of neutralizing antibodies and total antibody to AAV9 in the first 1–2 weeks post-infusion. Limited early time points from other participants were not assessed for complement activation. With appropriate monitoring of early time points following AAV exposure, TMA can be successfully managed. However, these early events should be considered related to the benefit-risk profile when using rAAV-based gene therapy for the treatment of DMD. <ce:inter-ref xlink:href=\"http://ClinicalTrials.gov\" xlink:type=\"simple\">ClinicalTrials.gov</ce:inter-ref> identifier: NCT03362502.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"19 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516073","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}