Molecular Therapy最新文献_第8页

TOX-induced lnc-SUMF2-8 compromises antitumor function and anti-PD-1 response of CD8+ T cells via lysosome-dependent degradation of TCF-1. xox诱导的lnc-SUMF2-8通过溶酶体依赖的TCF-1降解破坏CD8+ T细胞的抗肿瘤功能和抗pd -1应答。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-10 DOI: 10.1016/j.ymthe.2025.09.006

Pan Jiang,Dongming Chen,Jialin Chen,Junbin Wu,Yumin Zhong,Sijing Huang,Xiaoxin Mu,Xiaojie Lu,Xiaochen Wang

{"title":"TOX-induced lnc-SUMF2-8 compromises antitumor function and anti-PD-1 response of CD8+ T cells via lysosome-dependent degradation of TCF-1.","authors":"Pan Jiang,Dongming Chen,Jialin Chen,Junbin Wu,Yumin Zhong,Sijing Huang,Xiaoxin Mu,Xiaojie Lu,Xiaochen Wang","doi":"10.1016/j.ymthe.2025.09.006","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.006","url":null,"abstract":"The reduction of TCF-1 during CD8+ T cell exhaustion leads to attenuated antitumor activity and diminished responsiveness to immune checkpoint inhibitors. However, how TCF-1 is downregulated remains unclear. Here, we showed that during CD8+ T cell exhaustion, lnc-SUMF2-8, induced by transcription factor TOX, can bind to cytosolic TCF-1, and direct it to the lysosome for degradation. The reduction of TCF-1 promotes Texprog differentiation into Texint/eff and further drives functional Tex cells into a fully dysfunctional Texterm state. We demonstrated that TCF-1 reduction during T cell exhaustion is initiated by lnc-SUMF2-8-dependent lysosomal degradation of TCF-1 protein, followed by transcriptional suppression of TCF7 mRNA. Deletion of lnc-SUMF2-8 blocks lysosomal TCF-1 degradation, which maintains stable TCF-1 levels in Tex cells, thereby expands the anti-PD-1-responsive Texprog cells, and enhances the persistence of functional CD8+ T cells. Our findings suggest targeting lnc-SUMF2-8 could enhance the anti-tumor CD8+ T-cells function and synergistically improve the efficacy of anti-PD-1 treatment and CAR-T cell therapies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"135 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032161","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}

引用次数: 0

Complement C4b as a Key Mediator of Synaptic Loss and Cognitive Decline in Brain Aging. 补体C4b是脑衰老中突触丧失和认知能力下降的关键介质。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-09 DOI: 10.1016/j.ymthe.2025.09.005

Yi Zheng,Ting Liu,Lunan Luo,Feiyang Li,Cheng Tang,Changling Xu,Cheng Chen,Lu Yang,Ying Xiao,Ziyan Wang,Qing Yuan,Min Zheng,Hao Li,Jing Yang

{"title":"Complement C4b as a Key Mediator of Synaptic Loss and Cognitive Decline in Brain Aging.","authors":"Yi Zheng,Ting Liu,Lunan Luo,Feiyang Li,Cheng Tang,Changling Xu,Cheng Chen,Lu Yang,Ying Xiao,Ziyan Wang,Qing Yuan,Min Zheng,Hao Li,Jing Yang","doi":"10.1016/j.ymthe.2025.09.005","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.005","url":null,"abstract":"Brain aging is a major risk factor for cognitive decline and neurodegenerative diseases, driven by synaptic loss, reduced synaptic function, and inflammation. However, the molecular mechanisms underlying these dysfunctions remain unclear. Here, we conducted comparative transcriptomic analyses of brain regions (cortex and hippocampus) and kidney tissues, a peripheral organ with documented age-related dysfunction. Our study uncovered common and tissue-specific aging molecular signatures, highlighting the complexity of aging-related gene expression dynamics. Notably, we identified complement component C4b as a key mediator linking inflammation to synaptic degeneration. Experimental modulation of C4b expression in aged neurons restored synaptic integrity and neuronal activity in vitro, while in vivo CRISPR-Cas13d-mediated suppression enhanced synaptic density and improved cognitive performance in aged mice. These findings establish C4b as a critical driver of age-associated cognitive decline and a promising therapeutic target for mitigating neurodegenerative changes.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"33 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032056","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}

引用次数: 0

AAV-mediated delivery of a broadly neutralizing anti-flavivirus antibody protects against dengue and Zika viruses in a mouse model. 在小鼠模型中，aav介导的广泛中和性抗黄病毒抗体的递送可预防登革热和寨卡病毒。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-09 DOI: 10.1016/j.ymthe.2025.09.007

Hui-Ying Ko,Ya-Yuan Li,Yogy Simanjuntak,Han-Peng Yu,Ming-Tsai Chiang,Che-Yu Lee,Jian-Jong Liang,Yi-Ling Lee,Cheng-Pu Sun,Po-Sheng Wang,Pei-Yun Shu,Tsai-Ying Yen,Mi-Hua Tao,Yi-Ling Lin

{"title":"AAV-mediated delivery of a broadly neutralizing anti-flavivirus antibody protects against dengue and Zika viruses in a mouse model.","authors":"Hui-Ying Ko,Ya-Yuan Li,Yogy Simanjuntak,Han-Peng Yu,Ming-Tsai Chiang,Che-Yu Lee,Jian-Jong Liang,Yi-Ling Lee,Cheng-Pu Sun,Po-Sheng Wang,Pei-Yun Shu,Tsai-Ying Yen,Mi-Hua Tao,Yi-Ling Lin","doi":"10.1016/j.ymthe.2025.09.007","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.007","url":null,"abstract":"Flaviviruses contain many important human pathogens such as dengue virus (DENV) and Zika virus (ZIKV), for which effective and safe vaccines are still lacking, mainly because pre-existing cross-reactive non-neutralizing antibodies may exacerbate subsequent infections with related flaviviruses. To overcome this challenge, we explore Vectored ImmunoProphylaxis (VIP), which involves the passive transfer of protective antibody genes via viral vectors for in vivo expression. We utilized a recombinant adeno-associated virus (rAAV) to express a broad anti-flavivirus neutralizing human monoclonal antibody, bnAb 752-2C8, and tested its protection against four serotypes of DENV and ZIKV. The bnAb 752-2C8 antibody gene was cloned into an AAV plasmid and the recombinant AAV (rAAV) was successfully generated to express bnAb 752-2C8. After a single dose of rAAV administration into AGB6 mice, the human antibody concentrations increased to ∼1000 μg/mL and remained elevated for at least 48 weeks. VIP-treated mice were completely protected from a lethal challenge of DENVs and ZIKV, while control mice without bnAb 752-2C8 all succumbed to infection. Our results demonstrate the effectiveness of rAAV in delivering bnAb 752-2C8 for long-term protection against multiple flaviviruses, providing a potential strategy to control flavivirus infections and possibly other viral diseases.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"49 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032058","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}

引用次数: 0

Restoring Chloride Efflux in Cystic Fibrosis with TMEM16a Antisense Oligonucleotides. 利用TMEM16a反义寡核苷酸恢复囊性纤维化中的氯化物外排。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-08 DOI: 10.1016/j.ymthe.2025.08.045

Christie Mitri,Nathalie Rousselet,Pauline Bardin,Madara Dias Wickramanayaka,Tobias Foussignière,Gabrielle Dupuis,Marion Leblanc,Victoire Gournet,Florence Sonneville,Harriet Corvol,Olivier Tabary

{"title":"Restoring Chloride Efflux in Cystic Fibrosis with TMEM16a Antisense Oligonucleotides.","authors":"Christie Mitri,Nathalie Rousselet,Pauline Bardin,Madara Dias Wickramanayaka,Tobias Foussignière,Gabrielle Dupuis,Marion Leblanc,Victoire Gournet,Florence Sonneville,Harriet Corvol,Olivier Tabary","doi":"10.1016/j.ymthe.2025.08.045","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.08.045","url":null,"abstract":"Patients with cystic fibrosis (CF) who are non-responsive to treatments due to specific mutations need alternative CFTR-independent therapies. This study aims to assess the impact of TMEM16a expression by a specific oligonucleotide (TMEM16a ASO) on dysregulated parameters in CF, which will help prepare for preclinical studies. In this study, we analyzed the effects of TMEM16a oligonucleotide within a CF context by evaluating the impact, optimal administration route, toxicity, and specificity in primary cells and various mouse models. The oligonucleotide enhances TMEM16a activity, increases Cl--efflux, and improves mucociliary clearance in cells from all individuals tested with CF. TMEM16a antisense oligonucleotide (ASO) effect is detectable in mice 30 days after subcutaneous injection, enhances TMEM16a mRNA expression, and significantly extends the lifespan of CF mice. Acute administration of 50 times the effective dose showed no toxicity. Importantly, TMEM16a ASO is highly specific, not inducing inflammation or altering intracellular calcium mobilization and cell proliferation, instilling confidence in its potential effectiveness. Our study demonstrates that TMEM16a ASO can compensate for CFTR deficiency in CF models. Additionally, it's important to note that this strategy could apply to all CF patients, regardless of their CFTR mutation, thereby broadening the scope of treatment options for CF.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"87 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025424","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}

引用次数: 0

Immunology of RNA-based vaccines: the critical interplay between inflammation and expression. rna疫苗的免疫学：炎症和表达之间的关键相互作用。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-08 DOI: 10.1016/j.ymthe.2025.09.011

John S Tregoning,Ziyin Wang,Saranya Sridhar,Robin J Shattock,Frank DeRosa

{"title":"Immunology of RNA-based vaccines: the critical interplay between inflammation and expression.","authors":"John S Tregoning,Ziyin Wang,Saranya Sridhar,Robin J Shattock,Frank DeRosa","doi":"10.1016/j.ymthe.2025.09.011","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.011","url":null,"abstract":"Since its use during the COVID-19 pandemic, mRNA has emerged as a leading candidate vaccine platform for pandemic infections. A critical difference between RNA-encoded antigen and protein vaccines is that RNA-based vaccines require the antigen to be translated in the body, adding an important variable. Much of the research focus in the field has been on ways to increase expression, but inflammation plays a critical role. The vaccine delivered is a combination of the RNA and the formulation, so both elements need to be considered. Formulated RNA can act as a form of adjuvant but can also activate cellular pathways that inhibit expression. Expression and inflammation are interlinked, but independent - a deeper understanding of the quality and quantity of immune induction will help to develop more efficient RNA vaccines. Here we discuss factors that shape responses to RNA-based vaccines. These include the composition of the vaccine (the use of modified RNA bases, whether self-replicating or traditional mRNA, and critically, the formulation) and the type of cells which take up and translate the RNA. We then consider challenges presented by current generation RNA vaccines including clinical impact and how improved immunological understanding can inform the development of improved RNA vaccine platforms.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"138 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025423","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}

引用次数: 0

TAT-PBX1 fusion protein alleviates LPS-induced acute lung injury via AMPK-TFAM signaling activation. TAT-PBX1融合蛋白通过AMPK-TFAM信号激活减轻lps诱导的急性肺损伤。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-08 DOI: 10.1016/j.ymthe.2025.09.010

Ziyi Chen,Xiaomei Liu,Kuiyang Zuo,Ying Xin,Jinyu Liu

{"title":"TAT-PBX1 fusion protein alleviates LPS-induced acute lung injury via AMPK-TFAM signaling activation.","authors":"Ziyi Chen,Xiaomei Liu,Kuiyang Zuo,Ying Xin,Jinyu Liu","doi":"10.1016/j.ymthe.2025.09.010","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.010","url":null,"abstract":"Acute lung injury (ALI) represents a critical clinical challenge characterized by uncontrolled pulmonary inflammation and disrupted tissue homeostasis, often leading to severe respiratory dysfunction. Current pharmacological interventions and vaccines have demonstrated suboptimal clinical outcomes in modulating disease progression, highlighting the urgent need for innovative therapeutic strategies. A key pathophysiological feature of ALI involves dysregulation of redox homeostasis and excessive pulmonary inflammation. Based on PBX1's demonstrated capacity to mitigate reactive oxygen species (ROS)-induced cellular damage, we hypothesized its therapeutic potential for ALI management. Overexpression of PBX1 in A549 cells can alleviate the increase in tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6 levels caused by lipopolysaccharide (LPS). To circumvent the limitations associated with viral transduction while enabling efficient macromolecular delivery, we engineered a novel TAT-PBX1 fusion protein. In vivo, TAT-PBX1 effectively attenuated LPS-induced ROS accumulation and inflammatory cytokines, while preserving mitochondrial morphology. It restored ATP levels and NAD+/NADH ratio, upregulated PGC-1α/TFAM expression, and suppressed cGAS-STING pathway activation. Mechanistically, TAT-PBX1 targets AMPKγ2 to activate the AMPK-TFAM signaling pathway, exerting anti-inflammatory and lung-protective effects. These findings identify TAT-PBX1 as a promising therapeutic candidate for mitigating pathological responses in ALI.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"11 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025422","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}

引用次数: 0

Targeting O-GlcNAcylated METTL3 impedes MDS/AML progression via diminishing SRSF1 m6A modification. 靶向o - glcn酰化METTL3通过减少SRSF1 m6A修饰阻碍MDS/AML进展。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-05 DOI: 10.1016/j.ymthe.2025.08.042

Junjie Gou,Yi Wang,Jingjing Feng,Kaijing Chang,Kexin Wang,Jingjing Bi,Junqi Ge,Chongfu Zhao,Songdi Wu,Zengqi Tan,Feng Guan,Xiang Li

{"title":"Targeting O-GlcNAcylated METTL3 impedes MDS/AML progression via diminishing SRSF1 m6A modification.","authors":"Junjie Gou,Yi Wang,Jingjing Feng,Kaijing Chang,Kexin Wang,Jingjing Bi,Junqi Ge,Chongfu Zhao,Songdi Wu,Zengqi Tan,Feng Guan,Xiang Li","doi":"10.1016/j.ymthe.2025.08.042","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.08.042","url":null,"abstract":"N6-methyladenosine (m6A) modification, primarily regulated by methyltransferase-like protein 3 (METTL3), plays a pivotal role in RNA metabolism and leukemogenesis. However, the post-translational mechanisms governing METTL3 stability and function remain incompletely understood. Given the widespread occurrence of O-GlcNAcylation on nuclear and cytosolic proteins, we hypothesized that METTL3 might undergo O-GlcNAcylation, thereby influencing its stability and oncogenic function in myeloid malignancies. In this study, we found that METTL3 is O-GlcNAcylated in both myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) , and its expression positively correlates with O-GlcNAcylation levels. Functional assays demonstrated that O-GlcNAcylation enhances METTL3 protein stability and promotes leukemic cell survival. Mechanistically, O-GlcNAcylated METTL3 stabilizes mRNA of serine and arginine-rich splicing factor 1 (SRSF1), leading to increased expression of the anti-apoptotic protein MCL-1. This, in turn, suppresses apoptosis and supports MDS/AML cell viability. Targeting the O-GlcNAcylated form of METTL3 using a competitive peptide significantly inhibited MDS/AML progression in preclinical models. In conclusion, our findings reveal a novel O-GlcNAcylation-dependent mechanism that regulates METTL3 stability and oncogenic activity through the m6A-SRSF1-MCL1 axis, highlighting a potential therapeutic strategy for MDS and AML.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"24 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145007089","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}

引用次数: 0

A precision gene-engineered B cell medicine producing sustained levels of active factor IX for hemophilia B therapy. 一种精密基因工程B细胞药物产生持续水平的活性因子IX治疗血友病B。

IF 12 1区医学

Molecular Therapy Pub Date : 2025-09-05 DOI: 10.1016/j.ymthe.2025.09.001

Hanlan Liu, Swati Singh, Timothy J Mullen, Caroline Bullock, Sean Keegan, Troy Patterson, Sakshisingh Thakur, Amy Lundberg, Sol Shenker, Ryan Couto, Charuta Yadav, Shamael Dastagir, Lily Li, Wayne Bainter, Ella Liberzon, Connor R Malloy, Cicera R Lazzarotto, Toshiro K Ohsumi, Shalini Chilakala, Huei-Mei Chen, Rashmi Kshirsagar, Anja F Hohmann, Sean P Arlauckas, Adam Lazorchak, Chris Scull, Richard A Morgan

{"title":"A precision gene-engineered B cell medicine producing sustained levels of active factor IX for hemophilia B therapy.","authors":"Hanlan Liu, Swati Singh, Timothy J Mullen, Caroline Bullock, Sean Keegan, Troy Patterson, Sakshisingh Thakur, Amy Lundberg, Sol Shenker, Ryan Couto, Charuta Yadav, Shamael Dastagir, Lily Li, Wayne Bainter, Ella Liberzon, Connor R Malloy, Cicera R Lazzarotto, Toshiro K Ohsumi, Shalini Chilakala, Huei-Mei Chen, Rashmi Kshirsagar, Anja F Hohmann, Sean P Arlauckas, Adam Lazorchak, Chris Scull, Richard A Morgan","doi":"10.1016/j.ymthe.2025.09.001","DOIUrl":"10.1016/j.ymthe.2025.09.001","url":null,"abstract":"Hemophilia B gene therapy treatments have not addressed the need for predictable, durable, active, and redosable factor IX (FIX). Unlike conventional gene therapy, engineered B cell medicines (BCMs) are durable, redosable, and titratable and thus have the potential to address significant unmet needs in the hemophilia B treatment paradigm. BE-101 is an autologous BCM comprising expanded and differentiated B lymphocyte lineage cells genetically engineered ex vivo to secrete factor IX (FIX)-Padua. CRISPR-Cas9-mediated gene editing at the C-C chemokine receptor type 5 (CCR5) locus was used to facilitate transgene insertion of an adeno-associated virus 6-encoded DNA template via homology-directed repair. Transgene insertion did not alter B cell biology, viability, or differentiation into plasma cells. Appreciable levels of BE-101-derived FIX-Padua were detected within 1 day after IV administration in mice, and steady state was reached within 2 weeks and persisted for over 184 days. Redosing produced an increase in FIX-Padua production close to linear dose proportionality. Comprehensive genotoxicity analysis found no off-target issues of concern. No safety signals were observed in animal tolerability and Good Laboratory Practice toxicology studies. In conclusion, BE-101 produces sustained levels of active FIX-Padua with the ability to engraft without host preconditioning and with the potential for redosing and titratability.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.0,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008321","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}

引用次数: 0

Ablation of dysmorphic neurons is a safe and effective treatment for focal cortical dysplasia II. 畸形神经元消融是一种安全有效的治疗局灶性皮质发育不良II的方法。

IF 12 1区医学

Molecular Therapy Pub Date : 2025-09-03 Epub Date: 2025-05-27 DOI: 10.1016/j.ymthe.2025.05.023

Ying Xu, Jun Li, Zihao Wang, Rongrong Lu, Yingying Liu, Min Wang, Hao Li, Rui Zhao, Weijun Feng

{"title":"Ablation of dysmorphic neurons is a safe and effective treatment for focal cortical dysplasia II.","authors":"Ying Xu, Jun Li, Zihao Wang, Rongrong Lu, Yingying Liu, Min Wang, Hao Li, Rui Zhao, Weijun Feng","doi":"10.1016/j.ymthe.2025.05.023","DOIUrl":"10.1016/j.ymthe.2025.05.023","url":null,"abstract":"Focal cortical dysplasia type II (FCDII) is a leading cause of refractory epilepsy in children, yet treatment options remain limited. The most frequent genetic cause of FCDII is mosaic and somatic variants in genes of the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway, leading to hyperactivation of mTOR signaling. The presence of dysmorphic neurons (DNs) resulting from hyperactive mTOR signaling is critical for the development of epilepsy in FCDII. One critical therapeutic challenge and opportunity for FCDII is to selectively eliminate DNs. Here, we developed two strategies to specifically ablate DNs in FCDII mouse models, and the results demonstrate that DN ablation is sufficient to both prevent and eliminate epilepsy in mice. Moreover, the associated neurobehavioral abnormalities were also reversed following treatment. Therefore, our study provides proof-of-concept evidence that DN ablation is a highly promising approach for curing FCDII in the future.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4414-4430"},"PeriodicalIF":12.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174191","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}

引用次数: 0

From bench to bloodstream: Lipid nanoparticles drive on-demand CAR-T cells. 从工作台到血液：脂质纳米颗粒驱动按需CAR-T细胞。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-03 DOI: 10.1016/j.ymthe.2025.08.015

Carl H June,Haig Aghajanian

引用次数: 0