Molecular Therapy最新文献_第3页

miR-124 delivery to the hippocampus reduces excitability, enhances neurogenesis and affects microglia in a model of Alzheimer’s disease 在阿尔茨海默病模型中，向海马体递送miR-124可降低兴奋性，增强神经发生并影响小胶质细胞

IF 12.4 1区医学

Molecular Therapy Pub Date : 2026-10-12 DOI: 10.1016/j.ymthe.2026.10.001

Oliver Polzer,Léa Salette,Mae van Wijhe,Talya Levi Siva,Aleksandra Tsonkova,Ayinde Swildens,Rosa E. Randoe,Dilara Ayyildiz,Pascal Chameau,Paul J. Lucassen,Evgenia Salta,Carlos P. Fitzsimons

{"title":"miR-124 delivery to the hippocampus reduces excitability, enhances neurogenesis and affects microglia in a model of Alzheimer’s disease","authors":"Oliver Polzer,Léa Salette,Mae van Wijhe,Talya Levi Siva,Aleksandra Tsonkova,Ayinde Swildens,Rosa E. Randoe,Dilara Ayyildiz,Pascal Chameau,Paul J. Lucassen,Evgenia Salta,Carlos P. Fitzsimons","doi":"10.1016/j.ymthe.2026.10.001","DOIUrl":"https://doi.org/10.1016/j.ymthe.2026.10.001","url":null,"abstract":"MicroRNA-124 (miR-124) has been proposed as therapeutic candidate for Alzheimer's disease (AD), given its regulation of gene networks governing synaptic function, neurogenesis and inflammation. However, its functional role during early disease stages, and the cellular context-dependence of its effects, remain unclear. Here, we investigated the effects of targeted neuronal miR-124 delivery to the hippocampal dentate gyrus (DG) of AppNL-G-F mice. At an earlier ‘presymptomatic’ stage, miR-124 reduced intrinsic excitability of mature granule neurons and induced subtle changes in dendritic architecture. Integrative transcriptomic analyses revealed that predicted miR-124 targets were enriched among downregulated genes involved in synapse organization and cell junction assembly. At the same time, miR-124 increased the number of immature neurons and microglia, indicating structural and functional remodeling of the DG. At a later ‘symptomatic’ disease stage, where AD pathology is established, neuronal miR-124 supplementation reduced DG Aβ40 and Aβ42 levels and decreased local amyloid plaque burden, while also altering the plaque-associated microglial response. Together, these findings identify neuronal miR-124 as a context- and disease-stage-dependent regulator of the DG microenvironment and demonstrate effects extending from neuronal function to other cellular populations and local AD-associated pathology.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"38 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151815","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

News from Biotech 生物科技新闻

IF 12.4 1区医学

Molecular Therapy Pub Date : 2026-10-12 DOI: 10.1016/j.ymthe.2026.10.011

引用次数: 0

Intramuscular Non-replicating Tiantan Vaccinia Drives Superior Antibody Maturation and Sterilizing Protection Against Lethal Orthopoxvirus Challenge in Mice. 肌内非复制性天坛牛痘在小鼠中促进抗体成熟和对致命正痘病毒攻击的绝育保护。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-10-09 DOI: 10.1016/j.ymthe.2026.10.008

Yawei Wang, Changcheng Wu, Baoying Huang, Shuting Huo, Jingbin Huang, Juan Ma, Yujie Jiang, Liye Jin, Shiyuan Liu, Wenling Wang, Yao Deng, Wenjie Tan

{"title":"Intramuscular Non-replicating Tiantan Vaccinia Drives Superior Antibody Maturation and Sterilizing Protection Against Lethal Orthopoxvirus Challenge in Mice.","authors":"Yawei Wang, Changcheng Wu, Baoying Huang, Shuting Huo, Jingbin Huang, Juan Ma, Yujie Jiang, Liye Jin, Shiyuan Liu, Wenling Wang, Yao Deng, Wenjie Tan","doi":"10.1016/j.ymthe.2026.10.008","DOIUrl":"https://doi.org/10.1016/j.ymthe.2026.10.008","url":null,"abstract":"The global resurgence of orthopoxviruses, particularly MPXV, necessitates safe yet highly protective vaccines. Here, we systematically evaluated a non-replicating Tiantan vaccinia virus (NTV)-derived from the historically efficacious vaccinia Tiantan strain-across intramuscular (IM), subcutaneous (SC), and dose-sparing intradermal (ID) routes in lethal murine models. While all regimens elicited robust polyfunctional T cells, cross-neutralizing antibodies against MPXV, VTT, and ECTV, and protective immunity against standard lethal VACV-WR and ECTV challenges, under extreme viral exposure (70 LD50) and long-term challenge (16 week), only full-dose NTV-IM among the non-replicating regimens conferred complete sterilizing cross-protection, whereas the SC and dose-sparing ID regimens exhibited breakthrough virologic failure. Mechanistically, splenic transcriptomics revealed that NTV-IM uniquely enriched for a prominent germinal center (GC) transcriptional profile (marked by Aicda). This GC signature was multi-dimensionally validated by RT-qPCR, flow cytometry, and immunofluorescence, confirming robust expansion of GC B cells (CD95+GL7+) and highly organized follicular architecture in lymphoid organs. This optimized GC response closely correlated with superior affinity maturation and class-switch recombination, aligning with the production of the highest titers of IgG and cross-neutralizing antibodies in NTV-IM while without inducing systemic inflammation. Collectively, these findings highlight route-dependent immune programming, establishing NTV-IM as a scalable, next-generation orthopoxvirus vaccine candidate.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148409","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

Inhibition of CCN2/CTGF prevents heterotopic ossification in fibrodysplasia ossificans progressiva. 抑制CCN2/CTGF可防止进行性骨化纤维发育不良患者异位骨化。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-10-09 DOI: 10.1016/j.ymthe.2026.09.040

Alexandre Deber, Nicole Farfán-Beltrán, Marta Ferrer-Roig, Joel Moro, Meritxell Rovira, Jose Luis Rosa, Francesc Ventura

{"title":"Inhibition of CCN2/CTGF prevents heterotopic ossification in fibrodysplasia ossificans progressiva.","authors":"Alexandre Deber, Nicole Farfán-Beltrán, Marta Ferrer-Roig, Joel Moro, Meritxell Rovira, Jose Luis Rosa, Francesc Ventura","doi":"10.1016/j.ymthe.2026.09.040","DOIUrl":"10.1016/j.ymthe.2026.09.040","url":null,"abstract":"Heterotopic ossification (HO) is the aberrant formation of endochondral bone within soft tissues, triggered by trauma, burns, or the congenital disorder fibrodysplasia ossificans progressiva (FOP). In this study, we demonstrate that mesenchymal progenitors (MPs) harboring the ACVR1wt/R206H mutation exhibit resistance to apoptosis, likely contributing to their pathological accumulation during FOP flare-ups. Transcriptomic analysis of these mutant MPs reveals dysregulation of genes associated with fibrosis and osteogenic differentiation and elevated expression of matricellular signaling proteins, most notably Ccn2/Ctgf. We further show, using both genetic and pharmacological approaches, that Ccn2 induction in ACVR1wt/R206H MPs is driven by the cooperative interaction between SMAD1 and YAP-TEAD at the Ccn2 promoter. Osteochondrogenic specification of ACVR1wt/R206H MPs was blocked by the CCN2-neutralizing antibody pamrevlumab. Moreover, pamrevlumab not only partially suppresses activin A-regulated extracellular matrix organization and transforming growth factor β (TGF-β) family transcriptional programs in mutant MPs but also significantly ameliorates ectopic bone formation in an FOP mouse model. Collectively, these findings identify CCN2/CTGF as a critical mediator of HO and support its inhibition as a potential therapeutic strategy for FOP and disorders characterized by pathological ossification.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149149162","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

Dendrimer Delivered shRNA Targeting the CCL20-CCR6 Axis Suppresses Complement-Mediated Microglial Synaptic Pruning and Ameliorates Chronic Neuroinflammation After Repetitive Traumatic Brain Injury. 靶向CCL20-CCR6轴的树突递送shRNA抑制补体介导的小胶质突触修剪并改善重复性创伤性脑损伤后的慢性神经炎症

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-10-09 DOI: 10.1016/j.ymthe.2026.10.002

Karthick Mayilsamy, Parthvi Bharatkumar Patel, Ryan Green, Sashank Bikkasani, Kristina Tosi, Shreyasi Majumdar, Santosh Kumar Prajapati, Eleni Markoutsa, Tiara Wolf, Jennifer Guergues, Stanley M Stevens, Alison Willing, Shyam Mohapatra, Subhra Mohapatra

{"title":"Dendrimer Delivered shRNA Targeting the CCL20-CCR6 Axis Suppresses Complement-Mediated Microglial Synaptic Pruning and Ameliorates Chronic Neuroinflammation After Repetitive Traumatic Brain Injury.","authors":"Karthick Mayilsamy, Parthvi Bharatkumar Patel, Ryan Green, Sashank Bikkasani, Kristina Tosi, Shreyasi Majumdar, Santosh Kumar Prajapati, Eleni Markoutsa, Tiara Wolf, Jennifer Guergues, Stanley M Stevens, Alison Willing, Shyam Mohapatra, Subhra Mohapatra","doi":"10.1016/j.ymthe.2026.10.002","DOIUrl":"https://doi.org/10.1016/j.ymthe.2026.10.002","url":null,"abstract":"Repetitive traumatic brain injury (rTBI) induces persistent microglial activation and chronic neuroinflammation, yet the upstream signals driving long-term synaptic injury remain unclear. In this study, we identify the CCL20-CCR6 chemokine axis as a critical regulator of sustained microglial activation and complement-dependent synaptic loss after rTBI. Proteomic profiling at 30 days post-injury (dpi) showed broad normalization of complement-linked inflammatory and synaptic pathways in the cortex and hippocampus, underscoring a mechanistic link between chemokine signaling, microglial activation, and synaptic vulnerability. To therapeutically target this axis, we developed a dendrimer-based shRNA platform (shCombo-DPX) that simultaneously silences CCL20 and CCR6. Intranasal and intravenous delivery in rTBI mice effectively reduced CCL20-CCR6 expression, attenuated chronic microgliosis and astrogliosis, and suppressed complement activation. Treatment limited microglial synaptic engulfment, preserved synaptic proteins, restored BDNF levels, and improved motor, anxiety-related, and cognitive outcomes. In microglia-neuron coculture systems, CCL20 silencing reduced LPS-induced complement signaling and prevented synaptic loss, neuronal apoptosis, and BDNF depletion. Conversely, exposure to recombinant CCL20 induced dendritic degeneration, caspase-3 activation, microglial reactivity, complement dysregulation, and synaptic injury both in vitro and in vivo. Collectively, these findings establish CCL20-CCR6 as a key upstream driver of chronic complement-mediated synaptic degeneration after rTBI and support dendrimer-delivered shRNA therapy as a targeted strategy to mitigate long-term neurodegeneration.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137615","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

Five decades of gene therapy innovation and regulation in the US and EU: a historical analysis. 美国和欧盟50年的基因治疗创新和监管：历史分析。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-10-09 DOI: 10.1016/j.ymthe.2026.10.009

Thomas Wessel van de Voort, Jarno Hoekman, Elisabeth Henrica Maria Moors, Lourens Theo Bloem

{"title":"Five decades of gene therapy innovation and regulation in the US and EU: a historical analysis.","authors":"Thomas Wessel van de Voort, Jarno Hoekman, Elisabeth Henrica Maria Moors, Lourens Theo Bloem","doi":"10.1016/j.ymthe.2026.10.009","DOIUrl":"https://doi.org/10.1016/j.ymthe.2026.10.009","url":null,"abstract":"The development of gene therapy is characterized by expectations of patient benefits, but challenges persist, including rapid technological change and, typically, small target populations. This has thus far resulted in relatively few gene therapies reaching the market and benefiting patients. Regulation plays a central role in shaping how these challenges are addressed and how gene therapies reach patients. This study investigated how gene therapy regulatory regimes have developed in the US and EU between 1973 and 2025, and how gene therapy regulation events contributing to regulatory regime building have shaped gene therapy innovation outcomes. We conducted a scoping review of scientific literature and expert interviews, which together characterized all authorized gene therapies in the US and EU. We constructed and validated timelines of gene therapy regulation events in these regimes. Interviewees attributed observed differences in the timelines to factors specific to gene therapy regulation and to the broader medicines regulatory system. Regulatory leadership in gene therapy has shifted repeatedly between the US and the EU, reflecting differences in how each jurisdiction responds to scientific and technological uncertainty, societal risks and needs, and commercial pressure.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147751","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

Sustained Relief of Chronic Pain via a Nav1.7-Targeting ASO–siRNA Conjugate in Rats 通过nav1.7靶向ASO-siRNA偶联物持续缓解大鼠慢性疼痛

IF 12.4 1区医学

Molecular Therapy Pub Date : 2026-10-08 DOI: 10.1016/j.ymthe.2026.09.039

Bin Ren,Chang Yu,Weiqin Yin,Zhuangchuan Yuan,Hongyu Chen,Yicao Liu,Bin Fang,Chen Zhang,Jianming Wu,Suyuan Liu,Lianchao Gao,Zhiwei Cao,Qingqing Yu,Xin Qiu,Peixia Yu,Guohao Wang

{"title":"Sustained Relief of Chronic Pain via a Nav1.7-Targeting ASO–siRNA Conjugate in Rats","authors":"Bin Ren,Chang Yu,Weiqin Yin,Zhuangchuan Yuan,Hongyu Chen,Yicao Liu,Bin Fang,Chen Zhang,Jianming Wu,Suyuan Liu,Lianchao Gao,Zhiwei Cao,Qingqing Yu,Xin Qiu,Peixia Yu,Guohao Wang","doi":"10.1016/j.ymthe.2026.09.039","DOIUrl":"https://doi.org/10.1016/j.ymthe.2026.09.039","url":null,"abstract":"Chronic pain affects a large global population, yet safe, long-acting analgesics remain limited. Nav1.7 is a genetically validated pain target, but conventional small-molecule approaches have had limited success. Therapeutic oligonucleotides-antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs)-offer selective and durable gene silencing. Here, we developed N02C0702, an ASO–siRNA conjugate (ASC) that achieves efficient Nav1.7 knockdown and demonstrates greater activity than the individual ASO (N02A114) and siRNA (N02S154) components at both mRNA and protein levels, without requiring additional delivery systems. In rat models, N02C0702 was associated with reduced pain behaviors in both complete Freund’s adjuvant-induced inflammatory pain and spinal nerve ligation-induced neuropathic pain. A single intrathecal administration produced effects lasting up to 28 and 56 days in the respective models. These findings support Nav1.7 as a relevant analgesic target and suggest that the ASC platform may offer a promising approach for chronic pain and other CNS-related conditions.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"32 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124065","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 RGD-directed melittin/anti-41BB dual-lock prodrug safely reinvigorates robust anti-tumor immunity rgd导向的蜂毒素/抗41bb双锁前药安全重新激活强大的抗肿瘤免疫

IF 12.4 1区医学

Molecular Therapy Pub Date : 2026-10-08 DOI: 10.1016/j.ymthe.2026.09.041

Wen Zhu,Ying Qin,Yuntian Han,Gen Qi,Qiongya Zeng,Luyao Song,Zixiang Li,Haoran Deng,Xinyu Deng,Kaijuan Yi,Wei Yang,Yan Wang,Xiaojia Chen,Huili Lu

{"title":"A RGD-directed melittin/anti-41BB dual-lock prodrug safely reinvigorates robust anti-tumor immunity","authors":"Wen Zhu,Ying Qin,Yuntian Han,Gen Qi,Qiongya Zeng,Luyao Song,Zixiang Li,Haoran Deng,Xinyu Deng,Kaijuan Yi,Wei Yang,Yan Wang,Xiaojia Chen,Huili Lu","doi":"10.1016/j.ymthe.2026.09.041","DOIUrl":"https://doi.org/10.1016/j.ymthe.2026.09.041","url":null,"abstract":"The clinical application of agonist antibodies that provide a second signal for T cell activation, such as anti-41BB, is severely hampered by their systemic immune-related toxicity. Here, we introduce a novel dual-lock strategy, which involves the development of a prodrug comprising the melittin mutant MP5/41BB agonist antibody/RGD, named MmHm4R, to address this issue. MmHm4R consists of the lytic peptide MP5 and a human IgG1 hinge domain fused to the N-terminus of the 41BB agonist antibody via cleavable peptide linkers sensitive to tumor-enriched proteinases, and RGD peptides fused to the C-terminus to further enhance tumor specificity. This strategy effectively masks both MP5 and anti-41BB antibody in circulation, significantly reducing hemolysis and immune-related adverse events. Upon cleavage of the linkers in the tumor, MP5 and anti-41BB antibody are released from MmHm4R and restore their activities, resulting in significantly reduced toxicity and superior antitumor efficacy. Mechanistically, MP5 induces tumor cell lysis, enhances antigen exposure, and stimulates 41BB expression in intratumoral lymphocytes, thereby synergizing with anti-41BB antibody. Overall, our study highlights the clinical potential of the dual-lock prodrug strategy, which effectively combines the potent effects of immune agonists and tumor lytic peptides to develop safer and more effective cancer immunotherapies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"7 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124066","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

Breakthroughs in cell and gene therapy: Innovations in therapeutic modalities for the CNS, targeted delivery, translation, and CMC 细胞和基因治疗的突破：中枢神经系统、靶向递送、翻译和CMC治疗方式的创新

IF 12.4 1区医学

Molecular Therapy Pub Date : 2026-10-08 DOI: 10.1016/j.ymthe.2026.09.026

Allison M. Bradbury

引用次数: 0

Fifteen miRNAs, one network: Rethinking single-target therapy for aggressive cancer. 15个mirna，一个网络：重新思考侵袭性癌症的单靶点治疗。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-10-07 Epub Date: 2026-08-29 DOI: 10.1016/j.ymthe.2026.08.029

Jürgen Wittmann

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