Molecular Therapy最新文献_第4页

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

引用次数: 0

Prothrombin recognition and conformational modulation by anti-thrombin anticoagulant aptamers. 凝血酶原识别和抗凝血酶抗凝适体的构象调节。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-10-07 Epub Date: 2026-07-24 DOI: 10.1016/j.ymthe.2026.07.042

Romualdo Troisi, Alessandro Cangiano, Nathan Cowieson, Vera Spiridonova, Nicola Pozzi, Pompea Del Vecchio, Luigi Paduano, Filomena Sica

{"title":"Prothrombin recognition and conformational modulation by anti-thrombin anticoagulant aptamers.","authors":"Romualdo Troisi, Alessandro Cangiano, Nathan Cowieson, Vera Spiridonova, Nicola Pozzi, Pompea Del Vecchio, Luigi Paduano, Filomena Sica","doi":"10.1016/j.ymthe.2026.07.042","DOIUrl":"10.1016/j.ymthe.2026.07.042","url":null,"abstract":"Disorders of the blood coagulation cascade continue to pose a major clinical challenge, necessitating the development of new therapeutic agents capable of modulating this process. Several oligonucleotide aptamers targeting coagulation factors have been developed, and some are undergoing preclinical or clinical evaluation. Among them, anti-thrombin anticoagulant aptamers are promising dual-targeting agents in that, in addition to inhibiting enzyme activity, they may limit thrombin generation by binding to its precursor, prothrombin. In the present study, combined calorimetric and spectroscopic analyses reveal that these aptamers recognize proexosite I of prothrombin and exosite I of thrombin through broadly similar thermodynamic binding mechanisms. Integration of structural small-angle X-ray scattering (SAXS) studies and limited proteolysis assays shows that aptamer binding to proexosite I alters prothrombin structure, shifting the equilibrium from its more abundant closed form to the open conformation. Taken together, these results support the classification of these aptamers as dual-targeting agents capable of recognizing both thrombin and prothrombin and provide guidance for their continued development as anticoagulant therapeutics.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"6074-6085"},"PeriodicalIF":11.4,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148579362","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 splice defect to therapeutic opportunity: Insights from PRPF31 从剪接缺陷到治疗机会：来自PRPF31的见解

IF 12.4 1区医学

Molecular Therapy Pub Date : 2026-10-07 DOI: 10.1016/j.ymthe.2026.08.031

Frauke Coppieters

引用次数: 0

Synchronized latency reversal and immune clearance by a multifunctional fusion protein enables HIV-1 reservoir reduction. 一种多功能融合蛋白的同步潜伏期逆转和免疫清除使HIV-1水库减少。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-10-07 Epub Date: 2026-07-29 DOI: 10.1016/j.ymthe.2026.07.048

Fei Luo, Yinghui Cao, Na Liu, Xiaowei Wang, Wenjia Hu, Yajun Yan, Xiaoqing Xie, Dongmei Jiang, Yangyang Xu, Jun Wang, Hongyu Wang, Zhenyang Yu, Peng Qian, Shicheng Wan, Zhida Liu, Yan Gong, Tielong Chen, Shihui Song, Yong Xiong, Xiaoping Tang, Linghua Li, Li Wang, Haisheng Yu, Liang Cheng

{"title":"Synchronized latency reversal and immune clearance by a multifunctional fusion protein enables HIV-1 reservoir reduction.","authors":"Fei Luo, Yinghui Cao, Na Liu, Xiaowei Wang, Wenjia Hu, Yajun Yan, Xiaoqing Xie, Dongmei Jiang, Yangyang Xu, Jun Wang, Hongyu Wang, Zhenyang Yu, Peng Qian, Shicheng Wan, Zhida Liu, Yan Gong, Tielong Chen, Shihui Song, Yong Xiong, Xiaoping Tang, Linghua Li, Li Wang, Haisheng Yu, Liang Cheng","doi":"10.1016/j.ymthe.2026.07.048","DOIUrl":"10.1016/j.ymthe.2026.07.048","url":null,"abstract":"Strategies that concurrently reactivate latent reservoirs and enhance immune-mediated clearance hold significant promise for achieving an HIV cure. Here, we developed hyperIL-15×sCD4-Fc (15×sCD4-Fc), a fusion protein that integrates latency reactivation, targeted immune engagement, and effector-mediated killing into a single molecule. This agent not only potently reverses HIV-1 latency in CD4+ T cells from people living with HIV-1 (PLWHs) through coordinated IL-15 receptor signaling and sCD4-mediated HIV-1 envelope (Env) engagement but also enhances the antigen-specific CD8+ T cell response in peripheral blood mononuclear cells (PBMCs) derived from PLWHs. Furthermore, 15×sCD4-Fc enables Env-specific elimination of reactivated latently infected cells by NK cells while preventing off-target cytotoxicity. In PBMCs from PLWHs, 15×sCD4-Fc reduced replication-competent HIV-1 DNA by 93.8%. In antiretroviral-treated HIV-1-infected humanized mice, the molecule demonstrated both safety and efficacy in diminishing the viral reservoir in lymphoid organs. This spatiotemporally coupled approach to reservoir exposure and immune recognition establishes a clinically viable strategy for clearing the HIV-1 reservoir.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"6039-6059"},"PeriodicalIF":11.4,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620855","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

BTCE-secreting CAR T cells fight solid tumors. 分泌btce的CAR - T细胞对抗实体肿瘤。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-10-07 Epub Date: 2026-09-25 DOI: 10.1016/j.ymthe.2026.09.012

Claudia Arndt, Alexandra von Jutrzenka-Trzebiatowski

引用次数: 0

Lineage-tailored vesicles from human retinal ganglion-like cells drive metabolic homeostasis and bioenergetic recovery in glaucoma. 青光眼患者视网膜神经节样细胞的谱系定制囊泡驱动代谢稳态和生物能量恢复。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-10-07 Epub Date: 2026-07-29 DOI: 10.1016/j.ymthe.2026.07.051

Sandeep Kumar Vishwakarma, Mallikarjuna Rao Gedda, Stanislav I Tomarev

{"title":"Lineage-tailored vesicles from human retinal ganglion-like cells drive metabolic homeostasis and bioenergetic recovery in glaucoma.","authors":"Sandeep Kumar Vishwakarma, Mallikarjuna Rao Gedda, Stanislav I Tomarev","doi":"10.1016/j.ymthe.2026.07.051","DOIUrl":"10.1016/j.ymthe.2026.07.051","url":null,"abstract":"Retinal ganglion cells (RGCs) exhibit high bioenergetic demands, rendering them vulnerable to mitochondrial dysfunction and metabolic collapse during glaucomatous neurodegeneration. Therapeutic strategies capable of restoring mitochondrial homeostasis in human RGCs remain limited. We established a human retinal ganglion-like cell (RGLC) model of mitochondrial injury and evaluated neuroprotective efficacy of small extracellular vesicles (sEVs) derived from either undifferentiated BRN3B-H9 cells or differentiated lineage-tailored RGLCs. RGLC-derived sEVs (RGLC-sEVs) conferred robust neuroprotection, significantly enhancing neuronal survival, preserving neurite architecture, and mitigating mitochondrial stress following injury. These effects were reproducible in mixed retinal cultures and in an ocular hypertension mouse model of glaucoma, with neuroprotective benefits observed throughout the retinal landscape. Mechanistically, untargeted metabolomic profiling revealed extensive metabolic reprogramming involving oxidative phosphorylation, amino acid utilization, lipid metabolism, and redox regulatory pathways. In vitro tracking studies confirmed efficient uptake of sEVs by injured RGLCs, confirming effective vesicular cargo delivery under conditions that promote neuroprotection and metabolic recovery. Functional bioenergetic analysis further validated restoration of mitochondrial-glycolytic coupling and improved cellular energetic resilience. Collectively, our findings establish lineage-tailored RGLC-sEVs as a potent, cell-specific therapeutic candidate capable of reprogramming metabolic networks and restoring bioenergetic homeostasis in glaucomatous neurodegeneration, highlighting their translational potential for neuroprotective intervention in optic neuropathies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"5945-5969"},"PeriodicalIF":11.4,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620844","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

Mapping immunocompetent tissues for safer vaccines and gene therapy: A miRNA-based strategy for mRNA-LNP platforms 定位免疫组织以获得更安全的疫苗和基因治疗：基于mirna的mRNA-LNP平台策略

IF 12.4 1区医学

Molecular Therapy Pub Date : 2026-10-07 DOI: 10.1016/j.ymthe.2026.09.016

Mohamed A. Hammad,Hossam M. Ashour

引用次数: 0

In vivo engineering of T cells with a synthetic cytokine receptor enables selective enrichment and expansion of anti-CD22 CAR T cells. 在体内工程T细胞表达合成的细胞因子受体，使抗cd22 CAR - T细胞优先扩增和富集。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-10-07 Epub Date: 2026-08-10 DOI: 10.1016/j.ymthe.2026.08.003

Travis J Friesen, Alyssa Sheih, Nikole Perdue, Nolan G Ericson, Dillon Jarrell, Ashley M Yingst, Christopher J Nicolai, Timothy Gervascio, Seungjin Shin, Jessica Freeman, Laurie O Beitz, Samantha D O'Hara, Alessandra M Sullivan, Alissa H Brandes, Ryan P Larson, Jeffrey J Teoh

{"title":"In vivo engineering of T cells with a synthetic cytokine receptor enables selective enrichment and expansion of anti-CD22 CAR T cells.","authors":"Travis J Friesen, Alyssa Sheih, Nikole Perdue, Nolan G Ericson, Dillon Jarrell, Ashley M Yingst, Christopher J Nicolai, Timothy Gervascio, Seungjin Shin, Jessica Freeman, Laurie O Beitz, Samantha D O'Hara, Alessandra M Sullivan, Alissa H Brandes, Ryan P Larson, Jeffrey J Teoh","doi":"10.1016/j.ymthe.2026.08.003","DOIUrl":"10.1016/j.ymthe.2026.08.003","url":null,"abstract":"Ex vivo-manufactured chimeric antigen receptor (CAR) T cells targeting CD19 have transformed treatment strategies for patients with B cell malignancies and have shown promising results in autoimmune disease. Yet despite their success, significant barriers remain that impede patient access to these therapies, including their complex manufacturing and the need for lymphodepleting chemotherapy. Moreover, many patients who receive ex vivo-manufactured CD19 CAR T cells do not achieve durable responses, suggesting that the expansion and persistence of CAR T cells may need improvement, and/or that strategies targeting alternative antigens may be needed for patients who are refractory to or relapse following treatment with CD19-directed therapies. Umoja is developing a surface-engineered lentiviral vector platform capable of generating CAR T cells in vivo without lymphodepletion. UB-VV400 delivers a payload composed of a fully human anti-CD22 CAR and the rapamycin-activated cytokine receptor (RACR), which enable preferential expansion and enrichment of CAR T cells in response to rapamycin. Here, we describe preclinical studies demonstrating that UB-VV400 generates anti-CD22 CAR T cells that kill CD22-expressing B cells and tumor cells in vitro and in vivo, and that engagement of RACR results in the selective expansion and enrichment of CAR T cells in vivo leading to complete tumor clearance and B cell depletion.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"5783-5795"},"PeriodicalIF":11.4,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148707344","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

Targeted antisense oligonucleotide therapy rescues PRPF31 expression in retinitis pigmentosa caused by a splicing mutation. 靶向反义寡核苷酸治疗可挽救由剪接突变引起的视网膜色素变性中PRPF31的表达。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-10-07 Epub Date: 2026-06-03 DOI: 10.1016/j.ymthe.2026.05.033

Poulami Banik, Felix Zimmann, Prasoon K Thakur, Lubica Dudakova, Kateřina Večerková, Ondrej Kostov, Marvin H Caruthers, Michal Kolář, Inka Krejčířová, Marie Vajter, Petra Liskova, Tomáš Bárta, David Staněk

{"title":"Targeted antisense oligonucleotide therapy rescues PRPF31 expression in retinitis pigmentosa caused by a splicing mutation.","authors":"Poulami Banik, Felix Zimmann, Prasoon K Thakur, Lubica Dudakova, Kateřina Večerková, Ondrej Kostov, Marvin H Caruthers, Michal Kolář, Inka Krejčířová, Marie Vajter, Petra Liskova, Tomáš Bárta, David Staněk","doi":"10.1016/j.ymthe.2026.05.033","DOIUrl":"10.1016/j.ymthe.2026.05.033","url":null,"abstract":"Pathogenic variants in splicing factors are the second most common cause of autosomal dominant retinitis pigmentosa, with mutations in PRPF31 being the most prevalent. Here, we characterize a novel intronic variant in PRPF31 (c.1074-11C>G) that creates a cryptic 3' splice site, resulting in an aberrantly spliced transcript predicted to encode a protein with an altered C terminus. However, the pathogenic protein is unstable and undetectable in patient-derived induced pluripotent stem cells (iPSCs). In addition, expression of the full-length PRPF31 protein was reduced in patient-derived retinal pigment epithelium (RPE). To correct the splicing defect, we designed a panel of antisense oligonucleotides (ASOs) targeting putative RNA-binding sites in exon 10 and intron 10 and identified a candidate that corrects PRPF31 splicing in a minigene reporter system as well as in patient-derived iPSCs and RPE. We further showed that ASO treatment enhances PRPF31 protein expression in patient-derived iPSC and RPE carrying the intronic mutation, supporting the potential of the ASO-based approach to restore PRPF31 expression in patients with the same or similar splicing defects.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"6060-6073"},"PeriodicalIF":11.4,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148157377","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