Molecular Therapy最新文献_第5页

3AIM-seq: quality assessment of mRNA therapeutics using sequencing for 3′ polyA tails of in vitro transcribed mRNA 3AIM-seq：利用体外转录mRNA的3 ' polyA尾部测序对mRNA疗法进行质量评估

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-06-28 DOI: 10.1016/j.ymthe.2025.06.033

Jina Seo, Hyo-Jung Park, Ayoung Oh, Chang Beom Jeong, Sohee Kim, Sojeong Lee, Chuna Kim, Hyeshik Chang, Jae-Hwan Nam, Daechan Park

{"title":"3AIM-seq: quality assessment of mRNA therapeutics using sequencing for 3′ polyA tails of in vitro transcribed mRNA","authors":"Jina Seo, Hyo-Jung Park, Ayoung Oh, Chang Beom Jeong, Sohee Kim, Sojeong Lee, Chuna Kim, Hyeshik Chang, Jae-Hwan Nam, Daechan Park","doi":"10.1016/j.ymthe.2025.06.033","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.033","url":null,"abstract":"<ce:italic>In vitro</ce:italic> transcribed (IVT) mRNA therapeutics are promising for preventing and treating diseases, including infectious diseases and cancer, by delivering nucleic acid sequences. Assessing the stability of mRNA sequences and polyA tail lengths is crucial to minimize adverse effects and ensure drug efficacy. However, accurately measuring long homopolymeric nucleotides remains technically challenging, and a specialized method for IVT mRNAs is lacking. We introduced 3AIM-seq, a technique optimized experimentally and analytically for sequencing 3′ polyA tails in IVT mRNAs. To generate high-quality data, we used a ligation-free adapter followed by 3′ end amplification to prepare high-throughput sequencing libraries. The 3AIM-seq algorithm employed a sliding window approach to base quality scores, providing higher resolution and accuracy than base-calling method, and distinguishing polyA length differences as small as ±5 bp. Using <ce:italic>in silico</ce:italic> synthetic standard spike-in experiments, the method estimated the homogeneity of polyA tail lengths at the individual DNA molecule level in IVT mRNAs with various polyA tail structures. Although polyA tail of up to 70 bases were accurately measured, stretches exceeding 100 bases exhibited high heterogeneity for length, highlighting the importance of thorough assessments. Therefore, 3AIM-seq is a reliable method for evaluating the structural integrity of IVT mRNA products before clinical use.","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":"144516106","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

CD19xCD3 T-cell engager blinatumomab effective in refractory generalized myasthenic syndromes CD19xCD3 t细胞参与blinatumumab对难治性全身性肌无力综合征有效

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-06-28 DOI: 10.1016/j.ymthe.2025.06.042

Tobias Ruck M.D., Niklas Huntemann M.D., Menekse Öztürk M.D., Stefanie Schreiber M.D., Stefanie Lichtenberg Ph.D., Lars Masanneck M.D., Christopher Nelke M.D., Hend Ben Moussa M.D., Thomas Ulrych M.D., Marc Seifert Ph.D., Dimitrios Mougiakakos M.D., Sascha Dietrich M.D., Sven G. Meuth M.D. Ph.D.

{"title":"CD19xCD3 T-cell engager blinatumomab effective in refractory generalized myasthenic syndromes","authors":"Tobias Ruck M.D., Niklas Huntemann M.D., Menekse Öztürk M.D., Stefanie Schreiber M.D., Stefanie Lichtenberg Ph.D., Lars Masanneck M.D., Christopher Nelke M.D., Hend Ben Moussa M.D., Thomas Ulrych M.D., Marc Seifert Ph.D., Dimitrios Mougiakakos M.D., Sascha Dietrich M.D., Sven G. Meuth M.D. Ph.D.","doi":"10.1016/j.ymthe.2025.06.042","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.042","url":null,"abstract":"In this case series, we report the first off-label use of the CD19xCD3 T-cell engager blinatumomab in two patients with generalized myasthenia gravis (MG). Refractory MG remains a major therapeutic challenge, with patients experiencing severe disability and potentially life-threatening crises despite intensive immunotherapy. This study evaluates the clinical efficacy and safety of short-term blinatumomab treatment in two patients with severe, refractory generalized MG. Both individuals had been experiencing a persistent disease burden with myasthenic crises leading to severe disability, despite multimodal immunotherapy. Following treatment with blinatumomab, both patients showed rapid and sustained clinical improvements, reflected in significant reductions in MG-specific scores (MG-ADL, QMG, and revised MG Quality of Life-15), further patient-reported outcomes, digital activity markers, and gait analyses. Laboratory findings revealed persistent B-cell depletion in patient #1, whereas patient #2 demonstrated clinical improvement and autoantibody reduction despite B-cell repopulation by day 106. Both patients experienced grade 1 cytokine release syndrome during initial treatment phases, but no neurotoxicity or severe adverse events were observed. This report underscores the potential of CD19xCD3 T-cell engagers as a promising therapeutic approach in severe autoimmune neuroimmunological disorders, warranting further investigation in clinical trials and mechanistic studies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"24 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516031","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

Epigenetic networks coordinate DNA methylation across the genome 表观遗传网络协调整个基因组的DNA甲基化

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-06-27 DOI: 10.1016/j.ymthe.2025.06.037

Wolfgang Wagner

{"title":"Epigenetic networks coordinate DNA methylation across the genome","authors":"Wolfgang Wagner","doi":"10.1016/j.ymthe.2025.06.037","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.037","url":null,"abstract":"The epigenetic landscape governs cell-fate decisions during development, aging, and disease. Despite considerable progress in understanding of DNA methylation (DNAm), the mechanisms that orchestrate its coordinated regulation across the genome remain largely elusive. Recent breakthroughs in sequencing technologies and epigenetic editing tools enable more comprehensive exploration of these epigenetic interactions. Regulation of DNAm seems to be organized within epigenetic networks characterized by complex feedback mechanisms acting locally, between homologous alleles, and across the entire genome. This crosstalk is facilitated by an interplay of various molecular components, including distinct variants of epigenetic writers and erasers; methylation-sensitive binding of transcription factors and other regulatory proteins that recruit DNA methyltransferases; cross-regulation between DNAm and the histone code; 3D chromatin conformation; regulatory effects mediated by long non-coding RNAs (lncRNAs); and potentially by assimilation during homologous recombination events. This review explores how these diverse epigenetic mechanisms interact to collectively shape the methylome, and thereby control developmental and disease processes.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"11 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516108","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 WNT5A Noncanonical Signaling Attenuates Renal Fibrosis Progression in Acute Kidney Injury 靶向WNT5A非规范信号可减缓急性肾损伤的肾纤维化进展

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-06-27 DOI: 10.1016/j.ymthe.2025.06.039

Sijie Gu, Haoran Feng, Xiaomei Li, Yang Dong, Yonglin Peng, Qiye Liu, Xuhao Zhang, Jiayin You, Jinwei Zhu, Xiaodong Zhao, Xizhi Guo, Niansong Wang, Ying Fan

{"title":"Targeting WNT5A Noncanonical Signaling Attenuates Renal Fibrosis Progression in Acute Kidney Injury","authors":"Sijie Gu, Haoran Feng, Xiaomei Li, Yang Dong, Yonglin Peng, Qiye Liu, Xuhao Zhang, Jiayin You, Jinwei Zhu, Xiaodong Zhao, Xizhi Guo, Niansong Wang, Ying Fan","doi":"10.1016/j.ymthe.2025.06.039","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.039","url":null,"abstract":"Preventing progression from acute kidney injury (AKI) to chronic kidney disease (CKD) remains a considerable clinical challenge. In this study, we elucidate the role of WNT5A in accelerating the AKI-to-CKD transition and its underlying mechanisms. Renal biopsies from patients with AKI showed marked upregulation of WNT5A and its receptor CD146 in proximal tubules, with higher expression in patients with CKD progression. In murine AKI models, <ce:italic>Wnt5a</ce:italic> knockdown attenuated CKD progression. Conversely, proximal tubular overexpression of <ce:italic>Wnt5a</ce:italic> exacerbated renal fibrosis in ischemia-reperfusion injury (IRI) mice, which was alleviated by Box5, a specific WNT5A antagonist. <ce:italic>In vitro</ce:italic>, <ce:italic>WNT5A</ce:italic> overexpression in TGF-β-stimulated HK-2 cells promoted CD146 upregulation, activated JNK phosphorylation, and enhanced SNAI1 expression. The genetic silencing of <ce:italic>WNT5A</ce:italic>/<ce:italic>CD146</ce:italic> and JNK inhibition suppresses SNAI1 expression and attenuates fibrotic responses. Mechanistically, JNK-mediated c-JUN phosphorylation promoted its interaction with KLF5 at the <ce:italic>SNAI1</ce:italic> promoter, driving renal fibrosis. Elevated serum levels of soluble CD146 correlated with renal function in patients with AKI and were higher in patients exhibiting CKD progression. Inhibition of WNT5A could serve as a therapeutic target for delaying renal fibrosis in AKI progression.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"19 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516038","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

Targeted in vivo delivery of genetic medicines utilizing an engineered lentiviral vector platform results in CAR T and NK cell generation 利用工程慢病毒载体平台靶向遗传药物的体内递送导致CAR - T和NK细胞的生成

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-06-27 DOI: 10.1016/j.ymthe.2025.06.036

James I. Andorko, Ronnie M. Russell, Bruce C. Schnepp, Daniel Grubaugh, Karla F. Mullen, Aoi Wakabayashi, Léolène J. Carrington, Thomas O’Malley, Leticia Kuri-Cervantes, Timothy D. Culp, Philip R. Johnson

{"title":"Targeted in vivo delivery of genetic medicines utilizing an engineered lentiviral vector platform results in CAR T and NK cell generation","authors":"James I. Andorko, Ronnie M. Russell, Bruce C. Schnepp, Daniel Grubaugh, Karla F. Mullen, Aoi Wakabayashi, Léolène J. Carrington, Thomas O’Malley, Leticia Kuri-Cervantes, Timothy D. Culp, Philip R. Johnson","doi":"10.1016/j.ymthe.2025.06.036","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.036","url":null,"abstract":"The development of CAR T cell therapies has greatly impacted the treatment of B cell malignancies; however, manufacturing these patient-specific, autologous cell therapies is complex, costly and requires preconditioning chemotherapy prior to infusion, limiting patient access. Here we describe the development of a lentiviral platform based on a novel, detargeted viral fusogen (Gen 2.1 Fusogen) and a membrane-bound targeting moiety to enable <ce:italic>in vivo</ce:italic> targeted delivery of stably integrating genetic medicines without the need for lymphodepletion. INT2104 employs an scFv targeting CD7 (“CD7 Binder”) to deliver a CAR20 transgene to CD7<ce:sup loc=\"post\">+</ce:sup> T and NK cells. Preclinical data generated in mouse and cynomolgus macaque models indicate INT2104 results in both CAR T cells (CD4<ce:sup loc=\"post\">+</ce:sup> and CD8<ce:sup loc=\"post\">+</ce:sup>) and CAR NK cells with subsequent depletion of CD20<ce:sup loc=\"post\">+</ce:sup> B cells following a single intravenous administration. Thus, INT2104 could potentially provide a more accessible, off-the-shelf treatment option for patients who may benefit from CAR therapies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"272 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144516039","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

Memory matters: T cell phenotype shapes CAR T cell fate. 记忆很重要：T细胞表型决定CAR - T细胞的命运。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-06-25 DOI: 10.1016/j.ymthe.2025.06.011

Francesco Di Meo

引用次数: 0

In utero genetic therapy: Treatment of early onset neurological disorders before they start. 子宫内基因治疗：在发病前治疗早发性神经系统疾病。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-06-25 DOI: 10.1016/j.ymthe.2025.06.012

Beltran Borges,Stephen M Brown,Tippi C MacKenzie,Charlotte J Sumner

引用次数: 0

TNFAIP8L2 as a dual regulator of mTORC1 signaling: Implications for therapy in presbycusis. TNFAIP8L2作为mTORC1信号的双重调节因子：对老年性痴呆的治疗意义。