Molecular Therapy最新文献_第3页

Oncolytic viruses as cancer therapeutics: From mechanistic insights to clinical translation. 溶瘤病毒作为癌症治疗药物：从机制见解到临床转化。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-03-25 DOI: 10.1016/j.ymthe.2025.03.035

Akram Alwithenani, Pranaidej Hengswat, E Antonio Chiocca

{"title":"Oncolytic viruses as cancer therapeutics: From mechanistic insights to clinical translation.","authors":"Akram Alwithenani, Pranaidej Hengswat, E Antonio Chiocca","doi":"10.1016/j.ymthe.2025.03.035","DOIUrl":"10.1016/j.ymthe.2025.03.035","url":null,"abstract":"Oncolytic virotherapy is a therapeutic approach that leverages genetically engineered or naturally occurring viruses to selectively target and destroy cancer cells while sparing normal tissues. This review provides an overview of the mechanisms of action by oncolytic viruses (OVs), including direct oncolysis, immune activation, and tumor microenvironment (TME) modulation. Despite significant progress, challenges such as immune resistance, tumor evasion mechanisms, and delivery barriers continue to limit the efficacy of OVs. To address these obstacles, recent advances in OV engineering have focused on arming viruses with immunomodulatory molecules, utilizing tumor-specific promoters, and employing CRISPR-based genome editing. Emerging strategies, such as dual-targeting OVs and viral enhancer drugs, have demonstrated promising potential in preclinical and clinical settings. This review also highlights findings from recent clinical trials, underscoring the translational challenges in scaling OVs for widespread therapeutic application. By exploring these innovations and their implications, we aim to shed light on the future directions of oncolytic virotherapy and its transformative potential in cancer treatment.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2217-2228"},"PeriodicalIF":12.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720641","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

Next-generation replication-defective HSV vectors for delivery of large DNA payloads. 用于递送大DNA有效载荷的下一代复制缺陷HSV载体。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-04-02 DOI: 10.1016/j.ymthe.2025.03.055

Selene Ingusci, William F Goins, Justus B Cohen, Yoshitaka Miyagawa, David M Knipe, Joseph C Glorioso

{"title":"Next-generation replication-defective HSV vectors for delivery of large DNA payloads.","authors":"Selene Ingusci, William F Goins, Justus B Cohen, Yoshitaka Miyagawa, David M Knipe, Joseph C Glorioso","doi":"10.1016/j.ymthe.2025.03.055","DOIUrl":"10.1016/j.ymthe.2025.03.055","url":null,"abstract":"The application of gene therapy to the treatment of human disease with complex etiology and pathology will often require the delivery of large payloads exceeding 10 kbp in size. This is generally not possible with the most popular vectors such as adeno-associated viruses (AAVs), lentiviruses (LVs), retroviruses (RVs), and many nonviral delivery systems. There is a high likelihood that the correction of many human gene defects such as those associated with neurodegenerative diseases and inflammatory processes will require single large genes or complex genetic payloads that will often necessitate precise regulatory control of the specificity, timing, and duration of corrective gene expression. The regulation of cellular gene products typically depends on genomic promoter systems and splicing-driven transcription variants, necessitating a delivery vector with substantial payload capacity. Replication-defective herpes simplex virus (rdHSV) mutants lack at least one essential viral gene product and are propagated in host cells that supply the missing gene product. This review explores next-generation rdHSV vectors, which do not express viral genes, offer high payload capacity, and can be engineered for safe, long-term transgene expression. These advanced vectors enable the correction of complex diseases affecting neurons and other tissues, paving the way for large or intricate gene replacement strategies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2205-2216"},"PeriodicalIF":12.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780542","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

Immuno-oncology recapitulates ontogeny: Modern cell and gene therapy for cancer. 免疫肿瘤学概括了个体发生：癌症的现代细胞和基因治疗。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-03-27 DOI: 10.1016/j.ymthe.2025.03.042

Neil Carleton, Aaron B I Rosen, Jishnu Das, Michael T Lotze

{"title":"Immuno-oncology recapitulates ontogeny: Modern cell and gene therapy for cancer.","authors":"Neil Carleton, Aaron B I Rosen, Jishnu Das, Michael T Lotze","doi":"10.1016/j.ymthe.2025.03.042","DOIUrl":"10.1016/j.ymthe.2025.03.042","url":null,"abstract":"Immuno-oncology (IO) has had over a century to develop from the original seminal insights of Virchow in 1863, seeing inflammation and lymphoid infiltrates as a common anlage for many adult tumors. That IO has become a central pillar of cancer treatment has come about because of the remarkable clinical and subsequent commercial success of immune checkpoint blockade (ICB) in the last 15 years. This now includes approved cell and gene therapies for patients with cancer, including an armed adenovirus, oncolytic herpesvirus, and adoptive transfer of dendritic cells, chimeric antigen receptor T (CAR-T) cells, and tumor-infiltrating lymphocytes (TILs). The evolution of such applications has required the stepwise development of a deeper understanding of the molecular biology of cancer and the physiology of immunobiology. This also recapitulates, in a broader sense, our evolutionary trajectory with capture of \"evolvability,\" not only across the development of species but also within individuals. This review covers how our foundational understanding of immune system learning and evolvability have facilitated better understanding of the co-evolutionary interactions between the epithelium and the immune system. We highlight examples of this in breast, colon, prostate, pancreas, and lung cancer, and provide examples of next-generation cell and gene therapies that intercept cancer development.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2229-2237"},"PeriodicalIF":12.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743170","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

The deLIVERed promises of gene therapy: Past, present, and future of liver-directed gene therapy. 基因治疗的承诺：肝脏导向基因治疗的过去、现在和未来。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-03-27 DOI: 10.1016/j.ymthe.2025.03.041

Francesco Puzzo, Mark A Kay

{"title":"The deLIVERed promises of gene therapy: Past, present, and future of liver-directed gene therapy.","authors":"Francesco Puzzo, Mark A Kay","doi":"10.1016/j.ymthe.2025.03.041","DOIUrl":"10.1016/j.ymthe.2025.03.041","url":null,"abstract":"Gene therapy has revolutionized modern medicine by offering innovative treatments for genetic and acquired diseases. The liver has been and continues as a prime target for in vivo gene therapy due to its essential biological functions, vascular access to the major target cell (hepatocytes), and relatively immunotolerant environment. Adeno-associated virus (AAV) vectors have become the cornerstone of liver-directed therapies, demonstrating remarkable success in conditions such as hemophilia A and B, with US Food and Drug Administration (FDA)-approved therapies like etranacogene dezaparvovec, Beqvez, and Roctavian marking milestones in the field. Despite these advances, challenges persist, including vector immunogenicity, species-specific barriers, and high manufacturing costs. Innovative strategies, such as capsid engineering, immune modulation, and novel delivery systems, are continuing to address these issues in expanding the scope of therapeutic applications. Some of the challenges with many new therapies result in the discordance between preclinical success and translation into humans. The advent of various genome-editing tools to repair genomic mutations or insert therapeutic DNAs into precise locations in the genome further enhances the potential for a single-dose medicine that will offer durable life-long therapeutic treatments. As advancements accelerate, liver-targeted gene therapy is poised to continue to transform the treatment landscape for both genetic and acquired disorders, for which unmet challenges remain.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1966-1987"},"PeriodicalIF":12.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743181","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

Safety and efficacy of gene therapy for RAG1-deficient SCID. 基因治疗rag1缺陷SCID的安全性和有效性。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-03-18 DOI: 10.1016/j.ymthe.2025.02.044

Frank J T Staal, Karin Pike-Overzet, Sander de Kivit, Lisa Ott de Bruin, Lucia Mamede, Martine Pergent, Johan Prevot, Michael Rothe, Axel Schambach, Arjan Lankester

引用次数: 0

Intrinsic/proximal cell surface marker logic-gated extracellular targeted protein degradation in specific cell population. 内在/近端细胞表面标记逻辑门控细胞外靶向蛋白降解在特定细胞群。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-05-07 DOI: 10.1016/j.ymthe.2025.05.002

Yafeng Wang,Guiquan Zhang,Ping Rong,Panpan Guo,Shisheng Huang,Yang Hang,Pei Wang,Lin Tang,Xiaojing Li,Xiaojun Tang,Shuai Ding,Xingxu Huang,Jianghuai Liu,Lingyun Sun

{"title":"Intrinsic/proximal cell surface marker logic-gated extracellular targeted protein degradation in specific cell population.","authors":"Yafeng Wang,Guiquan Zhang,Ping Rong,Panpan Guo,Shisheng Huang,Yang Hang,Pei Wang,Lin Tang,Xiaojing Li,Xiaojun Tang,Shuai Ding,Xingxu Huang,Jianghuai Liu,Lingyun Sun","doi":"10.1016/j.ymthe.2025.05.002","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.05.002","url":null,"abstract":"Molecular tether-mediated extracellular targeted protein degradation (eTPD) presents an innovative technology and underlies a promising drug modality. However, to precisely implement eTPD within specific cell compartments remains a significant challenge. As eTPD depends on the degrader molecule expression and activity, we first seek to expand the panel of potential eTPD degraders. To this end, more than fifty receptors with variable tissue distributions are screened for identification of those with substantial endocytic rates. We subsequently assemble the bispecific, \"Selected endocytic carrier-targeting chimeras (SecTAC)\", and validate their efficacies to program the target cells to internalize membrane/extracellular protein cargoes (or nucleic acids). Moreover, administration of a SecTAC for removal of excessive IgG via a currently validated, emerging degrader (CD71) leads to evident therapeutic effect in a mouse lupus model. To further enhance cell-targeting specificity, we next develop logic-gated eTPD (LOG-eTPD) based on combination of chimeras that indirectly couple cargo and degrader via another cell surface gating marker. Particularly, we find that a selective surface marker from the neighboring cells may also be exploited as input for LOG-eTPD in a therapeutically relevant context. Taken together, the present work has laid strong foundation for developing eTPD agents that combine high potency with precision and safety.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"48 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926388","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

Template-assisted sequence knock-in rescues skeletal and cardiac muscle function in a deletion model of Duchenne muscular dystrophy. 在杜氏肌营养不良缺失模型中，模板辅助序列敲入可挽救骨骼肌和心肌功能。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-05-07 DOI: 10.1016/j.ymthe.2025.05.005

Sina Fatehi,Matthew J Rok,Ryan M Marks,Emily Huynh,Natalie Kozman,Hong Anh Truong,Lijun Chi,Bei Yan,Enzhe Khazeeva,Paul Delgado-Olguin,Evgueni A Ivakine,Ronald D Cohn

{"title":"Template-assisted sequence knock-in rescues skeletal and cardiac muscle function in a deletion model of Duchenne muscular dystrophy.","authors":"Sina Fatehi,Matthew J Rok,Ryan M Marks,Emily Huynh,Natalie Kozman,Hong Anh Truong,Lijun Chi,Bei Yan,Enzhe Khazeeva,Paul Delgado-Olguin,Evgueni A Ivakine,Ronald D Cohn","doi":"10.1016/j.ymthe.2025.05.005","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.05.005","url":null,"abstract":"Duchenne muscular dystrophy (DMD) poses challenges in therapy design due to dystrophin's complex role in maintaining muscle function since the restoration of truncated protein products has failed to completely address the disease's pathophysiology in clinical trials. As ∼70% of patients harbour deletions, strategies enabling targeted DNA insertion to restore full-length dystrophin protein are essential. Here, we present template-assisted sequence knock-in (TASK), a strategy that we employed to specifically correct the Dmd Δ52-54 mutation in a murine model. By co-delivering a repair template and the Cas9 nuclease using AAV9s, the splice-competent sequence for Dmd exons 52-54 was integrated into the residual intron 54 locus, resulting in the systemic restoration of full-length dystrophin at therapeutically relevant levels in the heart and across all skeletal muscles, leading to significant functional improvements. TASK demonstrates the highest efficiency of exogenous DNA knock-in reported to date, achieving rescue of key dystrophic hallmarks in a deletion model of DMD.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"16 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926390","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 vector development, back to the future. AAV载体发展，回到未来。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-04-03 DOI: 10.1016/j.ymthe.2025.03.064

Lester Suarez-Amaran, Liujiang Song, Anna P Tretiakova, Sheila A Mikhail, Richard Jude Samulski

{"title":"AAV vector development, back to the future.","authors":"Lester Suarez-Amaran, Liujiang Song, Anna P Tretiakova, Sheila A Mikhail, Richard Jude Samulski","doi":"10.1016/j.ymthe.2025.03.064","DOIUrl":"10.1016/j.ymthe.2025.03.064","url":null,"abstract":"Adeno-associated virus (AAV) has become a pivotal tool in gene therapy, providing a safe and efficient platform for long-term transgene expression. This review presents a comprehensive analysis of AAV's historical development, from its initial identification as a \"contaminant\" to its current clinical applications. We examine the molecular evolution of AAV, detailing advancements in vector engineering, rational design, directed evolution platforms, and computational modeling, which have expanded its therapeutic potential across diverse disease areas. Additionally, we explore AAV genome regulation, with a particular focus on inverted terminal repeats (ITRs) and AAV capsid-genome interactions, which play a crucial role in vector transduction efficiency and host adaptation. An assessment of past and present clinical trials as well as future directions is provided to illustrate the field's trajectory. Finally, another unique milestone in AAV research is also reported; namely, a pool of AAV libraries has been successfully administered to human decedents and analyzed, representing a transformative step in AAV evolution and selection for human applications. These studies should pave the way for more refined AAV vector optimization, accelerating the development of next-generation gene therapies with enhanced clinical translatability, potentially accelerating the gene therapy revolution.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1903-1936"},"PeriodicalIF":12.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788668","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

GMP manufacturing of cell and gene therapy products: Challenges, opportunities, and pathways forward. 细胞和基因治疗产品的GMP生产：挑战、机遇和前进的途径。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-02-25 DOI: 10.1016/j.ymthe.2025.02.022

Brian Fury, Gerhard Bauer

{"title":"GMP manufacturing of cell and gene therapy products: Challenges, opportunities, and pathways forward.","authors":"Brian Fury, Gerhard Bauer","doi":"10.1016/j.ymthe.2025.02.022","DOIUrl":"10.1016/j.ymthe.2025.02.022","url":null,"abstract":"Cell and gene therapy (CGT) products have been emerging as life-saving and life-changing therapies over the last 20 years. The United States has been a forerider in the development of these therapeutic products and has also developed the pertinent manufacturing methods for these complicated \"living medicines.\" California has emerged as a prominent hub for CGT manufacturing, hosting a variety of good manufacturing practice (GMP) facilities. These facilities are pivotal in advancing CGT products from phase 1 to phase 3 clinical trials and, eventually, to commercialization. Despite California's strategic advantages, including its biotech ecosystem and access to venture capital, numerous challenges hinder its full potential. These include funding disparities, expertise limitations, stringent regulatory demands, and a mismatch between facility utilization and demand. This review explores these factors more in depth and provides a comprehensive analysis of the current state of GMP manufacturing for CGTs in California. The example of the current situation in the state of California may also serve as an analogy for other states; we chose California due to our decades of experience manufacturing CGT products in this state.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1886-1888"},"PeriodicalIF":12.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516170","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

Current trends in gene therapy to treat inherited disorders of the brain. 基因疗法治疗遗传性脑部疾病的最新趋势。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-04-02 DOI: 10.1016/j.ymthe.2025.03.057

Zaneta Matuszek, Brandon L Brown, Carolyn M Yrigollen, Megan S Keiser, Beverly L Davidson

引用次数: 0