Molecular Therapy. Nucleic Acids最新文献_第6页

First-in-class transactivator-free, doxycycline-inducible IL-18-engineered CAR-T cells for relapsed/refractory B cell lymphomas 治疗复发/难治性 B 细胞淋巴瘤的不含转录因子、强力霉素诱导的 IL-18 工程 CAR-T 细胞，属同类产品之首

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-15 DOI: 10.1016/j.omtn.2024.102308

Pedro Justicia-Lirio, María Tristán-Manzano, Noelia Maldonado-Pérez, Carmen Barbero-Jiménez, Marina Cortijo-Gutiérrez, Kristina Pavlovic, Francisco J. Molina-Estevez, Pilar Muñoz, Ana Hinckley-Boned, Juan R. Rodriguez-Madoz, Felipe Prosper, Carmen Griñán-Lison, Saúl A. Navarro-Marchal, Julia Muñoz-Ballester, Pedro A. González-Sierra, Concha Herrera, Juan A. Marchal, Francisco Martín

{"title":"First-in-class transactivator-free, doxycycline-inducible IL-18-engineered CAR-T cells for relapsed/refractory B cell lymphomas","authors":"Pedro Justicia-Lirio, María Tristán-Manzano, Noelia Maldonado-Pérez, Carmen Barbero-Jiménez, Marina Cortijo-Gutiérrez, Kristina Pavlovic, Francisco J. Molina-Estevez, Pilar Muñoz, Ana Hinckley-Boned, Juan R. Rodriguez-Madoz, Felipe Prosper, Carmen Griñán-Lison, Saúl A. Navarro-Marchal, Julia Muñoz-Ballester, Pedro A. González-Sierra, Concha Herrera, Juan A. Marchal, Francisco Martín","doi":"10.1016/j.omtn.2024.102308","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102308","url":null,"abstract":"Although chimeric antigen receptor (CAR) T cell therapy has revolutionized type B cancer treatment, efficacy remains limited in various lymphomas and solid tumors. Reinforcing conventional CAR-T cells to release cytokines can improve their efficacy but also increase safety concerns. Several strategies have been developed to regulate their secretion using minimal promoters that are controlled by chimeric proteins harboring transactivators. However, these chimeric proteins can disrupt the normal physiology of T cells. Here, we present the first transactivator-free anti-CD19 CAR-T cells able to control IL-18 expression (iTRUCK19.18) under ultra-low doses of doxycycline and without altering cellular fitness. Interestingly, IL-18 secretion requires T cell activation in addition to doxycycline, allowing the external regulation of CAR-T cell potency. This effect was translated into an increased CAR-T cell antitumor activity against aggressive hematologic and solid tumor models. In a clinically relevant context, we generated patient-derived iTRUCK19.18 cells capable of eradicating primary B cells tumors in a doxycycline-dependent manner. Furthermore, IL-18-releasing CAR-T cells polarized pro-tumoral macrophages toward an antitumoral phenotype, suggesting potential for modulating the tumor microenvironment. In summary, we showed that our platform can generate exogenously controlled CAR-T cells with enhanced potency and in the absence of transactivators.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"40 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Plug-and-play nucleic acid-mediated multimerization of biparatopic nanobodies for molecular imaging 即插即用的核酸介导的双原子纳米抗体多聚化，用于分子成像

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-15 DOI: 10.1016/j.omtn.2024.102305

Laura Teodori, Sarah K. Ochoa, Marjan Omer, Veronica L. Andersen, Pernille Bech, Junyi Su, Jessica Bridoux, Jesper S. Nielsen, Mathias B. Bertelsen, Sophie Hernot, Kurt V. Gothelf, Jørgen Kjems

{"title":"Plug-and-play nucleic acid-mediated multimerization of biparatopic nanobodies for molecular imaging","authors":"Laura Teodori, Sarah K. Ochoa, Marjan Omer, Veronica L. Andersen, Pernille Bech, Junyi Su, Jessica Bridoux, Jesper S. Nielsen, Mathias B. Bertelsen, Sophie Hernot, Kurt V. Gothelf, Jørgen Kjems","doi":"10.1016/j.omtn.2024.102305","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102305","url":null,"abstract":"In cancer molecular imaging, selecting binders with high specificity and affinity for biomarkers is paramount for achieving high-contrast imaging within clinical time frames. Nanobodies have emerged as potent candidates, surpassing antibodies in pre-clinical imaging due to their convenient production, rapid renal clearance, and deeper tissue penetration. Multimerization of nanobodies is a popular strategy to enhance their affinity and pharmacokinetics; however, traditional methods are laborious and may yield heterogeneous products. In this study, we employ a Holliday junction (HJ)-like nucleic acid-based scaffold to create homogeneous nanostructures with precise multivalent and multiparatopic nanobody displays. The plug-and-play assembly allowed the screening of several nanobody multimer configurations for the detection of the breast cancer biomarker, human epidermal growth factor receptor 2 (HER2). studies demonstrated significant improvements in binding avidity, particularly with the biparatopic construct exhibiting high sensitivity, surpassing that of traditional antibody-based cell binding. Furthermore, our HJ platform allowed for adaptation from fluorescence-based to nuclear imaging, as demonstrated in xenografted mice, thereby allowing for future applications. This work highlights the potential of nucleic acid-mediated multimerization to markedly enhance nanobody binding, by exploring synergistic combinations and offering versatility for both diagnostics and cancer molecular imaging with prospects for future theranostic applications.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"30 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Nanobody against SARS-CoV-2 non-structural protein Nsp9 inhibits viral replication in human airway epithelia 抗 SARS-CoV-2 非结构蛋白 Nsp9 的纳米抗体可抑制病毒在人气道上皮细胞中的复制

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-15 DOI: 10.1016/j.omtn.2024.102304

Tomas Venit, Jeremy Blavier, Sibusiso B. Maseko, Sam Shu, Lilia Espada, Christopher Breunig, Hans-Peter Holthoff, Sabrina C. Desbordes, Martin Lohse, Gennaro Esposito, Jean-Claude Twizere, Piergiorgio Percipalle

{"title":"Nanobody against SARS-CoV-2 non-structural protein Nsp9 inhibits viral replication in human airway epithelia","authors":"Tomas Venit, Jeremy Blavier, Sibusiso B. Maseko, Sam Shu, Lilia Espada, Christopher Breunig, Hans-Peter Holthoff, Sabrina C. Desbordes, Martin Lohse, Gennaro Esposito, Jean-Claude Twizere, Piergiorgio Percipalle","doi":"10.1016/j.omtn.2024.102304","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102304","url":null,"abstract":"Nanobodies are emerging as critical tools for drug design. Several have been recently created to serve as inhibitors of severe acute respiratory syndrome coronavirus s (SARS-CoV-2) entry in the host cell by targeting surface-exposed spike protein. Here we have established a pipeline that instead targets highly conserved viral proteins made only after viral entry into the host cell when the SARS-CoV-2 RNA-based genome is translated. As proof of principle, we designed nanobodies against the SARS-CoV-2 non-structural protein (Nsp)9, which is required for viral genome replication. One of these anti-Nsp9 nanobodies, 2NSP23, previously characterized using immunoassays and nuclear magnetic resonance spectroscopy for epitope mapping, was expressed and found to block SARS-CoV-2 replication specifically. We next encapsulated 2NSP23 nanobody into lipid nanoparticles (LNPs) as mRNA. We show that this nanobody, hereby referred to as LNP-mRNA-2NSP23, is internalized and translated in cells and suppresses multiple SARS-CoV-2 variants, as seen by qPCR and RNA deep sequencing. These results are corroborated in three-dimensional reconstituted human epithelium kept at air-liquid interface to mimic the outer surface of lung tissue. These observations indicate that LNP-mRNA-2NSP23 is internalized and, after translation, it inhibits viral replication by targeting Nsp9 in living cells. We speculate that LNP-mRNA-2NSP23 may be translated into an innovative strategy to generate novel antiviral drugs highly efficient across coronaviruses.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"60 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 changing scenario of drug discovery using AI to deep learning: Recent advancement, success stories, collaborations, and challenges 利用人工智能和深度学习进行药物发现的变化情况：最新进展、成功案例、合作与挑战

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-08 DOI: 10.1016/j.omtn.2024.102295

Chiranjib Chakraborty, Manojit Bhattacharya, Sang-Soo Lee, Zhi-Hong Wen, Yi-Hao Lo

{"title":"The changing scenario of drug discovery using AI to deep learning: Recent advancement, success stories, collaborations, and challenges","authors":"Chiranjib Chakraborty, Manojit Bhattacharya, Sang-Soo Lee, Zhi-Hong Wen, Yi-Hao Lo","doi":"10.1016/j.omtn.2024.102295","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102295","url":null,"abstract":"Due to the transformation of artificial intelligence (AI) tools and technologies, AI-driven drug discovery has come to the forefront. It reduces the time and expenditure. Due to these advantages, pharmaceutical industries are concentrating on AI-driven drug discovery. Several drug molecules have been discovered using AI-based techniques and tools, and several newly AI-discovered drug molecules have already entered clinical trials. In this review, we first present the data and their resources in the pharmaceutical sector for AI-driven drug discovery and illustrated some significant algorithms or techniques used for AI and ML which are used in this field. We gave an overview of the deep neural network (NN) models and compared them with artificial NNs. Then, we illustrate the recent advancement of the landscape of drug discovery using AI to deep learning, such as the identification of drug targets, prediction of their structure, estimation of drug-target interaction, estimation of drug-target binding affinity, design of drug, prediction of drug toxicity, estimation of absorption, distribution, metabolism, excretion, toxicity; and estimation of drug-drug interaction. Moreover, we highlighted the success stories of AI-driven drug discovery and discussed several collaboration and the challenges in this area. The discussions in the article will enrich the pharmaceutical industry.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"60 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Enhancing peptide and PMO delivery to mouse airway epithelia by chemical conjugation with the amphiphilic peptide S10 通过与两亲性肽 S10 化学共轭，增强向小鼠气道上皮细胞输送肽和 PMO 的能力

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-07-31 DOI: 10.1016/j.omtn.2024.102290

Maud Auger, Luis Sorroza-Martinez, Nadine Brahiti, Carole-Ann Huppé, Laurence Faucher-Giguère, Imen Arbi, Maxime Hervault, Xue Cheng, Bruno Gaillet, Frédéric Couture, David Guay, Al-Halifa Soultan

{"title":"Enhancing peptide and PMO delivery to mouse airway epithelia by chemical conjugation with the amphiphilic peptide S10","authors":"Maud Auger, Luis Sorroza-Martinez, Nadine Brahiti, Carole-Ann Huppé, Laurence Faucher-Giguère, Imen Arbi, Maxime Hervault, Xue Cheng, Bruno Gaillet, Frédéric Couture, David Guay, Al-Halifa Soultan","doi":"10.1016/j.omtn.2024.102290","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102290","url":null,"abstract":"Delivery of antisense oligonucleotides (ASOs) to airway epithelial cells is arduous due to the physiological barriers that protect the lungs and the endosomal entrapment phenomenon, which prevents ASOs from reaching their intracellular targets. Various delivery strategies involving peptide-, lipid-, and polymer-based carriers are being investigated, yet the challenge remains. S10 is a peptide-based delivery agent that enables the intracellular delivery of biomolecules such as GFP, CRISPR-associated nuclease ribonucleoprotein (RNP), base editor RNP, and a fluorescent peptide into lung cells after intranasal or intratracheal administrations to mice, ferrets, and rhesus monkeys. Herein, we demonstrate that covalently attaching S10 to a fluorescently labeled peptide or a functional splice-switching phosphorodiamidate morpholino oligomer improves their intracellular delivery to airway epithelia in mice after a single intranasal instillation. Data reveal a homogeneous delivery from the trachea to the distal region of the lungs, specifically into the cells lining the airway. Quantitative measurements further highlight that conjugation via a disulfide bond through a pegylated (PEG) linker was the most beneficial strategy compared with direct conjugation (without the PEG linker) or conjugation via a permanent thiol-maleimide bond. We believe that S10-based conjugation provides a great strategy to achieve intracellular delivery of peptides and ASOs with therapeutic properties in lungs.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"46 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141932108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Identification of selective and non-selective C9ORF72 targeting in vivo active siRNAs 鉴定选择性和非选择性 C9ORF72 靶向体内活性 siRNA

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-07-31 DOI: 10.1016/j.omtn.2024.102291

James W. Gilbert, Zachary Kennedy, Bruno Godinho, Ashley Summers, Alexandra Weiss, Dimas Echeverria, Brianna Bramato, Nicholas McHugh, David Cooper, Ken Yamada, Matthew Hassler, Hélène Tran, Fen Biao Gao, Robert H. Brown Jr., Anastasia Khvorova

{"title":"Identification of selective and non-selective C9ORF72 targeting in vivo active siRNAs","authors":"James W. Gilbert, Zachary Kennedy, Bruno Godinho, Ashley Summers, Alexandra Weiss, Dimas Echeverria, Brianna Bramato, Nicholas McHugh, David Cooper, Ken Yamada, Matthew Hassler, Hélène Tran, Fen Biao Gao, Robert H. Brown Jr., Anastasia Khvorova","doi":"10.1016/j.omtn.2024.102291","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102291","url":null,"abstract":"A hexanucleotide (GC) repeat expansion (HRE) within intron one of is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). haploinsufficiency, formation of RNA foci, and production of dipeptide repeat (DPR) proteins have been proposed as mechanisms of disease. Here, we report the first example of disease-modifying siRNAs for driven ALS/FTD. Using a combination of reporter assay and primary cortical neurons derived from a C9-ALS/FTD mouse model, we screened a panel of more than 150 fully chemically stabilized siRNAs targeting different transcriptional variants. We demonstrate the lack of correlation between siRNA efficacy in reporter assay versus native environment; repeat-containing mRNA variants are found to preferentially localize to the nucleus, and thus mRNA accessibility and intracellular localization have a dominant impact on functional RNAi. Using a C9-ALS/FTD mouse model, we demonstrate that divalent siRNAs targeting mRNA variants specifically or non-selectively reduce the expression of mRNA and significantly reduce DPR proteins. Interestingly, siRNA silencing all mRNA transcripts was more effective in removing intranuclear mRNA aggregates than targeting only HRE-containing mRNA transcripts. Combined, these data support RNAi-based degradation of as a potential therapeutic paradigm.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"2 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141932107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Novel gene therapy for drug-resistant melanoma: Synergistic combination of PTEN plasmid and BRD4 PROTAC-loaded lipid nanocarriers 耐药性黑色素瘤的新型基因疗法：PTEN 质粒与 BRD4 PROTAC 脂质纳米载体的协同组合

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-07-31 DOI: 10.1016/j.omtn.2024.102292

Aishwarya Saraswat, Hari Priya Vemana, Vikas Dukhande, Ketan Patel

{"title":"Novel gene therapy for drug-resistant melanoma: Synergistic combination of PTEN plasmid and BRD4 PROTAC-loaded lipid nanocarriers","authors":"Aishwarya Saraswat, Hari Priya Vemana, Vikas Dukhande, Ketan Patel","doi":"10.1016/j.omtn.2024.102292","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102292","url":null,"abstract":"Patients suffering from BRAF mutant melanoma have tumor recurrence within merely 7 months of treatment with a potent BRAF inhibitor (BRAFi) like vemurafenib. It has been proven that diverse molecular pathways driving BRAFi resistance converge to activation of c-Myc in melanoma. Therefore, we identified a novel combinatorial therapeutic strategy by targeting loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene and upregulated BRD4 oncoprotein as Myc-dependent vulnerabilities of drug-resistant melanoma. Being promising therapeutic targets, we decided to concomitantly deliver PTEN plasmid and BRD4 targeted PROteolysis-TArgeting Chimera (ARV) to drug the “undruggable” c-Myc in BRAFi-resistant melanoma. Since PTEN plasmid and ARV are distinct in their physicochemical properties, we fabricated PTEN-plasmid loaded lipid nanoparticles (PL-NANO) and ARV-825-loaded nanoliposomes (AL-NANO) to yield a mean particle size of less than 100 nm and greater than 99% encapsulation efficiency for each therapeutic payload. Combination of PL-NANO and AL-NANO displayed synergistic tumor growth inhibition and substantial apoptosis in two-dimensional and three-dimensional models. Importantly, simultaneous delivery of PL-NANO and AL-NANO achieved significant upregulation of PTEN expression levels and degradation of BRD4 protein to ultimately downregulate c-Myc levels in BRAFi-resistant melanoma cells. Altogether, lipid nanocarriers delivering this novel lethal cocktail stands as one-of-a-kind gene therapy to target undruggable c-Myc oncogene in BRAFi-resistant melanoma.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"39 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141932071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

DNA/RNA heteroduplex technology with cationic oligopeptide reduces class-related adverse effects of nucleic acid drugs 带有阳离子寡肽的 DNA/RNA 异源复合物技术可减少核酸药物的类相关不良反应

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-07-31 DOI: 10.1016/j.omtn.2024.102289

Masahiro Ohara, Tetsuya Nagata, Rintaro Iwata Hara, Kie Yoshida-Tanaka, Nozomi Toide, Kazunori Takagi, Kazuki Sato, Tomoya Takenaka, Masanori Nakakariya, Kenichi Miyata, Maeda Yusuke, Kazuko Toh, Takeshi Wada, Takanori Yokota

{"title":"DNA/RNA heteroduplex technology with cationic oligopeptide reduces class-related adverse effects of nucleic acid drugs","authors":"Masahiro Ohara, Tetsuya Nagata, Rintaro Iwata Hara, Kie Yoshida-Tanaka, Nozomi Toide, Kazunori Takagi, Kazuki Sato, Tomoya Takenaka, Masanori Nakakariya, Kenichi Miyata, Maeda Yusuke, Kazuko Toh, Takeshi Wada, Takanori Yokota","doi":"10.1016/j.omtn.2024.102289","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102289","url":null,"abstract":"Antisense oligonucleotides (ASOs) are a therapeutic modality for incurable diseases. However, systemic injection of gapmer-type ASOs causes class-related toxicities, including prolongation of activated partial thromboplastin time (aPTT) and thrombocytopenia. We previously reported that cholesterol-conjugated DNA/RNA heteroduplex oligonucleotides (Chol-HDOs) exhibit significantly enhanced gene-silencing effects compared to ASOs, even in the central nervous system, by crossing the blood-brain barrier. In the present study, we initially evaluated the effect of the HDO structure on class-related toxicities. The HDO structure ameliorated the class-related toxicities associated with ASOs, but they remained to some extent. As a further antidote, we have developed artificial cationic oligopeptides, L-2,4-diaminobutanoic acid oligomers (DabOs), which bind to the phosphates in the major groove of the A-type double-helical structure of HDOs. The DabO/Chol-HDO complex showed significantly improved aPTT prolongation and thrombocytopenia in mice while maintaining gene-silencing efficacy. Moreover, the conjugation with DabOs effectively prevented cerebral infarction, a condition frequently observed in mice intravenously injected with high-dose Chol-HDO. These approaches, combining HDO technology with DabOs, offer distinct advantages over conventional strategies in reducing toxicities. Consequently, the DabO/HDO complex represents a promising platform for overcoming the class-related toxicities associated with therapeutic ASOs.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"98 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141932111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Suppression of HSV-1 infection and viral reactivation by CRISPR-Cas9 gene editing in 2D and 3D culture models 在二维和三维培养模型中通过 CRISPR-Cas9 基因编辑抑制 HSV-1 感染和病毒再活化

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-07-19 DOI: 10.1016/j.omtn.2024.102282

Anna Bellizzi, Senem Çakır, Martina Donadoni, Rahsan Sariyer, Shuren Liao, Hong Liu, Guo-Xiang Ruan, Jennifer Gordon, Kamel Khalili, Ilker K. Sariyer

{"title":"Suppression of HSV-1 infection and viral reactivation by CRISPR-Cas9 gene editing in 2D and 3D culture models","authors":"Anna Bellizzi, Senem Çakır, Martina Donadoni, Rahsan Sariyer, Shuren Liao, Hong Liu, Guo-Xiang Ruan, Jennifer Gordon, Kamel Khalili, Ilker K. Sariyer","doi":"10.1016/j.omtn.2024.102282","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102282","url":null,"abstract":"Although our understanding of herpes simplex virus type 1 (HSV-1) biology has been considerably enhanced, developing therapeutic strategies to eliminate HSV-1 in latently infected individuals remains a public health concern. Current antiviral drugs used for the treatment of HSV-1 complications are not specific and do not address latent infection. We recently developed a CRISPR-Cas9-based gene editing platform to specifically target the HSV-1 genome. In this study, we further used 2D Vero cell culture and 3D human induced pluripotent stem cell-derived cerebral organoid (CO) models to assess the effectiveness of our editing constructs targeting viral ICP0 or ICP27 genes. We found that targeting the ICP0 or ICP27 genes with AAV2-CRISPR-Cas9 vectors in Vero cells drastically suppressed HSV-1 replication. In addition, we productively infected COs with HSV-1, characterized the viral replication kinetics, and established a viral latency model. Finally, we discovered that ICP0- or ICP27-targeting AAV2-CRISPR-Cas9 vector significantly reduced viral rebound in the COs that were latently infected with HSV-1. In summary, our results suggest that CRISPR-Cas9 gene editing of HSV-1 is an efficient therapeutic approach to eliminate the latent viral reservoir and treat HSV-1-associated complications.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"69 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141782960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Immunoactive signatures of circulating tRNA- and rRNA-derived RNAs in chronic obstructive pulmonary disease 慢性阻塞性肺病中循环 tRNA 和 rRNA 衍生 RNA 的免疫活性特征

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-07-19 DOI: 10.1016/j.omtn.2024.102285

Megumi Shigematsu, Takuya Kawamura, Deepak A. Deshpande, Yohei Kirino

{"title":"Immunoactive signatures of circulating tRNA- and rRNA-derived RNAs in chronic obstructive pulmonary disease","authors":"Megumi Shigematsu, Takuya Kawamura, Deepak A. Deshpande, Yohei Kirino","doi":"10.1016/j.omtn.2024.102285","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102285","url":null,"abstract":"Chronic obstructive pulmonary disease (COPD) is the most prevalent lung disease, and macrophages play a central role in the inflammatory response in COPD. We here report a comprehensive characterization of circulating short non-coding RNAs (sncRNAs) in plasma from patients with COPD. While circulating sncRNAs are increasingly recognized for their regulatory roles and biomarker potential in various diseases, the conventional RNA sequencing (RNA-seq) method cannot fully capture these circulating sncRNAs due to their heterogeneous terminal structures. By pre-treating the plasma RNAs with T4 polynucleotide kinase, which converts all RNAs to those with RNA-seq susceptible ends (5′-phosphate and 3′-hydroxyl), we comprehensively sequenced a wide variety of non-microRNA sncRNAs, such as 5′-tRNA halves containing a 2′,3′-cyclic phosphate. We discovered a remarkable accumulation of the 5′-half derived from tRNA in plasma from COPD patients, whereas the 5′-tRNA half is predominant in healthy donors. Further, the 5′-tRNA half activates human macrophages via Toll-like receptor 7 and induces cytokine production. Additionally, we identified circulating rRNA-derived fragments that were upregulated in COPD patients and demonstrated their ability to induce cytokine production in macrophages. Our findings provide evidence of circulating, immune-active sncRNAs in patients with COPD, suggesting that they serve as inflammatory mediators in the pathogenesis of COPD.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"20 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141872466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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