Nucleic acid therapeutics最新文献_第3页

Considerations for Creating the Next Generation of RNA Therapeutics: Oligonucleotide Chemistry and Innate Immune Responses to Nucleic Acids. 创造下一代 RNA 疗法的考虑因素：寡核苷酸化学与核酸的先天免疫反应。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-04-01 DOI: 10.1089/nat.2024.29009.sud

Sudhir Agrawal

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Understanding and Rescuing the Splicing Defect Caused by the Frequent ABCA4 Variant c.4253+43G>A Underlying Stargardt Disease. 了解并挽救由频发 ABCA4 变异 c.4253+43G>A 导致的剪接缺陷，它是斯塔加特病的基础。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-04-01 Epub Date: 2024-03-12 DOI: 10.1089/nat.2023.0076

Nuria Suárez-Herrera, Alejandro Garanto, Rob W J Collin

{"title":"Understanding and Rescuing the Splicing Defect Caused by the Frequent ABCA4 Variant c.4253+43G>A Underlying Stargardt Disease.","authors":"Nuria Suárez-Herrera, Alejandro Garanto, Rob W J Collin","doi":"10.1089/nat.2023.0076","DOIUrl":"10.1089/nat.2023.0076","url":null,"abstract":"Pathogenic variants in ABCA4 are the underlying molecular cause of Stargardt disease (STGD1), an autosomal recessive macular dystrophy characterized by a progressive loss of central vision. Among intronic ABCA4 variants, c.4253+43G>A is frequently detected in STGD1 cases and is classified as a hypomorphic allele, generally associated with late-onset cases. This variant was previously reported to alter splicing regulatory sequences, but the splicing outcome is not fully understood yet. In this study, we attempted to better understand its effect on splicing and to rescue the aberrant splicing via antisense oligonucleotides (AONs). Wild-type and c.4253+43G>A variant-harboring maxigene vectors revealed additional skipping events, which were not previously detected upon transfection in HEK293T cells. To restore exon inclusion, we designed a set of 27 AONs targeting either splicing silencer motifs or the variant region and screened these in maxigene-transfected HEK293T cells. Candidate AONs able to promote exon inclusion were selected for further testing in patient-derived photoreceptor precursor cells. Surprisingly, no robust splicing modulation was observed in this model system. Overall, this research helped to adequately characterize the splicing alteration caused by the c.4253+43G>A variant, although future development of AON-mediated exon inclusion therapy for ABCA4 is needed.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"73-82"},"PeriodicalIF":4.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140102082","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}

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Simplified Oligonucleotide Phosphorus Deprotection Process with Reduced 3-(2-Cyanoethyl) Thymidine Impurities. 减少 3-(2-氰乙基)胸苷杂质的简化寡核苷酸去磷工艺。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-04-01 Epub Date: 2024-02-05 DOI: 10.1089/nat.2023.0060

Xuan Zhou, Xianglin Shi, Yannick Fillon, Firoz Antia, Thomas Pickel, Jing Yang, William Zhang, Armin Delavari, Jiabao Zhang

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Nucleic Acid Therapeutics: Successes, Milestones, and Upcoming Innovation. 核酸疗法：成功、里程碑和即将到来的创新。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-04-01 Epub Date: 2024-03-20 DOI: 10.1089/nat.2023.0068

Jillian Belgrad, Hassan H Fakih, Anastasia Khvorova

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RNA Interference Effectors Selectively Silence the Pathogenic Variant GNAO1 c.607 G > A In Vitro. RNA 干扰效应器可选择性地抑制体外致病变体 GNAO1 c.607 G > A。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-04-01 Epub Date: 2024-01-12 DOI: 10.1089/nat.2023.0043

Natalia V Klementieva, Evgenii A Lunev, Anna A Shmidt, Elizaveta M Loseva, Irina M Savchenko, Ekaterina A Svetlova, Ivan I Galkin, Anna V Polikarpova, Evgeny V Usachev, Svetlana G Vassilieva, Valeria I Marina, Marina A Dzhenkova, Anna D Romanova, Anton V Agutin, Anna A Timakova, Denis A Reshetov, Tatiana V Egorova, Maryana V Bardina

{"title":"RNA Interference Effectors Selectively Silence the Pathogenic Variant GNAO1 c.607 G > A In Vitro.","authors":"Natalia V Klementieva, Evgenii A Lunev, Anna A Shmidt, Elizaveta M Loseva, Irina M Savchenko, Ekaterina A Svetlova, Ivan I Galkin, Anna V Polikarpova, Evgeny V Usachev, Svetlana G Vassilieva, Valeria I Marina, Marina A Dzhenkova, Anna D Romanova, Anton V Agutin, Anna A Timakova, Denis A Reshetov, Tatiana V Egorova, Maryana V Bardina","doi":"10.1089/nat.2023.0043","DOIUrl":"10.1089/nat.2023.0043","url":null,"abstract":"RNA interference (RNAi)-based therapeutics hold the potential for dominant genetic disorders, enabling sequence-specific inhibition of pathogenic gene products. We aimed to direct RNAi for the selective suppression of the heterozygous GNAO1 c.607 G > A variant causing GNAO1 encephalopathy. By screening short interfering RNA (siRNA), we showed that GNAO1 c.607G>A is a druggable target for RNAi. The si1488 candidate achieved at least twofold allelic discrimination and downregulated mutant protein to 35%. We created vectorized RNAi by incorporating the si1488 sequence into the short hairpin RNA (shRNA) in the adeno-associated virus (AAV) vector. The shRNA stem and loop were modified to improve the transcription, processing, and guide strand selection. All tested shRNA constructs demonstrated selectivity toward mutant GNAO1, while tweaking hairpin structure only marginally affected the silencing efficiency. The selectivity of shRNA-mediated silencing was confirmed in the context of AAV vector transduction. To conclude, RNAi effectors ranging from siRNA to AAV-RNAi achieve suppression of the pathogenic GNAO1 c.607G>A and discriminate alleles by the single-nucleotide substitution. For gene therapy development, it is crucial to demonstrate the benefit of these RNAi effectors in patient-specific neurons and animal models of the GNAO1 encephalopathy.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"90-99"},"PeriodicalIF":4.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139432811","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

"Goldilocks Modifications" for mRNA Therapeutics Won the Nobel Prize. 用于 mRNA 治疗的 "金发修饰 "荣获诺贝尔奖。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-02-01 Epub Date: 2024-01-30 DOI: 10.1089/nat.2023.0062

Li Li

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Report of the European Medicines Agency Conference on RNA-Based Medicines. 欧洲药品管理局关于基于 RNA 的药物会议的报告。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-02-01 Epub Date: 2024-01-04 DOI: 10.1089/nat.2023.0021

Falk Ehmann, Andreas Kuhn, Anna Maria Gerdina Pasmooij, Anthony Humphreys, Arjon Van Hengel, Brian Dooley, Brigitte Anliker, Camilla Svensson, Daniel Capaldi, David Henshall, Emer Cooke, Haiyan Zhou, Hilde Bastaerts, Jeske Smink, Joop Van Gerven, Leonor Enes, Lubomir Nechev, Marcel Hoefnagel, Mariëtte Driessens, Michael Wenger, Oriane Blanquie, Pawel Widomski, Ralf Herold, René Thürmer, Sol Ruiz, Steffen Thirstrup, Susan Goody, Tal Zaks, Valentina Cordò, Annemieke M Aartsma-Rus

{"title":"Report of the European Medicines Agency Conference on RNA-Based Medicines.","authors":"Falk Ehmann, Andreas Kuhn, Anna Maria Gerdina Pasmooij, Anthony Humphreys, Arjon Van Hengel, Brian Dooley, Brigitte Anliker, Camilla Svensson, Daniel Capaldi, David Henshall, Emer Cooke, Haiyan Zhou, Hilde Bastaerts, Jeske Smink, Joop Van Gerven, Leonor Enes, Lubomir Nechev, Marcel Hoefnagel, Mariëtte Driessens, Michael Wenger, Oriane Blanquie, Pawel Widomski, Ralf Herold, René Thürmer, Sol Ruiz, Steffen Thirstrup, Susan Goody, Tal Zaks, Valentina Cordò, Annemieke M Aartsma-Rus","doi":"10.1089/nat.2023.0021","DOIUrl":"10.1089/nat.2023.0021","url":null,"abstract":"RNA-based medicines have potential to treat a large variety of diseases, and research in the field is very dynamic. Proactively, The European Medicines Agency (EMA) organized a virtual conference on February 2, 2023 to promote the development of RNA-based medicines. The initiative addresses the goal of the EMA Regulatory Science Strategy to 2025 to \"catalyse the integration of science and technology in medicines development.\" The conference focused on RNA technologies (excluding RNA vaccines) and involved different stakeholders, including representatives from academia, industry, regulatory authorities, and patient organizations. The conference comprised presentations and discussion sessions conducted by panels of subject matter experts. In this meeting report, we summarize the presentations and recap the main themes of the panel discussions.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"4-11"},"PeriodicalIF":4.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139087866","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

Reversible Aptamer Staining, Sorting, and Cleaning of Cells (Clean FACS) with Antidote Oligonucleotide or Nuclease Yields Fully Responsive Cells. 用解毒寡核苷酸或核酸酶对细胞进行可逆性色素染色、分选和清洁（清洁荧光激活细胞分选），产生完全响应的细胞。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-02-01 Epub Date: 2024-01-30 DOI: 10.1089/nat.2023.0050

Martin D Requena, Amy Yan, Telmo Llanga, Bruce A Sullenger

{"title":"Reversible Aptamer Staining, Sorting, and Cleaning of Cells (Clean FACS) with Antidote Oligonucleotide or Nuclease Yields Fully Responsive Cells.","authors":"Martin D Requena, Amy Yan, Telmo Llanga, Bruce A Sullenger","doi":"10.1089/nat.2023.0050","DOIUrl":"10.1089/nat.2023.0050","url":null,"abstract":"The ability to reverse the binding of aptamers to their target proteins has received considerable attention for developing controllable therapeutic agents. Recently, use of aptamers as reversible cell-sorting ligands has also sparked interest. Antibodies are currently utilized for isolating cells expressing a particular cell surface receptor. The inability to remove antibodies from isolated cells following sorting greatly limits their utility for many applications. Previously, we described how a particular aptamer-antidote oligonucleotide pair can isolate cells and clean them. Here, we demonstrate that this approach is generalizable; aptamers can simultaneously recognize more than one cell type during fluorescent activated cell sorting (FACS). Moreover, we describe a novel approach to reverse aptamer binding following cell sorting using a nuclease. This alternative strategy represents a cleaning approach that does not require the generation of antidote oligonucleotides for each aptamer and will greatly reduce the cost and expand the utility of Clean FACS.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"12-17"},"PeriodicalIF":4.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11302193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139575909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Safety and Tolerability of GalNAc₃-Conjugated Antisense Drugs Compared to the Same-Sequence 2'-O-Methoxyethyl-Modified Antisense Drugs: Results from an Integrated Assessment of Phase 1 Clinical Trial Data. GalNAc3共轭反义药物与同序列2'-O-甲氧基乙基修饰反义药物相比的安全性和耐受性：1期临床试验数据的综合评估结果。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-02-01 Epub Date: 2024-01-16 DOI: 10.1089/nat.2023.0026

Brenda F Baker, Shuting Xia, Wesley Partridge, Jeffery A Engelhardt, Sotirios Tsimikas, Stanley T Crooke, Sanjay Bhanot, Richard S Geary

{"title":"Safety and Tolerability of GalNAc3-Conjugated Antisense Drugs Compared to the Same-Sequence 2'-O-Methoxyethyl-Modified Antisense Drugs: Results from an Integrated Assessment of Phase 1 Clinical Trial Data.","authors":"Brenda F Baker, Shuting Xia, Wesley Partridge, Jeffery A Engelhardt, Sotirios Tsimikas, Stanley T Crooke, Sanjay Bhanot, Richard S Geary","doi":"10.1089/nat.2023.0026","DOIUrl":"10.1089/nat.2023.0026","url":null,"abstract":"The triantennary N-acetylgalactosamine (GalNAc3) cluster has demonstrated the utility of receptor-mediated uptake of ligand-conjugated antisense drugs targeting RNA expressed by hepatocytes. GalNAc3-conjugated 2'-O-methoxyethyl (2'MOE) modified antisense oligonucleotides (ASOs) have demonstrated a higher potency than the unconjugated form to support lower doses for an equivalent pharmacological effect. We utilized the Ionis integrated safety database to compare four GalNAc3-conjugated and four same-sequence unconjugated 2'MOE ASOs. This assessment evaluated data from eight randomized placebo-controlled dose-ranging phase 1 studies involving 195 healthy volunteers (79 GalNAc3 ASO, 24 placebo; 71 ASO, 21 placebo). No safety signals were identified by the incidence of abnormal threshold values in clinical laboratory tests for either ASO group. However, there was a significant increase in mean alanine transaminase levels compared with placebo in the upper dose range of the unconjugated 2'MOE ASO group. The mean percentage of subcutaneous injections leading to local cutaneous reaction was 30-fold lower in the GalNAc3-conjugated ASO group compared with the unconjugated ASO group (0.9% vs. 28.6%), with no incidence of flu-like reactions (0.0% vs. 0.7%). Three subjects (4.2%) in the unconjugated ASO group discontinued dosing. An improvement in the overall safety and tolerability profile of GalNAc3-conjugated 2'MOE ASOs is evident in this comparison of short-term clinical data in healthy volunteers.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"18-25"},"PeriodicalIF":4.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139479072","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

Acknowledgment of Reviewers 2023. 鸣谢 2023 年审稿人。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-02-01 Epub Date: 2023-12-14 DOI: 10.1089/nat.2023.29008.ack

引用次数: 0