Nucleic acid therapeutics最新文献_第2页

Optimized Chemical Modifications Enhance Lipid Nanoparticle-Mediated siRNA Silencing of YAP1 and WWTR1. 优化的化学修饰增强脂质纳米颗粒介导的siRNA沉默YAP1和WWTR1。

IF 4.5 2区医学

Nucleic acid therapeutics Pub Date : 2026-10-01 Epub Date: 2026-07-21 DOI: 10.1177/21593337261469503

Kaito Ueda, Tatsuki Sato, Jumpei Sasaki, Kazuki Hashiba, Tomonari Mizuno, Hiroshi Yamada, Masayuki Sugimoto

{"title":"Optimized Chemical Modifications Enhance Lipid Nanoparticle-Mediated siRNA Silencing of YAP1 and WWTR1.","authors":"Kaito Ueda, Tatsuki Sato, Jumpei Sasaki, Kazuki Hashiba, Tomonari Mizuno, Hiroshi Yamada, Masayuki Sugimoto","doi":"10.1177/21593337261469503","DOIUrl":"10.1177/21593337261469503","url":null,"abstract":"Lipid nanoparticles (LNPs) are clinically validated carriers for the delivery of small interfering RNA (siRNA). Their efficient tissue accessibility and cellular uptake complement conjugated siRNA approaches. While chemical modifications are critical for stabilizing siRNAs and enhancing their potency (particularly in conjugated formats), their contribution in LNP delivery is not fully understood. Here, we systematically evaluated advanced sequence-modification patterns in siRNAs targeting YAP1 and WWTR1 to define their impact on LNP-siRNAs. We found that siRNAs fully incorporating 2'-O-methyl (2'-OMe), 2'-fluoro nucleotides achieved superior knockdown efficacy in vivo compared with partially modified LNP-siRNAs typically used in clinical drugs. Further increasing the proportion of 2'-OMe to 86% did not impair RNA interference activity, and DNA substitutions provide additional opportunities for structural optimization to collectively enhance knockdown efficacy in mouse liver. In contrast, 5'-(E)-vinylphosphonate modification of the guide strand provides no benefit to knockdown efficacy in vitro or in vivo, likely owing to differences in endosomal trafficking between LNP and conjugated siRNAs. These findings provide a framework for chemical optimization of LNP-based siRNAs. The generation of siRNAs with greater efficacy and longer durability facilitates lower doses with less frequent administration, which mitigates LNP-associated toxicity and improves the therapeutic potential of LNP delivery systems.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"253-263"},"PeriodicalIF":4.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549809","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

Aptamers: Current Applications in Leukemia Diagnostics and Therapeutics. 适配体：目前在白血病诊断和治疗中的应用。

IF 4.5 2区医学

Nucleic acid therapeutics Pub Date : 2026-08-01 Epub Date: 2026-06-15 DOI: 10.1177/21593337261458148

Bahareh Hosseinpour, Joshua O'Grady, Neda Mohaghegh, Julie Hamati, Erin M McConnell, William G Willmore, Alireza Hassani Najafabadi, Maria C DeRosa

{"title":"Aptamers: Current Applications in Leukemia Diagnostics and Therapeutics.","authors":"Bahareh Hosseinpour, Joshua O'Grady, Neda Mohaghegh, Julie Hamati, Erin M McConnell, William G Willmore, Alireza Hassani Najafabadi, Maria C DeRosa","doi":"10.1177/21593337261458148","DOIUrl":"10.1177/21593337261458148","url":null,"abstract":"Aptamers are single-stranded synthetic oligonucleotides that bind noncovalently to targets with high affinity and selectivity. They are generated through an in vitro selection process known as Systematic Evolution of Ligands by Exponential Enrichment. Aptamers show significant promise in cancer diagnostics and therapeutics due to their specificity, versatility, and tunable biochemical properties. Aptamers can be used to target cellular biomarkers, which are detectable molecules that can indicate specific physiological states of cells, organs, and organisms, making them valuable indicators for diseases. Clinical trials on therapeutic aptamers are providing further insight into their potential use. Leukemia is a hematological malignancy characterized by the uncontrolled proliferation of abnormal blood-forming cells, primarily affecting the bone marrow and peripheral blood. This review will highlight the applications of aptamers in relation to the diagnosis and treatment of leukemia. Novel research on leukemia-related aptamers will be presented along with future directions for aptamer-based diagnostic and therapeutic methods.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"187-201"},"PeriodicalIF":4.5,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148259071","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

Unraveling the Stereochemical Complexity of Phosphorothioate-Modified Oligonucleotides Using Analytical Technologies. 利用分析技术揭示硫代磷修饰寡核苷酸的立体化学复杂性。

IF 4.5 2区医学

Nucleic acid therapeutics Pub Date : 2026-08-01 Epub Date: 2026-05-27 DOI: 10.1177/21593337261452594

Akanksha Manghrani, Maharshi C Patel, Frank Delaglio, Mohsin Ali, Mirandia Szramowski, Steven Fletcher, Jace W Jones, Robert G Brinson

{"title":"Unraveling the Stereochemical Complexity of Phosphorothioate-Modified Oligonucleotides Using Analytical Technologies.","authors":"Akanksha Manghrani, Maharshi C Patel, Frank Delaglio, Mohsin Ali, Mirandia Szramowski, Steven Fletcher, Jace W Jones, Robert G Brinson","doi":"10.1177/21593337261452594","DOIUrl":"10.1177/21593337261452594","url":null,"abstract":"Oligonucleotide therapeutics are emerging as a promising modality for targeting disease-associated RNAs. Phosphorothioate (PS)-containing oligonucleotides have gained prominence due to their enhanced stability and pharmacodynamic properties. However, current manufacturing practices afford a mixture of Rp and Sp stereoisomers, and this distribution has been linked to changes in product efficacy. Understanding the sensitivity of analytical methods to changes in this quality attribute has therefore become critically important. Here, we used a suite of analytical techniques-ultraviolet (UV) thermal denaturation, circular dichroism (CD), and nuclear magnetic resonance (NMR) spectroscopy-to evaluate the PS diastereomer distribution using Tegsedi, a Food and Drug Administration-approved PS-containing antisense oligonucleotide, and with other synthetic inotersen samples having varied PS diastereomer distributions. While UV and CD techniques showed limited sensitivity, NMR excelled in detecting small changes in the PS diastereomer distribution. The univariate metric of 31P integration was shown to be insufficient for this quality metric evaluation; application of principal component analysis to both 1D 31P and 2D 1H,13C spectra revealed distinct PS changes that arose from the different activators used during manufacturing. This comprehensive evaluation highlights the necessity of advanced analytical techniques in ensuring the quality and consistency of PS-containing oligonucleotide therapeutics.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"202-215"},"PeriodicalIF":4.5,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148033671","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

Exploring Clearance Pathways for GalNAc-siRNAs: Insights into Intracellular Kinetics and Therapeutic Implications. 探索galnac - sirna的清除途径：细胞内动力学和治疗意义的见解。

IF 4.5 2区医学

Nucleic acid therapeutics Pub Date : 2026-08-01 Epub Date: 2026-06-09 DOI: 10.1177/21593337261457402

Madeline C Tompach, Kevin Craig, Shrutokirti De

{"title":"Exploring Clearance Pathways for GalNAc-siRNAs: Insights into Intracellular Kinetics and Therapeutic Implications.","authors":"Madeline C Tompach, Kevin Craig, Shrutokirti De","doi":"10.1177/21593337261457402","DOIUrl":"10.1177/21593337261457402","url":null,"abstract":"Small interfering RNA (siRNA) represents a transformative therapeutic class that enables precise gene silencing through RNA interference (RNAi). N-acetyl galactosamine (GalNAc)-conjugated siRNAs have achieved remarkable clinical success with six FDA-approved therapeutics targeting liver diseases. Following subcutaneous administration, GalNAc-siRNAs rapidly accumulate in hepatocytes via asialoglycoprotein receptor (ASGPR)-mediated endocytosis and are sequestered within endolysosomal compartments, creating an intracellular depot that sustains therapeutic effects for weeks to months. While RNAi-mediated degradation and nuclease metabolism contribute to siRNA clearance, the detection of full-length, active siRNA in circulation long after dosing suggests alternative clearance mechanisms exist. This review examines the pharmacokinetic properties and intracellular trafficking of GalNAc-siRNA, with particular focus on underexplored clearance pathways from hepatocytes. We discuss potential mechanisms including endosomal recycling, efflux via exosomes and lysosomal exocytosis that may facilitate siRNA redistribution from tissues to circulation. Understanding these clearance mechanisms could enable correlation of plasma and tissue drug concentrations, reduce preclinical animal use, inform clinical dosing strategies and guide the design of next-generation siRNA therapeutics with optimized tissue residence time and enhanced therapeutic durability.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"177-186"},"PeriodicalIF":4.5,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148212049","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 Approval of Redemplo for Familial Chylomicronemia Syndrome and the Many Flavors of GalNAc-Oligonucleotides. Redemplo治疗家族性乳糜微粒血症综合征的批准及galnac -寡核苷酸的多种风味。

IF 4.5 2区医学

Nucleic acid therapeutics Pub Date : 2026-06-01 Epub Date: 2026-03-24 DOI: 10.1177/21593337261435980

Julia F Alterman, Katherine Y Gross, Anastasia Khvorova

引用次数: 0

Efficient Downregulation of Flt-1 Mediated by Splice Switching ASO in Murine Endothelial Cells. 剪接开关ASO介导的Flt-1在小鼠内皮细胞中的有效下调

IF 4.5 2区医学

Nucleic acid therapeutics Pub Date : 2026-06-01 Epub Date: 2026-04-03 DOI: 10.1177/21593337261435971

Mathilde Blitek, Olivier Le Coz, Vincent Ogor, Hassan H Fakih, Anastasia Khvorova, Aurélie Goyenvalle

{"title":"Efficient Downregulation of Flt-1 Mediated by Splice Switching ASO in Murine Endothelial Cells.","authors":"Mathilde Blitek, Olivier Le Coz, Vincent Ogor, Hassan H Fakih, Anastasia Khvorova, Aurélie Goyenvalle","doi":"10.1177/21593337261435971","DOIUrl":"10.1177/21593337261435971","url":null,"abstract":"Impaired angiogenesis is a common feature of several pathological conditions, including neuromuscular disorders. Such vascular defects not only contribute to disease progression but also may compromise the efficacy of systemically delivered therapies such as antisense oligonucleotides (ASOs) and adeno-associated virus vectors. Enhancing muscle vascularization is therefore an attractive strategy to improve both therapeutic delivery and tissue regeneration. Vascular endothelial growth factor A (VEGF-A) is the principal driver of angiogenesis, but its bioavailability is negatively regulated by VEGFR1/Flt-1, a high-affinity decoy receptor. Here, we investigated a splice-switching ASO (SSO) approach to downregulate Flt-1 expression in murine endothelial cells. We designed ASOs to induce skipping of an out-of-frame exon in the Flt1 transcript, triggering nonsense-mediated decay and reducing protein expression. Screening in C166 endothelial cells identified a lead SSO that efficiently skipped exon 5, resulting in robust Flt-1 downregulation, similar to levels achieved with a control siRNA. Functionally, Flt-1 knockdown enhanced endothelial cell proliferation, survival, and migration upon VEGF-A stimulation. These results provide proof-of-concept for targeting Flt-1 via exon skipping to promote angiogenesis, with potential applications in degenerative or ischemic contexts where vascularization is impaired.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"147-157"},"PeriodicalIF":4.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147616531","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

Rat and Rabbit Whole-Embryo Culture as a New Approach Method for Unlabeled Therapeutic Antisense Oligonucleotide Hazard Identification with No Requirement for Microinjection or Assisted Transfection. 大鼠和家兔全胚胎培养作为无标记治疗性反义寡核苷酸危险鉴定的新方法，无需显微注射或辅助转染。

IF 4.5 2区医学

Nucleic acid therapeutics Pub Date : 2026-06-01 Epub Date: 2026-05-04 DOI: 10.1177/21593337261442471

Sara M Bender, Sharon Chapman, Sreenivas Nannapaneni, Joel D Parry, Joyce Rendemonti, Stanley Robinson, Bradley Spencer-Dene, Dinesh Stanislaus

{"title":"Rat and Rabbit Whole-Embryo Culture as a New Approach Method for Unlabeled Therapeutic Antisense Oligonucleotide Hazard Identification with No Requirement for Microinjection or Assisted Transfection.","authors":"Sara M Bender, Sharon Chapman, Sreenivas Nannapaneni, Joel D Parry, Joyce Rendemonti, Stanley Robinson, Bradley Spencer-Dene, Dinesh Stanislaus","doi":"10.1177/21593337261442471","DOIUrl":"10.1177/21593337261442471","url":null,"abstract":"The developmental hazard screening of oligonucleotide therapeutics (ONTs) presents challenges due to their frequent lack of pharmacology in nonclinical species and embryo-fetal exposure is presumed to be limited in vivo. This study demonstrates that direct culture in media containing mipomersen, a 2'-O-methoxyethyl phosphorothioated antisense oligonucleotide (ASO), results in dose-responsive morphological changes in rat and rabbit whole-embryo culture (WEC). Automated miRNAscope in situ hybridization was used to confirm dose-dependent embryonic exposure and visualize the distribution pattern of mipomersen in the embryo and extraembryonic membranes, suggesting that ONTs may enter the umbilical vasculature and pass into embryo circulation. Neither microinjections nor assisted transfections were required to achieve embryonic exposure. These findings support the utility of WEC as a new approach method (NAM) for developmental hazard identification of ONTs. WEC could complement or partially replace in vivo studies, reducing animal use and required test material amounts, while enabling robust developmental hazard identification for ONTs. This work informs future safety assessment strategies and regulatory guidance for ONTs.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"158-170"},"PeriodicalIF":4.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147818285","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

Reduced Genotoxicity Testing Is Possible for Noncoding Oligonucleotide-Based Therapeutics Containing Well-Characterized Modifications: A European Regulatory Perspective. 减少基因毒性测试是可能的非编码寡核苷酸为基础的治疗含有良好表征的修饰：欧洲监管的观点。

IF 4.5 2区医学

Nucleic acid therapeutics Pub Date : 2026-06-01 Epub Date: 2026-03-12 DOI: 10.1177/21593337261429852

Clara Stock, Britt Duijndam, Christine L E Siezen, Anna M G Pasmooij

{"title":"Reduced Genotoxicity Testing Is Possible for Noncoding Oligonucleotide-Based Therapeutics Containing Well-Characterized Modifications: A European Regulatory Perspective.","authors":"Clara Stock, Britt Duijndam, Christine L E Siezen, Anna M G Pasmooij","doi":"10.1177/21593337261429852","DOIUrl":"10.1177/21593337261429852","url":null,"abstract":"There is a current lack of harmonized regulatory guidance in evaluating the genotoxic potential of oligonucleotide-based therapeutics (ONTs). In particular, guidance has not established the circumstances under which it is acceptable to deviate from the standard test battery. In this study, we analyzed genotoxicity testing strategies and supporting rationales for 91 noncoding ONTs receiving European Scientific Advice between 2004 and 2024. While the standard test battery was performed for the majority of ONTs, reduced test approaches were proposed for 10 products. Furthermore, we examined both the positions of applicants and corresponding European Union (EU) regulatory opinions to identify critical considerations in evaluating genotoxicity. Our findings show that EU regulators see opportunities to deviate from the standard test battery for ONTs if sufficient evidence for class experience can be demonstrated. This was confirmed for several ONTs with well-characterized chemical modifications (ie, phosphorothioate, 2'-methoxyethyl, and 2'-Omethyl), making the standard battery redundant in these cases. Although all reported genotoxicity tests have been uniformly negative, uncertainty remains for future modifications. Ideally, what constitutes sufficient evidence for class experience should be defined in the upcoming International Council for Harmonisation guideline addressing the nonclinical safety evaluation of ONTs (ICH S13), which would allow regulators to accept reduced testing. Together with the industry sharing more knowledge and underlying data that support growing class experience, this development can promote a harmonized approach for future genotoxicity testing of noncoding ONTs.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"135-146"},"PeriodicalIF":4.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147444492","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

Effects of N-1-Mer Impurities in Antisense Oligonucleotides on the Target RNA Suppression. 反义寡核苷酸中N-1-Mer杂质对靶RNA抑制的影响。

IF 4.5 2区医学

Nucleic acid therapeutics Pub Date : 2026-04-01 Epub Date: 2026-02-04 DOI: 10.1177/21593337261419436

Tomoka Akita, Elisa Tomita-Sudo, Renshin Sano, Nae Sakimoto, Shigenori Iwai, Hirokazu Nankai, Satoshi Obika, Takao Inoue, Junji Kawakami

引用次数: 0

Conjugated Antisense Oligonucleotides for Skipping of Duchenne Muscular Dystrophy Exon 53: A Cautionary Study. 杜氏肌萎缩症外显子53的共轭反义寡核苷酸跳跃：一个警示研究。

IF 4.5 2区医学

Nucleic acid therapeutics Pub Date : 2026-04-01 Epub Date: 2025-12-22 DOI: 10.1177/21593337251405312

Emma T Groenwold, Alicia Montulet, Tiberiu Stan, Davy van de Vijver, Diana McCorquodale, Nicholas McHugh, Dimas Echeverria, Christa Tanganyika-de Winter, Maarten van de Wal, Daniel O'Reilly, Anastasia Khvorova, Annemieke Aartsma-Rus, Masad J Damha

引用次数: 0