Nucleic acid therapeutics最新文献

{"title":"Programmable RNA Editing via Adenosine Deaminase Acting on RNA Enzymes: Current Advances and Clinical Potential.","authors":"Jinsil Kim, Hyuk Gyoon Lee, Minwook Shin","doi":"10.1177/21593337251415115","DOIUrl":"10.1177/21593337251415115","url":null,"abstract":"<p><p>Adenosine deaminase acting on RNA (ADAR)-mediated RNA editing has emerged as a powerful and precise technology for modifying RNA transcripts, enabling correction of disease-causing mutations without permanent changes to the genome. Recent advances in ADAR protein engineering, guide RNA design, and delivery methods have significantly improved editing efficiency and specificity, overcoming many initial limitations. These developments have expanded the therapeutic potential of ADAR-based editing across a range of conditions, including genetic disorders, cancer, metabolic diseases, and neurodegenerative disorders. Notably, several ADAR-based therapeutics have now entered early clinical trials, marking a critical milestone in translating this technology from bench to bedside. Moreover, its inherent programmability, reversibility, and transient nature make ADAR-mediated RNA editing a highly attractive platform for personalized medicine, enabling tailored interventions based on individual genetic profiles and disease contexts. This review provides a comprehensive comparison of recent innovative advancements in ADAR-based RNA editing technologies, their use in diverse contexts pertinent to human diseases, the key challenges that remain, and future directions for their therapeutic implementation.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"61-83"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147628061","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}

{"title":"Investigating the Biophysical Properties and <i>In Vivo</i> Activity of 7',5'-Alpha-Bicyclo-DNA Phosphodiester Backbone Gapmer Antisense Oligonucleotides.","authors":"Damien Evequoz, Remya R Nair, Martina Cadeddu, Inês Fial, Tarin Taleb, Jasmine E Bird, Hemaprakash Nanja Reddy, Alexander W Jackson, Andrés Correa-Sánchez, Xiao Wan, Joanna E Parkes, Wolfgang Renner, Peter L Oliver","doi":"10.1177/21593337261417504","DOIUrl":"10.1177/21593337261417504","url":null,"abstract":"<p><p>Advances in backbone modifications are driving the development of nucleic acid therapeutics, yet there is still a need to establish compounds that avoid the potential dose-limiting toxicity of phosphorothioate internucleosidic linkages, particularly outside the central nervous system. We have developed a novel 7',5'-α-bc-DNA (abcDNA) scaffold, and here we benchmark the biophysical and <i>in vivo</i> gene knockdown efficacy of gapmer antisense oligonucleotides (ASOs) containing abcDNA nucleotides. Melting curve analyses show gapmers with abcDNA bases in both wings maintain a good affinity for complementary RNA and demonstrate stable mismatch discrimination, in addition to a high degree of serum biostability. To assess <i>in vivo</i> on-target activity and tolerability, mice were dosed systemically with abcDNA ASOs targeting <i>Malat-1</i>, with or without conjugation to palmitic acid. Multiple tissues were assessed for on-target knockdown efficiency by RT-PCR and <i>in situ</i> hybridization alongside biodistribution analysis by immunohistochemistry. abcDNA ASOs were well tolerated and performed at a comparable level to an equivalent 2'-<i>O</i>-methoxyethylribose gapmer. We also present the first <i>in vivo</i> pharmacokinetic data generated using an enzyme-free nucleic acid nanorobotics method. Together, these data support the utility of abcDNA as a valuable addition to ASO technology that maintains a natural phosphodiester backbone, providing a combination of preferred biostability and on-target affinity with acceptable <i>in vivo</i> tolerability.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"84-99"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146227545","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}

{"title":"An RNA Aptamer Targeting PAI-1 That Restores tPA Activity, Unexpectedly Suppresses Cancer Cell Progression.","authors":"Christopher Hu, Austin Schneidler, Mamadou Barry, Michelle Gimba, Sihan Zhou, Yolanda M Fortenberry","doi":"10.1177/21593337251404397","DOIUrl":"10.1177/21593337251404397","url":null,"abstract":"<p><p>Plasminogen activator inhibitor-1 (PAI-1), the primary physiological inhibitor of tissue-type plasminogen activator (tPA), is a key regulator of fibrinolysis. Elevated levels of PAI-1 are linked to thrombotic disorders and correlate with poor prognosis across various cancers. In this study, we further characterize the RNA aptamer R10-4, previously shown to bind PAI-1 with high affinity and inhibit its antiproteolytic activity. While R10-4's role in modulating fibrinolysis is established, its influence on cancer cell behavior remains unclear. Here, we demonstrate that intracellular transfection of R10-4 in triple negative breast cancer cells significantly impairs migration and invasion without affecting proliferation, mirroring the effects observed with other PAI-1-specific RNA aptamers. Moreover, conditioned media from R10-4 transfected cells suppress endothelial tube formation and exhibit reduced secretion of the pro-angiogenic chemokine (C-C) motif ligand 5 (CCL5). Collectively, these findings reveal that R10-4 restores fibrinolytic balance and disrupts PAI-1-mediated tumor progression, positioning it as a promising multifunctional candidate for therapeutic development.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"117-121"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724970","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}

{"title":"Targeting a Pathogenic Variant Creating an Upstream AUG in the <i>ENG</i> 5' Untranslated Region with Antisense Oligonucleotides Fails to Restore Protein Expression.","authors":"Mathilde Doisy, Aris Gaci, Omar Soukarieh, Carole Proust, David-Alexandre Trégouët, Aurélie Goyenvalle","doi":"10.1177/21593337251396711","DOIUrl":"10.1177/21593337251396711","url":null,"abstract":"<p><p>Pathogenic variants creating upstream open reading frames (uORFs) in the 5' untranslated region (5'UTR) of the <i>ENG</i> gene can disrupt translation from the main ORF and contribute to hereditary hemorrhagic telangiectasia (HHT). This is the case of the <i>ENG</i> c.-79C>T that introduces a uAUG shown to decrease endoglin expression and associates with HHT. Here, we investigated whether 2'-O-methyl (2'OMe) antisense oligonucleotides (ASOs) could restore protein levels by masking this aberrant uAUG or by targeting predicted secondary structures within the <i>ENG</i> 5'UTR. Several ASOs of varying lengths and backbone chemistries (full phosphodiester or full phosphorothioate) were designed to target the mutant region. Their effects were evaluated in HeLa cells transfected and in HUVECs transduced with wild-type or mutant <i>ENG</i> constructs. Transfection efficiency was verified by <i>MALAT1</i> knockdown via qPCR, and endoglin protein levels were assessed by Western blot. Despite efficient ASO delivery and optimized experimental conditions, no reproducible increase in endoglin expression was observed upon ASO treatment. These findings highlight the limitations of steric-blocking ASOs targeting 5'UTR variants and underscore the need for deeper mechanistic understanding of uORF-mediated translational regulation.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"12-22"},"PeriodicalIF":4.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145541537","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}

{"title":"Class-Specific Adverse Events of Patients Treated with Small Interfering RNA Therapeutics: A Disproportionality Analysis of the United States Food and Drug Administration Adverse Event Reporting System Database Based on the MY FAERS Platform.","authors":"Ze Li, Xiaozhen Wang, Dandan Li, Yiqi Sun, Lin Zhang, Xingang Li","doi":"10.1177/21593337251391029","DOIUrl":"10.1177/21593337251391029","url":null,"abstract":"<p><p>Small interfering RNA (siRNA) therapeutics represent a transformative class of drugs, but their class-specific adverse events (CAE-siRNA) remain incompletely characterized. This study aimed to identify and quantify CAE-siRNA associated with U.S. Food and Drug Administration (FDA)-approved siRNA drugs (patisiran, givosiran, vutrisiran, inclisiran, and lumasiran) using real-world pharmacovigilance data, focusing on potential class-wide effects. A disproportionality analysis was conducted using the FDA Adverse Event Reporting System database (2014-2025Q2) accessed via the MY FAERS platform. The reporting odds ratio (ROR) with 95% confidence interval (CI) was calculated, with signals defined by a lower CI >1 and ≥3 cases. Sensitivity analyses included indication-matched populations (IMPs) and exclusion of concomitant medications. Causality was assessed using Bradford Hill criteria. Among 6200 siRNA-treated patients, 45 CAE-siRNA spanning 10 system organ classes were identified. Pain and pain in extremity, fatigue, and gastrointestinal disorders were the most frequently reported. Notably, patisiran was associated with an elevated risk of back pain (ROR: 2.28, 95% CI: 1.84-2.83), whereas givosiran exhibited significant signals for stress (ROR: 5.29, 95% CI: 3.64-7.70) and weight loss (ROR: 2.35, 95% CI: 1.74-3.16). Of particular concern, inclisiran demonstrated strong hepatic toxicity signals (ROR ranging from 9.11 to 86.06) along with discomfort (ROR: 3.60, 95% CI: 1.34-9.65). Sensitivity analyses confirmed robustness across subgroups. Furthermore, causality assessment supported a likely association between the hepatic toxicity and inclisiran. This study identified clinically relevant CAE-siRNA, particularly hepatic toxicity for inclisiran, supporting enhanced monitoring. While disproportionality analyses are hypothesis generating, these findings underscore the need for targeted pharmacovigilance to optimize the safety of this promising drug class.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"23-36"},"PeriodicalIF":4.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582266","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}

{"title":"Antisense Oligonucleotide Quantification via Splint-Ligation PCR Assay in Nonhuman Primate Central Nervous System Tissues and Biofluids.","authors":"Thomas Jepp, Sarah Christian, Scott V Dindot","doi":"10.1177/21593337251391564","DOIUrl":"10.1177/21593337251391564","url":null,"abstract":"<p><p>Antisense oligonucleotides (ASOs) are chemically modified single-stranded oligonucleotides used to modulate the expression or processing of a target RNA transcript. The development of ASOs to treat human disease requires extensive preclinical studies in animal models. A critical component of these studies is determining the concentration of the ASO in tissues and biofluids, which are used to estimate the distribution, half-life, and dose-response relationship. The methods used to quantify ASOs are often constrained by low sensitivities, poor dynamic ranges, and the use of highly specialized equipment. Here, we describe the development of a Splint-Ligation-based quantitative PCR assay to measure the concentration of ASOs in nonhuman primate (NHP) tissues and biofluids. Our results show that the Splint Ligation Assay was highly sensitive across central nervous system (CNS) tissues and biofluids (as low as 100 pM in NHP CNS tissue and 1 pM in NHP plasma), with broad linear dynamic ranges. Overall, our results show that the Splint-Ligation PCR Assay is a reliable, sensitive, and feasible method of ASO quantification.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"37-46"},"PeriodicalIF":4.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145669368","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}

{"title":"Applying Synthetic Nucleic Acid Therapeutics to Gene Activation for Haploinsufficient Diseases.","authors":"Victor Tse, David R Corey","doi":"10.1177/21593337251404407","DOIUrl":"10.1177/21593337251404407","url":null,"abstract":"<p><p>Haploinsufficient autosomal dominant diseases are due to heterozygous mutations that cause inadequate protein expression. Compounds that increase expression of the wild-type allele would be one strategy for treating patients. Synthetic antisense oligonucleotides and double-stranded RNAs have the potential to increase gene expression, making them starting points for drug development. Our goal is to outline strategies for using synthetic nucleic acids to enhance gene expression. We discuss the strengths and limitations of these strategies and the practical challenges behind upregulating the expression of genes as a treatment for haploinsufficient autosomal dominant diseases.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"1-11"},"PeriodicalIF":4.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13535617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145810334","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}

{"title":"Unveiling Liver Micro-Distribution: NanoSIMS Imaging Reveals Critical Intracellular Distribution of Chemically Modified Antisense Oligonucleotides.","authors":"Hidenori Yasuhara, Kenta Kadotsuji, Kenichi Watanabe, Tomomi Kakutani, Tomoaki Tochitani, Izuru Mise, Mei Konishi, Tetsuya Nakagawa, Izuru Miyawaki","doi":"10.1177/21593337251399181","DOIUrl":"10.1177/21593337251399181","url":null,"abstract":"<p><p>Antisense oligonucleotides (ASOs) represent a promising class of therapeutic agents; yet, their efficacy and/or toxicity profiles are heavily dependent on their tissue distribution and cellular uptake. This study employs nanoscale secondary ion mass spectrometry (NanoSIMS) imaging to elucidate the intracellular distribution of chemically modified ASOs in liver tissue with ultra-high resolution. We demonstrated that fully phosphorothioated ASOs predominantly accumulated in the vesicular structures near nonparenchymal cells, including Kupffer cells. In contrast, partially phosphorothioated ASOs exhibit a uniform distribution throughout the liver. Notably, despite similar overall liver concentrations, ASOs with different chemical modifications exhibited markedly distinct intracellular distribution patterns. These findings highlight the critical importance of subcellular distribution in ASO drug discovery and underscore the utility of NanoSIMS in visualizing the ASO biodistribution. This approach, when combined with electron microscopy, provides invaluable insights into the chemical composition and localization of ASOs within cellular compartments. This study not only advances our understanding of ASO behavior <i>in vivo</i> but also highlights the potential of high-resolution imaging techniques in optimizing ASO delivery strategies. These insights are crucial for enhancing the efficacy and minimizing the adverse effects of ASO-based therapeutics, paving the way for more targeted and effective treatments.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"47-55"},"PeriodicalIF":4.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636848","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}

{"title":"Use of a Transgenic Human PNPLA3^I148M Knock-in Mouse for Translational Safety Evaluations of siRNA Therapeutics.","authors":"Ben Brooks, Artem Shkumatov, Jackson Kalanzi, Kim Henderson Park, Julie M Lade, Diana Wong, Hui Dou, Jason Long, Ingrid C Rulifson, Justin K Murray, Lauren Mihalcik, Tod A Harper","doi":"10.1177/21593337251375804","DOIUrl":"10.1177/21593337251375804","url":null,"abstract":"<p><p>The <i>PNPLA3</i> single nucleotide polymorphism, rs738409, is the strongest known genetic risk factor for metabolic dysfunction-associated steatotic liver disease; thus, targeting the minor allele with a GalNAc-conjugated siRNA is an attractive strategy to treat patients carrying the genetic variant. To enable translational safety assessment of a GalNAc-conjugated siRNA that specifically targets the rs738409 sequence of <i>PNPLA3</i>, a transgenic human <i>PNPLA3^I148M</i> knock-in mouse (hu<i>PNPLA3^I148M</i>) was utilized. This model showed no significant genotype-related phenotypic differences to wild-type mice in a phenotype characterization study when maintained on standard rodent chow. Additionally, a repeat-dose toxicology study using a GalNAc-conjugated siRNA specific for rs738409 resulted in comparable findings between genotypes (i.e., liver enzyme and histopathology changes), indicating the findings were due to the siRNA therapeutic and not a result of target knockdown in hu<i>PNPLA3^I148M</i> mice. Overall, these data demonstrate the hu<i>PNPLA3^I148M</i> mouse is suitable for repeat-dose toxicology studies, suggesting this approach could be applied to other siRNA programs lacking a pharmacologically relevant nonclinical species to support translational safety assessments during drug development.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"298-303"},"PeriodicalIF":4.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144963276","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}

{"title":"Cryopreservation of siRNA-Treated Cells Is Feasible.","authors":"Melanie Sauer, Xavier Segarra-Visent, Leon Breuer, Vasileios Tzirtziganis, Tatyana Ryaykenen, David A Cooper, Dimas Echeverria, Anastasia Kremer, Reka A Haraszti","doi":"10.1177/21593337251381041","DOIUrl":"10.1177/21593337251381041","url":null,"abstract":"<p><p>Cryopreservation is a routine step in the manufacturing process of adoptive cell therapies (ACT), providing critical logistic flexibility. RNA interference (RNAi)-based therapies are increasingly being explored as enhancers or modulators of ACT. However, the impact of cryopreservation on cells treated with RNAi-based therapies has not been investigated before. In this study, we addressed this knowledge gap by examining silencing efficacy in small interfering RNA (siRNA)-treated cells that undergo cryopreservation. Our findings demonstrate that silencing in cryopreserved cells is comparable to that in cells maintained continuously in culture. Moreover, we found that the duration of siRNA exposure plays a significant role in cells that later undergo cryopreservation, with extended exposure improving silencing efficiency. However, this effect diminishes at higher siRNA concentrations. Additionally, we showed that siRNA treatment is feasible at low temperatures (2°C-8°C), and siRNA-treated cells can be cryopreserved for extended periods (at least 1 month) without loss of efficacy. Our work establishes the feasibility of integrating siRNA treatments into current manufacturing processes for ACT.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"280-285"},"PeriodicalIF":4.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13622942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131499","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}