Nucleic acid therapeutics最新文献

Cell Type Distribution of Intrathecal Antisense Oligonucleotide Activity in Deep Brain Regions of Non-Human Primates. 非人灵长类动物脑深部鞘内反义寡核苷酸活性的细胞类型分布。

IF 4.7 2区医学

Nucleic acid therapeutics Pub Date : 2025-10-01 Epub Date: 2025-09-06 DOI: 10.1177/21593337251371594

Jeannine A Frei, Juliana E Gentile, Yuan Lian, Meredith A Mortberg, Juliana Capitanio, Paymaan Jafar-Nejad, Sonia M Vallabh, Hien T Zhao, Eric Vallabh Minikel

{"title":"Cell Type Distribution of Intrathecal Antisense Oligonucleotide Activity in Deep Brain Regions of Non-Human Primates.","authors":"Jeannine A Frei, Juliana E Gentile, Yuan Lian, Meredith A Mortberg, Juliana Capitanio, Paymaan Jafar-Nejad, Sonia M Vallabh, Hien T Zhao, Eric Vallabh Minikel","doi":"10.1177/21593337251371594","DOIUrl":"10.1177/21593337251371594","url":null,"abstract":"Intrathecally administered RNase H1-active gapmer antisense oligonucleotides (ASOs) are promising therapeutics for brain diseases where lowering the expression of one target gene is expected to be therapeutically beneficial. Such ASOs are active, to varying degrees, across most or all cell types in the cortex and cerebellum of mouse and non-human primate (NHP) brain regions with substantial drug accumulation. Intrathecally delivered ASOs, however, exhibit a gradient of exposure across the brain, with more limited drug accumulation and weaker target engagement in deep brain regions of NHP. Here, we profiled the activity of a tool, ASO, against Malat1 in three deep brain regions of NHP: thalamus, caudate, and putamen. All neuronal subtypes exhibited knockdown similar to, or deeper than, the bulk tissue. Among non-neuronal cells, knockdown was deepest in microglia and weakest in endothelial stalk. Overall, we observed broad target engagement across all cell types detected, supporting the relevance of intrathecal ASOs to diseases with deep brain involvement.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"234-240"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144963311","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

Context Matters: The Importance of a Comprehensive Genomic Region When Assessing the Therapeutic Potential of Antisense Oligonucleotides in Splicing Assays. 背景问题：在剪接分析中评估反义寡核苷酸的治疗潜力时，综合基因组区域的重要性。

IF 4.7 2区医学

Nucleic acid therapeutics Pub Date : 2025-10-01 Epub Date: 2025-08-25 DOI: 10.1177/21593337251371582

Dyah W Karjosukarso, Julia F Kiefmann, Femke Bukkems, Lonneke Duijkers, Rob W J Collin

引用次数: 0

A Workflow for Transcriptome-Wide Assessment of Antisense Oligonucleotide Selectivity. 反义寡核苷酸选择性转录组范围评估工作流程。

IF 4.7 2区医学

Nucleic acid therapeutics Pub Date : 2025-09-29 DOI: 10.1177/21593337251378141

Sagar S Damle, Andy Watt, Steven Kuntz, Amanda Crutchfield, Emma Carlborg, Judy Webb, Clare Quirk, Dorde Relic, Scott Donovan, Christopher E Hart, Frank Rigo

{"title":"A Workflow for Transcriptome-Wide Assessment of Antisense Oligonucleotide Selectivity.","authors":"Sagar S Damle, Andy Watt, Steven Kuntz, Amanda Crutchfield, Emma Carlborg, Judy Webb, Clare Quirk, Dorde Relic, Scott Donovan, Christopher E Hart, Frank Rigo","doi":"10.1177/21593337251378141","DOIUrl":"https://doi.org/10.1177/21593337251378141","url":null,"abstract":"Antisense oligonucleotides (ASOs) designed to recruit RNase H1 (gapmer ASOs) have been used successfully to downregulate the expression of therapeutic targets. Gapmer ASOs can be identified that selectively reduce the expression of transcripts containing the perfectly complementary intended ASO target site without affecting the expression of unintended transcripts (selective ASOs). However, ASOs can also be identified that reduce the expression of unintended transcripts with target sites that are not perfectly complementary to the ASO (nonselective ASOs). Currently, the understanding of in silico rules for predicting off-targets is suboptimal. In order to determine the selectivity of gapmer ASOs, we therefore developed an experimental workflow called concentration-response digital gene expression (CR-DGE). In CR-DGE, ASO treatment is performed at increasing concentrations, and the effect on the transcriptome is measured using 3'Tag-Seq. Expression data are then analyzed to identify genes with concentration-responsive knockdown. We demonstrate that CR-DGE identifies gapmer ASO concentration-responsive genes with high reproducibility and greater sensitivity than conventional single-concentration assays. Applying CR-DGE to a panel of gapmer ASOs identifies ASOs with a range of selectivity. These results demonstrate that CR-DGE can be used effectively to assess the selectivity of gapmer ASOs, offering a valuable tool for research and therapeutic development.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186693","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

Cryopreservation of siRNA-Treated Cells Is Feasible. sirna处理细胞的低温保存是可行的。

IF 4.7 2区医学

Nucleic acid therapeutics Pub Date : 2025-09-23 DOI: 10.1177/21593337251381041

Melanie Sauer, Xavier Segarra-Visent, Leon Breuer, Vasileios Tzirtziganis, Tatyana Ryaykenen, David A Cooper, Dimas Echeverria, Anastasia Kremer, Reka A Haraszti

{"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":"https://doi.org/10.1177/21593337251381041","url":null,"abstract":"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.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Quantification of mRNA Decay Rates in HeLa and SH-SY5Y Cell Lines Reveals Novel Properties of Membrane Protein Coding Transcripts. HeLa和SH-SY5Y细胞系mRNA衰减率的量化揭示了膜蛋白编码转录物的新特性

IF 4.7 2区医学

Nucleic acid therapeutics Pub Date : 2025-09-23 DOI: 10.1177/21593337251377561

Melanie B Martinez, Colton J Williamson, Tareian Cazares, Chunlao Tang, Marjoke F Debets, Pooja Gangras

{"title":"Quantification of mRNA Decay Rates in HeLa and SH-SY5Y Cell Lines Reveals Novel Properties of Membrane Protein Coding Transcripts.","authors":"Melanie B Martinez, Colton J Williamson, Tareian Cazares, Chunlao Tang, Marjoke F Debets, Pooja Gangras","doi":"10.1177/21593337251377561","DOIUrl":"https://doi.org/10.1177/21593337251377561","url":null,"abstract":"Posttranscriptional regulation is crucial for siRNA design, as decay rates in cell lines influence perceived siRNA potency. This study profiles transcripts with 'fast' and 'slow' half-lives in HeLa and SH-SY5Y cells, commonly used in drug discovery. We calculated half-lives for 1,815 HeLa and 5,376 SH-SY5Y transcripts, finding comparable half-lives between cell lines, though HeLa cells generally had longer half-lives. Comparing mRNA and protein half-lives, 'fast' decay transcripts encoded proteins with shorter half-lives, while 'slow' decay transcripts encoded stable proteins. We linked mRNA decay rates to siRNA activity by comparing HeLa data to a previous siRNA screen, discovering that faster decay transcripts had lower knockdown. Surprisingly, stable transcripts, more amenable to knockdown, were over-represented by membrane protein-coding transcripts. Despite their stability, these transcripts had low-to-moderate expression, regardless of miRNA regulation. We explored cis- and trans- features affecting mRNA stability and expression, suggesting that low RNA binding protein (RBP) binding, combined with specific stabilizing RBP regulation, contributes to the stability of these membrane protein-coding transcripts. This study highlights the importance of understanding transcript features, mRNA decay and its potential impact on siRNA efficacy, particularly for transcripts encoding membrane proteins.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131541","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

Use of a Transgenic Human PNPLA3^I148M Knock-in Mouse for Translational Safety Evaluations of siRNA Therapeutics. 使用转基因人PNPLA3I148M敲入小鼠进行siRNA疗法的翻译安全性评估。

IF 4.7 2区医学

Nucleic acid therapeutics Pub Date : 2025-09-06 DOI: 10.1177/21593337251375804

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

{"title":"Use of a Transgenic Human PNPLA3I148M 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":"The PNPLA3 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 PNPLA3, a transgenic human PNPLA3I148M knock-in mouse (huPNPLA3I148M) 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 huPNPLA3I148M mice. Overall, these data demonstrate the huPNPLA3I148M 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.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-09-06","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}

引用次数: 0

Design and In Vitro Evaluation of a Novel Antisense Oligonucleotide for Treatment of BK Virus Infection. 一种治疗BK病毒感染的新型反义寡核苷酸的设计和体外评价。

IF 4.7 2区医学

Nucleic acid therapeutics Pub Date : 2025-08-01 Epub Date: 2025-06-04 DOI: 10.1089/nat.2025.0010

Jurriën Prins, Janneke Kouwenberg, Anouk Spruit, Lizanne Daleman, Iris van Wissen, Bianca Matthee, Angela Koudijs, Caroline de Brouwer, Ellen Lievers, Franca Witjas, Vita Dauksaite, Carla van Alem, Roel Bijkerk, Annemieke Aartsma-Rus, Jessica Sipkens, Ton Rabelink, Mariet Feltkamp, Tamara Pfaff, Holger Zimmermann, Anton Jan van Zonneveld, Peter Lischka, Eric van der Veer

{"title":"Design and In Vitro Evaluation of a Novel Antisense Oligonucleotide for Treatment of BK Virus Infection.","authors":"Jurriën Prins, Janneke Kouwenberg, Anouk Spruit, Lizanne Daleman, Iris van Wissen, Bianca Matthee, Angela Koudijs, Caroline de Brouwer, Ellen Lievers, Franca Witjas, Vita Dauksaite, Carla van Alem, Roel Bijkerk, Annemieke Aartsma-Rus, Jessica Sipkens, Ton Rabelink, Mariet Feltkamp, Tamara Pfaff, Holger Zimmermann, Anton Jan van Zonneveld, Peter Lischka, Eric van der Veer","doi":"10.1089/nat.2025.0010","DOIUrl":"10.1089/nat.2025.0010","url":null,"abstract":"BK polyomavirus, a virus that latently resides in tubular epithelial cells of human kidneys, represents a major clinical problem for immunocompromised patients undergoing kidney transplantation. No proven effective specific antiviral therapies other than reduction of immunosuppressants exist. We exploited splice-modulating antisense oligonucleotides (ASOs) to block expression of the viral \"gatekeeper protein\" T antigen to specifically inhibit viral replication. Candidate oligonucleotides were screened for inhibitory activity in BK virus-infected cells, resulting in up to 97% reduction of viral T antigen mRNA and virus-encapsulating protein. The most promising ASO candidates were validated in BK virus-infected human kidney epithelial cells, showing sequence-specific activity that was exacerbated by chemical modifications. Administration of the candidate oligonucleotide in mice revealed long-lasting uptake in proximal tubules of the kidney, where BK virus resides. A final optimization round yielded an oligonucleotide displaying superior activity. Studies in transformed cells revealed a discernible shift in T antigen splicing not observed with a scrambled control, indicating that targeting of the donor splice site was responsible for the observed effects. Here, we demonstrate proof-of-principle for a direct-acting, splice-modulating, universal ASO that distributes to sites where BK viral replication occurs, warranting further development of this novel therapeutic to combat BK virus replication in kidney transplant patients.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"182-197"},"PeriodicalIF":4.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216439","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

Hepatotoxicity Reduction Profiles of Antisense Oligonucleotides Containing Amido-Bridged Nucleic Acid and 2'-O,4'-C-Spirocyclopropylene Bridged Nucleic Acid. 含有氨基桥接核酸和2'-O,4'- c -螺环丙烯桥接核酸的反义寡核苷酸的肝毒性还原谱。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2025-06-01 Epub Date: 2025-03-26 DOI: 10.1089/nat.2024.0047

Takaaki Kawanobe, Shinya Asano, Hitoshi Kandori, Masami Aoki, Ajaya Ram Shrestha, Kazuo Sekiguchi, Kotaro Yokoyama, Ryo Fukuda, Tadashi Umemoto

{"title":"Hepatotoxicity Reduction Profiles of Antisense Oligonucleotides Containing Amido-Bridged Nucleic Acid and 2'-O,4'-C-Spirocyclopropylene Bridged Nucleic Acid.","authors":"Takaaki Kawanobe, Shinya Asano, Hitoshi Kandori, Masami Aoki, Ajaya Ram Shrestha, Kazuo Sekiguchi, Kotaro Yokoyama, Ryo Fukuda, Tadashi Umemoto","doi":"10.1089/nat.2024.0047","DOIUrl":"10.1089/nat.2024.0047","url":null,"abstract":"Amido-bridged nucleic acid (AmNA) and a 2'-O,4'-C-spirocyclopropylene bridged nucleic acid (scpBNA) are bridged nucleic acid analogs with high binding affinity toward complementary strands along with high nuclease resistance. AmNA and scpBNA have been developed to overcome phosphorothioate modified gapmer hepatotoxicity, while the mechanism of reducing hepatotoxicity still remains unknown. Here, we found that antisense oligonucleotides (ASOs) with combination of AmNA, scpBNA, and phosphodiester (PO) bonds could significantly reduce hepatotoxicity in mice. Histopathological findings of the periportal spaces of the liver were observed only in the locked nucleic acid and AmNA-scpBNA groups, but not in the AmNA-scpBNA-PO group. Furthermore, bioinformatics and histopathological analysis revealed that the reduced hepatotoxicity might be related to mitochondrial abnormalities, such as decreased expression levels of Atp5o and Sdhb genes. Taken together, the results of this study demonstrated that AmNA, scpBNA, and PO modification are able to reduce hepatotoxicity for improving the potential of ASOs.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"114-124"},"PeriodicalIF":4.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710655","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

Developmental and Reproductive Toxicity Testing Strategies for Oligonucleotides: A Workshop Proceedings. 寡核苷酸的发育和生殖毒性测试策略：研讨会论文集。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2025-06-01 Epub Date: 2025-05-30 DOI: 10.1089/nat.2025.0013

Bethany R Hannas, Sara M Bender, Eileen Blasi, Christopher J Bowman, Joy A Cavagnaro, Connie L Chen, Pragati S Coder, Britt Duijndam, Alan Hoberman, Tae-Won Kim, Isabelle Leconte, Kazushige Maki, Mineo Matsumoto, Fumito Mikashima, Dinah L Misner, Lutz Mueller, Nicola Powles-Glover, Stephanie Rayhon, Camelia Saffarini, Christine Siezen, Jennifer Sisler, Ronald L Wange, Tacey White, Michael V Templin

{"title":"Developmental and Reproductive Toxicity Testing Strategies for Oligonucleotides: A Workshop Proceedings.","authors":"Bethany R Hannas, Sara M Bender, Eileen Blasi, Christopher J Bowman, Joy A Cavagnaro, Connie L Chen, Pragati S Coder, Britt Duijndam, Alan Hoberman, Tae-Won Kim, Isabelle Leconte, Kazushige Maki, Mineo Matsumoto, Fumito Mikashima, Dinah L Misner, Lutz Mueller, Nicola Powles-Glover, Stephanie Rayhon, Camelia Saffarini, Christine Siezen, Jennifer Sisler, Ronald L Wange, Tacey White, Michael V Templin","doi":"10.1089/nat.2025.0013","DOIUrl":"10.1089/nat.2025.0013","url":null,"abstract":"A 2023 workshop brought together stakeholders involved in the development and safety assessment of oligonucleotide (ONT) therapeutics. The purpose was to discuss potential strategies and opportunities for enhancing developmental and reproductive toxicity (DART) assessment of ONTs. The workshop was timely, bringing together regulators, industry representatives, consultants, and contract research organization partners interested in the ongoing development of internationally harmonized guidance for nonclinical safety assessment of ONTs. Given DART's importance in nonclinical safety assessment and the unique attributes of ONTs, the forum discussed case studies, consensus approaches, and areas needing further development to optimize DART strategies. This report covers the workshop proceedings, highlighting methods to achieve a robust DART assessment for ONTs. It includes case studies that described strategies for dose level selection, dosing frequency, species selection, and alternative animal model approaches. Topics also cover surrogate ONT use, exposure of the placenta and embryo/fetal compartment, and weight of evidence approaches. A goal of these workshop proceedings is to describe example approaches to hopefully inform the DART strategy expectations in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidance currently under development for nonclinical safety assessment of ONTs.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"93-113"},"PeriodicalIF":4.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187392","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

Systematic Evaluation of Position-Specific Tolerability of Seven Backbone and Ribose Modifications in Fully Chemically Stabilized siRNAs. 在完全化学稳定的sirna中，7种主链和核糖修饰的位置特异性耐受性的系统评价。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2025-06-01 Epub Date: 2025-05-26 DOI: 10.1089/nat.2024.0077

Daniel O'Reilly, Raymond Furgal, Vignesh Hariharan, Clemens Lochmann, David Cooper, Dimas Echeverria, Anastasia Khvorova

{"title":"Systematic Evaluation of Position-Specific Tolerability of Seven Backbone and Ribose Modifications in Fully Chemically Stabilized siRNAs.","authors":"Daniel O'Reilly, Raymond Furgal, Vignesh Hariharan, Clemens Lochmann, David Cooper, Dimas Echeverria, Anastasia Khvorova","doi":"10.1089/nat.2024.0077","DOIUrl":"10.1089/nat.2024.0077","url":null,"abstract":"Chemically modified short interfering RNAs (siRNAs) unequivocally represent a groundbreaking class of drugs. The deliberate chemical modification of the natural structure has been pivotal to their resounding success. Specific modifications at certain positions bolster their potency, safety, stability, and specificity. In clinical research, 2'-O-methyl and 2'-fluoro are the most used modifications. The effects of a wide range of chemical changes in fully modified siRNAs have not been thoroughly evaluated for tolerability. In this study, we utilized two sequences in a fully modified siRNA to systematically assess the tolerability of single nucleotide backbone and sugar modifications, including deoxyribonucleic acid, 2'-O-(2-methoxyethyl), locked nucleic acid, unlocked nucleic acid, mismatches, butane diol substitution, and butane diol insertion. We synthesized 522 siRNA variants and evaluated their efficacy in vitro. Our findings demonstrate that individual tolerability is significantly influenced by the modification's sequence, pattern, and position, with limited universal principles identifiable from this dataset. The efficacy results are probably driven by the thermodynamic balance defined by a combination of parameters. The framework presented here will serve as a reference dataset to facilitate the expansion of chemical diversity in therapeutic siRNAs.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"137-149"},"PeriodicalIF":4.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12167845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143193","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