Nucleic acid therapeutics最新文献_第6页

Modulation of Gene Expression in the Eye with Antisense Oligonucleotides. 反义寡核苷酸对眼睛基因表达的调控。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2023-12-01 Epub Date: 2023-11-02 DOI: 10.1089/nat.2023.0044

Jiaxin Hu, Xin Gong, Yan Fan, Selina Aguilar, Frank Rigo, Thahza P Prakash, David R Corey, V Vinod Mootha

{"title":"Modulation of Gene Expression in the Eye with Antisense Oligonucleotides.","authors":"Jiaxin Hu, Xin Gong, Yan Fan, Selina Aguilar, Frank Rigo, Thahza P Prakash, David R Corey, V Vinod Mootha","doi":"10.1089/nat.2023.0044","DOIUrl":"10.1089/nat.2023.0044","url":null,"abstract":"One advantage of antisense oligonucleotides (ASOs) for drug development is their long-lasting gene knockdown after administration in vivo. In this study, we examine the effect on gene expression after intraocular injection in target tissues in the eye. We examined expression levels of the Malat1 gene after intracameral or intravitreal (IV) injection of an anti-Malat1 ASO in corneal epithelium/stroma, corneal endothelium, lens capsule epithelium, neurosensory retina, and retinal pigment epithelium/choroid of the mouse eye. We assessed potency of the compound at 7 days as well as duration of the gene knockdown at 14, 28, 60, 90, and 120 days. The ASO was more potent when delivered by IV injection relative to intracameral injection, regardless of whether the tissues analyzed were at the front or back of the eye. For corneal endothelium, inhibition was >50% after 120 days for ASO at 50 μg. At IV dosages of 6 μg, we observed >75% inhibition of gene expression in the retina and lens epithelium for up to 120 days. ASOs have potential as long-lasting gene knockdown agents in the mouse eye, but efficacy varies depending on the specific ocular target tissue and injection protocol.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"339-347"},"PeriodicalIF":4.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10698777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71425545","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

Cholesterol-Conjugated Supramolecular Multimeric siRNAs: Effect of siRNA Length on Accumulation and Silencing In Vitro and In Vivo. 胆固醇偶联的超分子多聚siRNA：siRNA长度对体外和体内积累和沉默的影响。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2023-12-01 Epub Date: 2023-11-09 DOI: 10.1089/nat.2023.0051

Ivan V Chernikov, Ul'yana A Ponomareva, Mariya I Meschaninova, Irina K Bachkova, Anna A Teterina, Daniil V Gladkikh, Innokenty A Savin, Valentin V Vlassov, Marina A Zenkova, Elena L Chernolovskaya

{"title":"Cholesterol-Conjugated Supramolecular Multimeric siRNAs: Effect of siRNA Length on Accumulation and Silencing In Vitro and In Vivo.","authors":"Ivan V Chernikov, Ul'yana A Ponomareva, Mariya I Meschaninova, Irina K Bachkova, Anna A Teterina, Daniil V Gladkikh, Innokenty A Savin, Valentin V Vlassov, Marina A Zenkova, Elena L Chernolovskaya","doi":"10.1089/nat.2023.0051","DOIUrl":"10.1089/nat.2023.0051","url":null,"abstract":"Conjugation of small interfering RNA (siRNA) with lipophilic molecules is one of the most promising approaches for delivering siRNA in vivo. The rate of molecular weight-dependent siRNA renal clearance is critical for the efficiency of this process. In this study, we prepared cholesterol-containing supramolecular complexes containing from three to eight antisense strands and examined their accumulation and silencing activity in vitro and in vivo. We have shown for the first time that such complexes with 2'F, 2'OMe, and LNA modifications exhibit interfering activity both in carrier-mediated and carrier-free modes. Silencing data from a xenograft tumor model show that 4 days after intravenous injection of cholesterol-containing monomers and supramolecular trimers, the levels of MDR1 mRNA in the tumor decreased by 85% and 68%, respectively. The in vivo accumulation data demonstrated that the formation of supramolecular structures with three or four antisense strands enhanced their accumulation in the liver. After addition of two PS modifications at the ends of antisense strands, 47% and 67% reductions of Ttr mRNA levels in the liver tissue were detected 7 days after administration of monomers and supramolecular trimers, respectively. Thus, we have obtained a new type of RNAi inducer that is convenient for synthesis and provides opportunities for modifications.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"361-373"},"PeriodicalIF":4.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72014971","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

Impact of the Inhibition of Organic Anion Transporter on Tricyclo-DNA-Mediated Exon Skipping in the mdx Mouse Model. 有机阴离子转运蛋白对三环dna介导的mdx小鼠外显子跳变的影响

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2023-12-01 Epub Date: 2023-11-15 DOI: 10.1089/nat.2023.0046

Flavien Bizot, Thomas Tensorer, Luis Garcia, Aurélie Goyenvalle

引用次数: 0

Delivery Characterization of SPL84 Inhaled Antisense Oligonucleotide Drug for 3849 + 10 kb C- > T Cystic Fibrosis Patients. SPL84吸入3849反义寡核苷酸药物的递送特性 + 10 kb C->T囊性纤维化患者。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2023-10-01 Epub Date: 2023-08-29 DOI: 10.1089/nat.2023.0015

Efrat Ozeri-Galai, Lital Friedman, Ofra Barchad-Avitzur, Matthew R Markovetz, William Boone, Kaitlyn R Rouillard, Chava D Stampfer, Yifat S Oren, David B Hill, Batsheva Kerem, Gili Hart

{"title":"Delivery Characterization of SPL84 Inhaled Antisense Oligonucleotide Drug for 3849 + 10 kb C- > T Cystic Fibrosis Patients.","authors":"Efrat Ozeri-Galai, Lital Friedman, Ofra Barchad-Avitzur, Matthew R Markovetz, William Boone, Kaitlyn R Rouillard, Chava D Stampfer, Yifat S Oren, David B Hill, Batsheva Kerem, Gili Hart","doi":"10.1089/nat.2023.0015","DOIUrl":"10.1089/nat.2023.0015","url":null,"abstract":"Recent advances in the therapeutic potential of RNA-related treatments, specifically for antisense oligonucleotide (ASO)-based drugs, have led to increased numbers of ASO regulatory approvals. In this study, we focus on SPL84, an inhaled ASO-based drug, developed for the treatment of the pulmonary disease cystic fibrosis (CF). Pulmonary drug delivery is challenging, due to a variety of biological, physical, chemical, and structural barriers, especially when targeting the cell nucleus. The distribution of SPL84 throughout the lungs, penetration into the epithelial cells and nucleus, and structural stability are critical parameters that will impact drug efficacy in a clinical setting. In this study, we demonstrate broad distribution, as well as cell and nucleus penetration of SPL84 in mouse and monkey lungs. In vivo and in vitro studies confirmed the stability of our inhaled drug in CF patient-derived mucus and in lung lysosomal extracts. The mobility of SPL84 through hyperconcentrated mucus was also demonstrated. Our results, supported by a promising preclinical pharmacological effect of full restoration of cystic fibrosis transmembrane conductance regulator channel activity, emphasize the high potential of SPL84 as an effective drug for the treatment of CF patients. In addition, successfully tackling the lung distribution of SPL84 offers immense opportunities for further development of SpliSense's inhaled ASO-based drugs for unmet needs in pulmonary diseases.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"306-318"},"PeriodicalIF":4.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10467738","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

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2023-10-01 Epub Date: 2023-08-17 DOI: 10.1089/nat.2023.0011

Cindy L Berman, Madeleine Antonsson, Sandor Batkai, Sieto Bosgra, Girish R Chopda, Wouter Driessen, Jeffrey Foy, Chopie Hassan, Xiao Shelley Hu, Hyun Gyung Jang, Meena, Mark Sanseverino, Thomas Thum, Yanfeng Wang, Martin Wild, Jing-Tao Wu

{"title":"OSWG Recommended Approaches to the Nonclinical Pharmacokinetic (ADME) Characterization of Therapeutic Oligonucleotides.","authors":"Cindy L Berman, Madeleine Antonsson, Sandor Batkai, Sieto Bosgra, Girish R Chopda, Wouter Driessen, Jeffrey Foy, Chopie Hassan, Xiao Shelley Hu, Hyun Gyung Jang, Meena, Mark Sanseverino, Thomas Thum, Yanfeng Wang, Martin Wild, Jing-Tao Wu","doi":"10.1089/nat.2023.0011","DOIUrl":"10.1089/nat.2023.0011","url":null,"abstract":"This white paper summarizes the recommendations of the absorption, distribution, metabolism, and excretion (ADME) Subcommittee of the Oligonucleotide Safety Working Group for the characterization of absorption, distribution, metabolism, and excretion of oligonucleotide (ON) therapeutics in nonclinical studies. In general, the recommended approach is similar to that for small molecule drugs. However, some differences in timing and/or scope may be warranted due to the greater consistency of results across ON classes as compared with the diversity among small molecule classes. For some types of studies, a platform-based approach may be appropriate; once sufficient data are available for the platform, presentation of these data should be sufficient to support development of additional ONs of the same platform. These recommendations can serve as a starting point for nonclinical study design and foundation for discussions with regulatory agencies.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"287-305"},"PeriodicalIF":4.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10561745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10011698","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

New Oligonucleotide 2'-O-Alkyl N3'→P5' (Thio)-Phosphoramidates as Potent Antisense Agents: Physicochemical Properties and Biological Activity. 新寡核苷酸2'-O-烷基N3'→P5’（硫代）-磷酰胺类有效反义试剂的理化性质和生物活性。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2023-10-01 Epub Date: 2023-08-28 DOI: 10.1089/nat.2023.0014

Saúl Martínez-Montero, Vivek K Rajwanshi, Rajendra K Pandey, N Tilani S De Costa, Jin Hong, Leonid Beigelman, Sergei M Gryaznov, Soheil Pourshahian

{"title":"New Oligonucleotide 2'-O-Alkyl N3'→P5' (Thio)-Phosphoramidates as Potent Antisense Agents: Physicochemical Properties and Biological Activity.","authors":"Saúl Martínez-Montero, Vivek K Rajwanshi, Rajendra K Pandey, N Tilani S De Costa, Jin Hong, Leonid Beigelman, Sergei M Gryaznov, Soheil Pourshahian","doi":"10.1089/nat.2023.0014","DOIUrl":"10.1089/nat.2023.0014","url":null,"abstract":"We describe here the design, synthesis, physicochemical properties, and hepatitis B antiviral activity of new 2'-O-alkyl ribonucleotide N3'→P5' phosphoramidate (2'-O-alkyl-NPO) and (thio)-phosphoramidite (2'-O-alkyl-NPS) oligonucleotide analogs. Oligonucleotides with different 2'-O-alkyl modifications such as 2'-O-methyl, -O-ethyl, -O-allyl, and -O-methoxyethyl combined with 3'-amino sugar-phosphate backbone were synthesized and evaluated. These molecules form stable duplexes with complementary DNA and RNA strands. They show an increase in duplex melting temperatures of up to 2.5°C and 4°C per linkage, respectively, compared to unmodified DNA. The results agree with predominantly C3'-endo sugar pucker conformation. Moreover, 2'-O-alkyl phosphoramidites demonstrate higher hydrolytic stability at pH 5.5 than 2'-deoxy NPOs. In addition, the relative lipophilicity of the 2'-O-alkyl-NPO and NPS oligonucleotides is higher than that of their 3'-O- counterparts. The 2'-O-alkyl-NPS oligonucleotides were evaluated as antisense (ASO) compounds in vitro and in vivo using Hepatitis B virus as a model system. Subcutaneous delivery of GalNAc conjugated 2'-O-MOE-NPS gapmers demonstrated higher activity than the 3'-O-containing 2'-O-MOE counterpart. The properties of 2'-O-alkyl-NPS constructs make them attractive candidates as ASO suitable for further evaluation and development.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"319-328"},"PeriodicalIF":4.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10088221","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

Development of Long Asymmetric siRNA Structure for Target Gene Silencing and Immune Stimulation in Mammalian Cells. 用于哺乳动物细胞靶基因沉默和免疫刺激的长不对称siRNA结构的开发。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2023-10-01 DOI: 10.1089/nat.2023.0003

Soonkap Kim, Young Gyu Kang, Jaejin Kim, Pooja Dua, Dong-Ki Lee

{"title":"Development of Long Asymmetric siRNA Structure for Target Gene Silencing and Immune Stimulation in Mammalian Cells.","authors":"Soonkap Kim, Young Gyu Kang, Jaejin Kim, Pooja Dua, Dong-Ki Lee","doi":"10.1089/nat.2023.0003","DOIUrl":"10.1089/nat.2023.0003","url":null,"abstract":"Post-transcriptional regulation of transcript abundances by RNA interference (RNAi) is a widely conserved regulatory mechanism to control cellular processes. We previously introduced an alternative siRNA structure called asymmetric siRNA (asiRNA), and showed that asiRNA exhibits comparable gene-silencing efficiency with reduced off-target effects compared with conventional siRNAs. However, to what extent the length of the guide strand affects the gene-silencing efficiency of asiRNAs is still elusive. In this study, we analyzed in detail the gene-silencing ability of asiRNAs along the guide strand length and immunostimulatory capacity of asiRNAs. We generated asiRNAs containing various guide strand lengths ranging from 25 to 29 nt, called long asiRNA (lasiRNA). We found that the gene-silencing activity of lasiRNAs decreased as the length of the guide strand increased. Nonetheless, the 3'-end overhangs that are complementary to the target gene have higher efficiency for gene silencing compared with mismatched overhangs. In addition, we found that the silencing efficiency of lasiRNAs correlates with their Ago2-binding affinity. Finally, replacing the mismatched overhang with a TLR7- or TLR9-associated immune response motif induced a toll-like receptor (TLR)-specific immune response and retained gene-silencing activity. Our findings demonstrate that lasiRNA structures can be tailored to function as bifunctional siRNA, which trigger a specific immune response combined with target gene silencing. Taken together, we anticipate that our findings provide a road map for the subsequent development of immune-stimulating lasiRNA, which bear the potential to be applied for therapeutic benefits.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"33 5","pages":"329-337"},"PeriodicalIF":4.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41179507","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

Sequence-Controlled Spherical Nucleic Acids: Gene Silencing, Encapsulation, and Cellular Uptake. 序列控制的球形核酸:基因沉默、包封和细胞摄取。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2023-08-01 DOI: 10.1089/nat.2022.0062

Sepideh Kaviani, Hassan H Fakih, Jathavan Asohan, Adam Katolik, Masad J Damha, Hanadi F Sleiman

{"title":"Sequence-Controlled Spherical Nucleic Acids: Gene Silencing, Encapsulation, and Cellular Uptake.","authors":"Sepideh Kaviani, Hassan H Fakih, Jathavan Asohan, Adam Katolik, Masad J Damha, Hanadi F Sleiman","doi":"10.1089/nat.2022.0062","DOIUrl":"https://doi.org/10.1089/nat.2022.0062","url":null,"abstract":"Antisense oligonucleotides (ASOs) can predictably alter RNA processing and control protein expression; however, challenges in the delivery of these therapeutics to specific tissues, poor cellular uptake, and endosomal escape have impeded progress in translating these agents into the clinic. Spherical nucleic acids (SNAs) are nanoparticles with a DNA external shell and a hydrophobic core that arise from the self-assembly of ASO strands conjugated to hydrophobic polymers. SNAs have recently shown significant promise as vehicles for improving the efficacy of ASO cellular uptake and gene silencing. However, to date, no studies have investigated the effect of the hydrophobic polymer sequence on the biological properties of SNAs. In this study, we created a library of ASO conjugates by covalently attaching polymers with linear or branched [dodecanediol phosphate] units and systematically varying polymer sequence and composition. We show that these parameters can significantly impact encapsulation efficiency, gene silencing activity, SNA stability, and cellular uptake, thus outlining optimized polymer architectures for gene silencing.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"33 4","pages":"265-276"},"PeriodicalIF":4.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10472929","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

Rosalind Franklin Society Proudly Announces the 2022 Award Recipient for Nucleic Acid Therapeutics. 罗莎琳德·富兰克林协会自豪地宣布2022年核酸治疗奖获得者。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2023-08-01 DOI: 10.1089/nat.2023.29007.rfs2022

Laura Sepp-Lorenzino

引用次数: 0

From Failure to Meet the Clinical Endpoint to U.S. Food and Drug Administration Approval: 15th Antisense Oligonucleotide Therapy Approved Qalsody (Tofersen) for Treatment of SOD1 Mutated Amyotrophic Lateral Sclerosis. 从未能达到临床终点到美国食品和药物管理局批准:第15个反义寡核苷酸疗法Qalsody (Tofersen)被批准用于治疗SOD1突变的肌萎缩侧索硬化症。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2023-08-01 DOI: 10.1089/nat.2023.0027

Willeke van Roon-Mom, Chantal Ferguson, Annemieke Aartsma-Rus

引用次数: 2