Nucleic acid therapeutics最新文献

{"title":"Structural Fingerprinting of siRNA Therapeutics by Solution NMR Spectroscopy.","authors":"Owen B Becette,&nbsp;Anh Tran,&nbsp;Jace W Jones,&nbsp;John P Marino,&nbsp;Robert G Brinson","doi":"10.1089/nat.2021.0098","DOIUrl":"https://doi.org/10.1089/nat.2021.0098","url":null,"abstract":"<p><p>Nucleic acids are an increasingly popular platform for the development of biotherapeutics to treat a wide variety of illnesses, including diseases where traditional drug development efforts have failed. To date, there are 14 short oligonucleotide therapeutics and 2 messenger RNA (mRNA) vaccines approved by the U.S. Food and Drug Administration (FDA), which demonstrates the potential of nucleic acids as a platform for the development of safe and effective medicines and vaccines. Despite the increasing popularity of nucleic acid-based drugs, there has been a paucity of high-resolution structural techniques applied to rigorously characterize these molecules during drug development. Here, we present application of nuclear magnetic resonance (NMR) methods to structurally \"fingerprint\" short oligonucleotide therapeutics at natural isotope abundance under full formulation conditions. The NMR methods described herein leverage signals arising from the native structural features of nucleic acids, including imino, aromatic, and ribose resonances, in addition to non-native chemistries, such as 2'-fluoro (2'-F), 2'-<i>O</i>-methyl (2'-OMe), and phosphorothioate (PS) modifications, introduced during drug development. We demonstrate the utility of the NMR methods to structurally \"fingerprint\" a model short interfering RNA (siRNA) and a sample that simulated the drug product Givosiran. We anticipate broad applicability of the NMR methods to other nucleic acid-based therapeutics due to the generalized nature of the approach and ability to monitor many quality attributes simultaneously.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"32 4","pages":"267-279"},"PeriodicalIF":4.0,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9416564/pdf/nat.2021.0098.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10288985","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":"Exon Skipping Through Chimeric Antisense <i>U1</i> snRNAs to Correct Retinitis Pigmentosa GTPase-Regulator (<i>RPGR</i>) Splice Defect.","authors":"Giuseppina Covello,&nbsp;Gehan H Ibrahim,&nbsp;Niccolò Bacchi,&nbsp;Simona Casarosa,&nbsp;Michela Alessandra Denti","doi":"10.1089/nat.2021.0053","DOIUrl":"https://doi.org/10.1089/nat.2021.0053","url":null,"abstract":"<p><p>Inherited retinal dystrophies are caused by mutations in more than 250 genes, each of them carrying several types of mutations that can lead to different clinical phenotypes. Mutations in <i>Retinitis Pigmentosa GTPase-Regulator</i> (<i>RPGR</i>) cause X-linked Retinitis pigmentosa (RP). A nucleotide substitution in intron 9 of <i>RPGR</i> causes the increase of an alternatively spliced isoform of the mature mRNA, bearing exon 9a (E9a). This introduces a stop codon, leading to truncation of the protein. Aiming at restoring impaired gene expression, we developed an antisense RNA-based therapeutic approach for the skipping of <i>RPGR</i> E9a. We designed a set of specific <i>U1</i> antisense snRNAs (U1_asRNAs) and tested their efficacy <i>in vitro</i>, upon transient cotransfection with <i>RPGR</i> minigene reporter systems in HEK-293T, 661W, and PC-12 cell lines. We thus identified three chimeric U1_asRNAs that efficiently mediate E9a skipping, correcting the genetic defect. Unexpectedly, the U1-5'antisense construct, which exhibited the highest exon-skipping efficiency in PC-12 cells, induced E9a inclusion in HEK-293T and 661W cells, indicating caution in the choice of preclinical model systems when testing RNA splicing-correcting therapies. Our data provide a proof of principle for the application of U1_snRNA exon skipping-based approach to correct splicing defects in <i>RPGR</i>.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"333-349"},"PeriodicalIF":4.0,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e5/1a/nat.2021.0053.PMC9416563.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39801256","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":"NAT10 and DDX21 Proteins Interact with RNase H1 and Affect the Performance of Phosphorothioate Oligonucleotides.","authors":"Lingdi Zhang,&nbsp;Karla D Bernardo,&nbsp;Timothy A Vickers,&nbsp;Jun Tian,&nbsp;Xue-Hai Liang,&nbsp;Stanley T Crooke","doi":"10.1089/nat.2021.0107","DOIUrl":"https://doi.org/10.1089/nat.2021.0107","url":null,"abstract":"<p><p>RNase H1-dependent phosphorothioate oligonucleotides (PS-ASOs) have been developed to treat various diseases through specific degradation of target RNAs. Although many factors or features of RNA and PS-ASOs have been demonstrated to affect antisense activity of PS-ASOs, little is known regarding the roles of RNase H1-associated proteins in PS-ASO performance. In this study, we report that two nucleolar proteins, NAT10 and DDX21, interact with RNase H1 and affect the potency and safety of PS-ASOs. The interactions of these two proteins with RNase H1 were determined using BioID proximity labeling in cells and confirmed biochemically. Reduction of NAT10 and DDX21 decreased PS-ASO activity in cells, and purified NAT10 and DDX21 proteins enhanced RNase H1 cleavage rates, indicating that these two proteins facilitate RNase H1 endoribonuclease activity. Consistently, reduction of these proteins increased the levels of R-loops, and impaired pre-rRNA processing. In addition, reduction of the two proteins increased the cytotoxicity of toxic PS-ASOs, and treatment of toxic PS-ASOs also altered the localization of these proteins. Together, this study shows for the first time that NAT10 and DDX21 interact with RNase H1 protein and enhance its enzymatic activity, contributing to the potency and safety of PS-ASOs.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"280-299"},"PeriodicalIF":4.0,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9f/04/nat.2021.0107.PMC9416547.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40606383","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":"Altered Biodistribution and Hepatic Safety Profile of a Gapmer Antisense Oligonucleotide Bearing Guanidine-Bridged Nucleic Acids.","authors":"Takashi Sasaki,&nbsp;Yoko Hirakawa,&nbsp;Fumiko Yamairi,&nbsp;Takashi Kurita,&nbsp;Karin Murahashi,&nbsp;Hirokazu Nishimura,&nbsp;Norihiko Iwazaki,&nbsp;Hidenori Yasuhara,&nbsp;Takashi Tateoka,&nbsp;Tetsuya Ohta,&nbsp;Satoshi Obika,&nbsp;Jun Kotera","doi":"10.1089/nat.2021.0034","DOIUrl":"https://doi.org/10.1089/nat.2021.0034","url":null,"abstract":"<p><p>Guanidine-bridged nucleic acid (GuNA) is a novel 2',4'-bridged nucleic acid/locked nucleic acid (2',4'-BNA/LNA) analog containing cations that exhibit strong affinity for target RNA and superior nuclease resistance. In this study, <i>Malat1</i> antisense oligonucleotide (ASO) bearing GuNA was evaluated for target knockdown (KD) activity and tolerability. The GuNA ASO did not interfere with RNase H recruitment on the target RNA/ASO heteroduplex and did show potent target KD activity in a skeletal muscle-derived cell line equivalent to that of the LNA ASO under gymnotic conditions, whereas almost no KD activity was observed in a hepatocyte-derived cell line. The GuNA ASO exhibited potent KD activity in various tissues; the KD activity in the skeletal muscle was equivalent with that of the LNA ASO, but the KD activities in the liver and kidney were clearly lower compared with the LNA ASO. In addition, despite the higher accumulation of the GuNA ASO in the liver, levels of aspartate aminotransferase and alanine aminotransferase with the GuNA ASO administration were not elevated compared with those induced by the LNA ASO. Our data indicate that the GuNA ASO is tolerable and exhibits unique altered pharmacological activities in comparison with the LNA ASO in terms of the relative effect between liver and skeletal muscle.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"177-184"},"PeriodicalIF":4.0,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39944691","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":"Allele-Selective LNA Gapmers for the Treatment of Fibrodysplasia Ossificans Progressiva Knock Down the Pathogenic ACVR1^R206H Transcript and Inhibit Osteogenic Differentiation.","authors":"Rika Maruyama,&nbsp;Quynh Nguyen,&nbsp;Rohini Roy Roshmi,&nbsp;Aleksander Touznik,&nbsp;Toshifumi Yokota","doi":"10.1089/nat.2021.0009","DOIUrl":"https://doi.org/10.1089/nat.2021.0009","url":null,"abstract":"<p><p>Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by episodic heterotopic ossification. The median life span of people with this disorder is ∼40 years, and currently, there is no effective treatment available. More than 95% of cases are caused by a recurrent mutation (c.617G>A; R206H) of Activin A receptor, type I (ACVR1)/Activin receptor-like kinase-2 (ALK2), a bone morphogenetic protein type I receptor. The mutation renders ACVR1 responsive to activin A, which does not activate wild-type ACVR1. Ectopic activation of ACVR1^R206H by activin A induces heterotopic ossification. Since ACVR1^R206H is a hyperactive receptor, a promising therapeutic strategy is to decrease the activity of mutated ACVR1. To accomplish this goal, we developed locked nucleic acid (LNA) gapmers. These are short DNA oligonucleotides with LNA modification at both ends. They induce targeted mRNA degradation and specific knockdown of gene expression. We demonstrated that some of these gapmers efficiently knocked down ACVR1^R206H expression at RNA levels, while ACVR1^WT was mostly unaffected in human FOP fibroblasts. Also, the gapmers suppressed osteogenic differentiation induced by ACVR1^R206H and activin A. These gapmers may be promising drug candidates for FOP. This novel strategy will also pave the way for antisense-mediated therapy of other autosomal dominant disorders.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"185-193"},"PeriodicalIF":4.0,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39953711","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":"Combining Heparin and a FX/Xa Aptamer to Reduce Thrombin Generation in Cardiopulmonary Bypass and COVID-19.","authors":"Charlene V Chabata,&nbsp;James W Frederiksen,&nbsp;Lyra B Olson,&nbsp;Ibtehaj A Naqvi,&nbsp;Sharon E Hall,&nbsp;Ruwan Gunaratne,&nbsp;Bryan D Kraft,&nbsp;Loretta G Que,&nbsp;Lingye Chen,&nbsp;Bruce A Sullenger","doi":"10.1089/nat.2021.0077","DOIUrl":"https://doi.org/10.1089/nat.2021.0077","url":null,"abstract":"<p><p>Known limitations of unfractionated heparin (UFH) have encouraged the evaluation of anticoagulant aptamers as alternatives to UFH in highly procoagulant settings such as cardiopulmonary bypass (CPB). Despite progress, these efforts have not been totally successful. We take a different approach and explore whether properties of an anticoagulant aptamer can complement UFH, rather than replace it, to address shortcomings with UFH use. Combining RNA aptamer 11F7t, which targets factor X/Xa, with UFH (or low molecular weight heparin) yields a significantly enhanced anticoagulant cocktail effective in normal and COVID-19 patient blood. This aptamer-UFH combination (1) supports continuous circulation of human blood through an <i>ex vivo</i> membrane oxygenation circuit, as is required for patients undergoing CPB and COVID-19 patients requiring extracorporeal membrane oxygenation, (2) allows for a reduced level of UFH to be employed, (3) more effectively limits thrombin generation compared to UFH alone, and (4) is rapidly reversed by the administration of protamine sulfate, the standard treatment for reversing UFH clinically following CPB. Thus, the combination of factor X/Xa aptamer and UFH has significantly improved anticoagulant properties compared to UFH alone and underscores the potential of RNA aptamers to improve medical management of acute care patients requiring potent yet rapidly reversible anticoagulation.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"32 3","pages":"139-150"},"PeriodicalIF":4.0,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221171/pdf/nat.2021.0077.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10158745","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":"miRNA-Mediated Knockdown of ATXN3 Alleviates Molecular Disease Hallmarks in a Mouse Model for Spinocerebellar Ataxia Type 3.","authors":"Rui Jorge Nobre,&nbsp;Diana D Lobo,&nbsp;Carina Henriques,&nbsp;Sonia P Duarte,&nbsp;Sara M Lopes,&nbsp;Ana C Silva,&nbsp;Miguel M Lopes,&nbsp;Fanny Mariet,&nbsp;Lukas K Schwarz,&nbsp;M S Baatje,&nbsp;Valerie Ferreira,&nbsp;Astrid Vallès,&nbsp;Luis Pereira de Almeida,&nbsp;Melvin M Evers,&nbsp;Lodewijk J A Toonen","doi":"10.1089/nat.2021.0020","DOIUrl":"https://doi.org/10.1089/nat.2021.0020","url":null,"abstract":"<p><p>Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by the expansion of a CAG repeat in the <i>ATXN3</i> gene. This mutation leads to a toxic gain of function of the ataxin-3 protein, resulting in neuronal dysfunction and atrophy of specific brain regions over time. As ataxin-3 is a dispensable protein in rodents, ataxin-3 knockdown by gene therapy may be a powerful approach for the treatment of SCA3. In this study, we tested the feasibility of an adeno-associated viral (AAV) vector carrying a previously described artificial microRNA against <i>ATXN3</i> in a striatal mouse model of SCA3. Striatal injection of the AAV resulted in good distribution throughout the striatum, with strong dose-dependent ataxin-3 knockdown. The hallmark intracellular ataxin-3 inclusions were almost completely alleviated by the microRNA-induced <i>ATXN3</i> knockdown. In addition, the striatal lesion of dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32) in the SCA3 mice was rescued by <i>ATXN3</i> knockdown, indicating functional rescue of neuronal signaling and health upon AAV treatment. Together, these data suggest that microRNA-induced ataxin-3 knockdown is a promising therapeutic strategy in the treatment of SCA3.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"194-205"},"PeriodicalIF":4.0,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39791512","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":"Differential Uptake of Antisense Oligonucleotides in Mouse Hepatocytes and Macrophages Revealed by Simultaneous Two-Photon Excited Fluorescence and Coherent Raman Imaging.","authors":"Prabuddha Mukherjee,&nbsp;Edita Aksamitiene,&nbsp;Aneesh Alex,&nbsp;Jindou Shi,&nbsp;Kajari Bera,&nbsp;Chi Zhang,&nbsp;Darold R Spillman,&nbsp;Marina Marjanovic,&nbsp;Michael Fazio,&nbsp;Punit P Seth,&nbsp;Kendall Frazier,&nbsp;Steve R Hood,&nbsp;Stephen A Boppart","doi":"10.1089/nat.2021.0059","DOIUrl":"https://doi.org/10.1089/nat.2021.0059","url":null,"abstract":"<p><p>Antisense oligonucleotides (ASOs), a novel paradigm in modern therapeutics, modulate cellular gene expression by binding to complementary messenger RNA (mRNA) sequences. While advances in ASO medicinal chemistry have greatly improved the efficiency of cellular uptake, selective uptake by specific cell types has been difficult to achieve. For more efficient and selective uptake, ASOs are often conjugated with molecules with high binding affinity for transmembrane receptors. Triantennary N-acetyl-galactosamine conjugated phosphorothioate ASOs (GalNAc-PS-ASOs) were developed to enhance targeted ASO delivery into liver through the hepatocyte-specific asialoglycoprotein receptor (ASGR). We assessed the kinetics of uptake and subsequent intracellular distribution of AlexaFluor 488 (AF488)-labeled PS-ASOs and GalNAc-PS-ASOs in J774A.1 mouse macrophages and primary mouse or rat hepatocytes using simultaneous coherent anti-Stokes Raman scattering (CARS) and two-photon fluorescence (2PF) imaging. The CARS modality captured the dynamic lipid distributions and overall morphology of the cells; two-photon fluorescence (2PF) measured the time- and dose-dependent localization of ASOs delivered by a modified treatment of suspension cells. Our results show that in macrophages, the uptake rate of PS-ASOs did not significantly differ from that of GalNAc-PS-ASOs. However, in hepatocytes, GalNAc-PS-ASOs exhibited a peripheral uptake distribution compared to a polar uptake distribution observed in macrophages. The peripheral distribution correlated with a significantly larger amount of internalized GalNAc-PS-ASOs compared to the PS-ASOs. This work demonstrates the relevance of multimodal imaging for elucidating the uptake mechanism, accumulation, and fate of different ASOs in liver cells that can be used further in complex <i>in vitro</i> models and liver tissues to evaluate ASO distribution and activity.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"163-176"},"PeriodicalIF":4.0,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39892218","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":"Acute Neurotoxicity of Antisense Oligonucleotides After Intracerebroventricular Injection Into Mouse Brain Can Be Predicted from Sequence Features.","authors":"Peter H Hagedorn,&nbsp;Jeffrey M Brown,&nbsp;Amy Easton,&nbsp;Maria Pierdomenico,&nbsp;Kelli Jones,&nbsp;Richard E Olson,&nbsp;Stephen E Mercer,&nbsp;Dong Li,&nbsp;James Loy,&nbsp;Anja M Høg,&nbsp;Marianne L Jensen,&nbsp;Martin Gill,&nbsp;Angela M Cacace","doi":"10.1089/nat.2021.0071","DOIUrl":"https://doi.org/10.1089/nat.2021.0071","url":null,"abstract":"<p><p>Antisense oligonucleotides are a relatively new therapeutic modality and safety evaluation is still a developing area of research. We have observed that some oligonucleotides can produce acute, nonhybridization dependent, neurobehavioral side effects after intracerebroventricular (ICV) dosing in mice. In this study, we use a combination of <i>in vitro</i>, <i>in vivo</i>, and bioinformatics approaches to identify a sequence design algorithm, which can reduce the number of acutely toxic molecules synthesized and tested in mice. We find a cellular assay measuring spontaneous calcium oscillations in neuronal cells can predict the behavioral side effects after ICV dosing, and may provide a mechanistic explanation for these observations. We identify sequence features that are overrepresented or underrepresented among oligonucleotides causing these reductions in calcium oscillations. A weighted linear combination of the five most informative sequence features predicts the outcome of ICV dosing with >80% accuracy. From this, we develop a bioinformatics tool that allows oligonucleotide designs with acceptable acute neurotoxic potential to be identified, thereby reducing the number of toxic molecules entering drug discovery pipelines. The informative sequence features we identified also suggest areas in which to focus future medicinal chemistry efforts.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"151-162"},"PeriodicalIF":4.0,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39632122","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":"Modulation of RNA Splicing by Oligonucleotides: Mechanisms of Action and Therapeutic Implications.","authors":"Olga V Sergeeva,&nbsp;Evgeniya Y Shcherbinina,&nbsp;Noam Shomron,&nbsp;Timofei S Zatsepin","doi":"10.1089/nat.2021.0067","DOIUrl":"https://doi.org/10.1089/nat.2021.0067","url":null,"abstract":"<p><p>Dysregulation of RNA splicing causes many diseases and disorders. Several therapeutic approaches have been developed to correct aberrant alternative splicing events for the treatment of cancers and hereditary diseases, including gene therapy and redirecting splicing, using small molecules or splice switching oligonucleotides (SSO). Significant advances in the chemistry and pharmacology of nucleic acid have led to the development of clinically approved SSO drugs for the treatment of spinal muscular dystrophy and Duchenne muscular dystrophy (DMD). In this review, we discuss the mechanisms of SSO action with emphasis on \"less common\" approaches to modulate alternative splicing, including bipartite and bifunctional SSO, oligonucleotide decoys for splice factors and SSO-mediated mRNA degradation <i>via</i> AS-NMD and NGD pathways. We briefly discuss the current progress and future perspectives of SSO therapy for rare and ultrarare diseases.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"123-138"},"PeriodicalIF":4.0,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39925085","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}