Nucleic acid therapeutics最新文献

{"title":"Considerations for the Terminal Sterilization of Oligonucleotide Drug Products.","authors":"Daniel Paul DeCollibus,&nbsp;Justin Searcy,&nbsp;Anna Tivesten,&nbsp;Nadim Akhtar,&nbsp;Christian Lindenberg,&nbsp;Nounja Abarrou,&nbsp;Sujana Pradhan,&nbsp;Maggie Fiandaca,&nbsp;Jenny Franklin,&nbsp;Geetha Govindan,&nbsp;Hung-Yi Liu,&nbsp;David Royle,&nbsp;Patrick Lim Soo,&nbsp;Kirsten Storch","doi":"10.1089/nat.2022.0073","DOIUrl":"https://doi.org/10.1089/nat.2022.0073","url":null,"abstract":"<p><p>A primary function of the parenteral drug product manufacturing process is to ensure sterility of the final product. The two most common methods for sterilizing parenteral drug products are terminal sterilization (TS), whereby the drug product is sterilized in the final container following filling and finish, and membrane sterilization, whereby the product stream is sterilized by membrane filtration and filled into presterilized containers in an aseptic processing environment. Although TS provides greater sterility assurance than membrane sterilization and aseptic processing, not all drug products are amenable to TS processes, which typically involve heat treatment or exposure to ionizing radiation. Oligonucleotides represent an emerging class of therapeutics with great potential for treating a broad range of indications, including previously undruggable targets. Owing to their size, structural complexity, and relative lack of governing regulations, several challenges in drug development are unique to oligonucleotides. This exceptionality justifies a focused assessment of traditional chemistry, manufacturing, and control strategies before their adoption. In this article, we review the current state of sterile oligonucleotide drug product processing, highlight the key aspects to consider when assessing options for product sterilization, and provide recommendations to aid in the successful evaluation and development of TS processes. We also explore current regulatory expectations and provide our interpretation as it pertains to oligonucleotide drug products.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"33 3","pages":"159-177"},"PeriodicalIF":4.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10277985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10021709","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":"DNAzymes: Expanding the Potential of Nucleic Acid Therapeutics.","authors":"Leon M Larcher,&nbsp;Ianthe L Pitout,&nbsp;Niall P Keegan,&nbsp;Rakesh N Veedu,&nbsp;Sue Fletcher","doi":"10.1089/nat.2022.0066","DOIUrl":"https://doi.org/10.1089/nat.2022.0066","url":null,"abstract":"<p><p>Nucleic acids drugs have been proven in the clinic as a powerful modality to treat inherited and acquired diseases. However, key challenges including drug stability, renal clearance, cellular uptake, and movement across biological barriers (foremost the blood-brain barrier) limit the translation and clinical efficacy of nucleic acid-based therapies, both systemically and in the central nervous system. In this study we provide an overview of an emerging class of nucleic acid therapeutic, called DNAzymes. In particular, we review the use of chemical modifications and carrier molecules for the stabilization and/or delivery of DNAzymes in cell and animal models. Although this review focuses on DNAzymes, the strategies described are broadly applicable to most nucleic acid technologies. This review should serve as a general guide for selecting chemical modifications to improve the therapeutic performance of DNAzymes.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"33 3","pages":"178-192"},"PeriodicalIF":4.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10278027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9670408","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":"Rapid and Reliable Quantification of Prime Editing Targeting Within the Porcine <i>ABCA4</i> Gene Using a BRET-Based Sensor.","authors":"Tobias Wimmer,&nbsp;Hannah Sawinski,&nbsp;Anne M Urban,&nbsp;Jan Motlik,&nbsp;Knut Stieger","doi":"10.1089/nat.2022.0037","DOIUrl":"https://doi.org/10.1089/nat.2022.0037","url":null,"abstract":"Stargardt disease (STGD) leads to blindness in children and young adults. So far, no curative therapy is available and gene augmentation therapies have not yet advanced to the clinics, in part, due to the limited packaging capacity of adeno-associated viruses used to transfer genes into photoreceptor cells. Prime editing offers a new perspective to treat mutations on the genomic level. A nicking variant of Cas9 fused to a reverse transcriptase complex with an elongated guideRNA force intracellular mismatch repair to correct the targeted mutation even in postmitotic cells such as photoreceptors in the eye. Using a custom-made bioluminescence resonance energy transfer (BRET)-based editing sensor in HEK293 cells, we tested 27 different prime editing guide RNAs (pegRNAs) and additional 4 nicking guide RNAs (ngRNAs) with regard to their efficiency to induce sequences changes in exon 43 of the porcine ATP binding cassette subfamily A member 4 (ABCA4) gene that eliminate a mutagenic adenine frameshift insertion, which has been associated with STGD in humans. We identified nine working pegRNAs, and in combination with ngRNAs, we achieved a correction rate of up to ≈92% measured with the BRET-based reporter system. Our data prove the high efficiency of prime editors to correct mutations and highlight the importance of optimal ngRNA design, thus offering a promising editing tool to correct ABCA4 mutations in the disease context.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"33 3","pages":"226-232"},"PeriodicalIF":4.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10278032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9666363","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":"Next Generation Exon 51 Skipping Antisense Oligonucleotides for Duchenne Muscular Dystrophy.","authors":"Judith van Deutekom,&nbsp;Chantal Beekman,&nbsp;Suzanne Bijl,&nbsp;Sieto Bosgra,&nbsp;Rani van den Eijnde,&nbsp;Dennis Franken,&nbsp;Bas Groenendaal,&nbsp;Bouchra Harquouli,&nbsp;Anneke Janson,&nbsp;Paul Koevoets,&nbsp;Melissa Mulder,&nbsp;Daan Muilwijk,&nbsp;Galyna Peterburgska,&nbsp;Bianca Querido,&nbsp;Janwillem Testerink,&nbsp;Ruurd Verheul,&nbsp;Peter de Visser,&nbsp;Rudie Weij,&nbsp;Annemieke Aartsma-Rus,&nbsp;Jukka Puoliväli,&nbsp;Timo Bragge,&nbsp;Charles O'Neill,&nbsp;Nicole A Datson","doi":"10.1089/nat.2022.0063","DOIUrl":"https://doi.org/10.1089/nat.2022.0063","url":null,"abstract":"<p><p>In the last two decades, antisense oligonucleotides (AONs) that induce corrective exon skipping have matured as promising therapies aimed at tackling the dystrophin deficiency that underlies the severe and progressive muscle fiber degeneration in Duchenne muscular dystrophy (DMD) patients. Pioneering first generation exon 51 skipping AONs like drisapersen and eteplirsen have more recently been followed up by AONs for exons 53 and 45, with, to date, a total of four exon skipping AON drugs having reached (conditional) regulatory US Food and Drug Administration (FDA) approval for DMD. Nonetheless, considering the limited efficacy of these drugs, there is room for improvement. The aim of this study was to develop more efficient [2'-<i>O</i>-methyl-modified phosphorothioate (2'OMePS) RNA] AONs for <i>DMD</i> exon 51 skipping by implementing precision chemistry as well as identifying a more potent target binding site. More than a hundred AONs were screened in muscle cell cultures, followed by a selective comparison in the hDMD and hDMDdel52/<i>mdx</i> mouse models. Incorporation of 5-methylcytosine and position-specific locked nucleic acids in AONs targeting the drisapersen/eteplirsen binding site resulted in 15-fold higher exon 51 skipping levels compared to drisapersen in hDMDdel52/<i>mdx</i> mice. However, with similarly modified AONs targeting an alternative site in exon 51, 65-fold higher skipping levels were obtained, restoring dystrophin up to 30% of healthy control. Targeting both sites in exon 51 with a single AON further increased exon skipping (100-fold over drisapersen) and dystrophin (up to 40%) levels. These dystrophin levels allowed for normalization of creatine kinase (CK) and lactate dehydrogenase (LDH) levels, and improved motor function in hDMDdel52/<i>mdx</i> mice. As no major safety observation was obtained, the improved therapeutic index of these next generation AONs is encouraging for further (pre)clinical development.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"33 3","pages":"193-208"},"PeriodicalIF":4.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10277991/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10022270","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":"Complement C3d/C4d Deposition on Platelets Correlates with 2'-O-Methoxyethyl Antisense Oligonucleotide-Induced Thrombocytopenia in Monkeys.","authors":"Lijiang Shen,&nbsp;Andrea Wong,&nbsp;Satoru Oneda,&nbsp;Brian R Curtis,&nbsp;Joe Schroeder,&nbsp;Tom Zanardi,&nbsp;Jeffery A Engelhardt,&nbsp;Scott P Henry,&nbsp;Padmakumar Narayanan","doi":"10.1089/nat.2022.0042","DOIUrl":"https://doi.org/10.1089/nat.2022.0042","url":null,"abstract":"<p><p>2'-O-Methoxyethyl antisense oligonucleotide (2'-MOE ASO)-induced severe thrombocytopenia (TCP) [platelet (PLT) count <50 K/μL] was observed in the Asian-sourced cynomolgus monkeys with low incidence (2%-4% at doses >5 mg/kg/week). The potential mechanisms for TCP were studied using the Mauritian-sourced cynomolgus monkeys, which were shown to be more susceptible to ASO-induced TCP, along with the Asian-sourced animals. ISIS 405879, a 2'-MOE ASO, induced severe TCP (PLT <50 K/μL) in seven of nine Mauritian-sourced monkeys but not in the Asian-sourced monkeys after 16 weeks of treatment at 40 mg/kg/week. Marked increases in PLT-bound C3d/C4d were detected in all thrombocytopenic Mauritian-sourced monkeys but not in the unaffected Mauritian- or Asian-sourced monkeys, suggesting increased PLT clearance due to complement deposition on the PLTs. However, this effect was independent of the ASO-mediated fluid-phase alternative complement activation. A correlation was also observed between serum antiglycoprotein (GP) IIb/IIIa immunoglobulin G (IgG) and PLT reduction. In addition, increases in total serum IgM, anti-PLT IgM, and anti-PLT factor 4 IgM levels were observed in monkeys from both sources but were more evident in the Mauritian-sourced monkeys. These data suggest an enhanced innate immune cell activation to ISIS 405879, leading to increased PLT destruction through complement fixation on the PLTs or PLT crossreacting polyclonal antibody production.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"33 3","pages":"209-225"},"PeriodicalIF":4.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9953445","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":"Time Is a Critical Factor When Evaluating Oligonucleotide Therapeutics in hERG Assays.","authors":"Yusheng Qu,&nbsp;Robert Kirby,&nbsp;Richard Davies,&nbsp;Ayesha Jinat,&nbsp;Stefano Stabilini,&nbsp;Bin Wu,&nbsp;Longchuan Yu,&nbsp;BaoXi Gao,&nbsp;Hugo M Vargas","doi":"10.1089/nat.2022.0043","DOIUrl":"https://doi.org/10.1089/nat.2022.0043","url":null,"abstract":"<p><p>In accord with International Conference on Harmonization S7B guidelines, an <i>in vitro</i> human ether-a-go-go-related gene (hERG) assay is one component of an integrated risk assessment for delayed ventricular repolarization. Function of hERG could be affected by direct (acute) mechanisms, or by indirect (chronic) mechanisms. Some approved oligonucleotide therapeutics had submitted hERG data to regulatory agents, which were all collected with the same protocol used for small-molecule testing (incubation time <20 min; acute), however, oligonucleotides have unique mechanisms and time courses of action (indirect). To reframe the hERG testing strategy for silencing RNA (siRNA), an investigation was performed to assess the time course for siRNA-mediated inhibition of hERG function and gene expression. Commercially available siRNAs of hERG were evaluated in a stable hERG-expressed cell line by whole-cell voltage clamp using automated electrophysiology and polymerase chain reaction. In the acute hERG study, no effects were observed after treatment with 100 nM siRNA for 20 min. The chronic effects of 100 nM siRNAs on hERG function were evaluated and recorded over 8-48 h following transfection. At 8 h there was no significant effect, whereas 77% reduction was observed at 48 h. Measurement of hERG mRNA levels demonstrated a 79% and 93% decrease of hERG mRNA at 8 and 48 h, respectively, consistent with inhibition of hERG transcription. The results indicate that an anti-hERG siRNA requires a long exposure time (48 h) in the hERG assay to produce a maximal reduction in hERG current; short exposures (20 min-8 h) had no effect. These findings imply that off-target profiling of novel oligonucleotides could benefit from using hERG protocol with long incubation times to de-risk potential off-target (indirect) effects on the hERG channel. This hERG assay modification may be important to consider if the findings are used to support an integrated nonclinical-clinical risk assessment for QTc (the duration of the QT interval adjusted for heart rate) prolongation.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"33 2","pages":"132-140"},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10066779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9332968","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":"Chemical Modifications and Design Influence the Potency of <i>Huntingtin</i> Anti-Gene Oligonucleotides.","authors":"Osama Saher,&nbsp;Eman M Zaghloul,&nbsp;Tea Umek,&nbsp;Daniel W Hagey,&nbsp;Negin Mozafari,&nbsp;Mathias B Danielsen,&nbsp;Alaa S Gouda,&nbsp;Karin E Lundin,&nbsp;Per T Jørgensen,&nbsp;Jesper Wengel,&nbsp;C I Edvard Smith,&nbsp;Rula Zain","doi":"10.1089/nat.2022.0046","DOIUrl":"https://doi.org/10.1089/nat.2022.0046","url":null,"abstract":"<p><p>Huntington's disease is a neurodegenerative, trinucleotide repeat (TNR) disorder affecting both males and females. It is caused by an abnormal increase in the length of CAG•CTG TNR in exon 1 of the <i>Huntingtin</i> gene (<i>HTT</i>). The resultant, mutant HTT mRNA and protein cause neuronal toxicity, suggesting that reduction of their levels would constitute a promising therapeutic approach. We previously reported a novel strategy in which chemically modified oligonucleotides (ONs) directly target chromosomal DNA. These anti-gene ONs were able to downregulate both <i>HTT</i> mRNA and protein. In this study, various locked nucleic acid (LNA)/DNA mixmer anti-gene ONs were tested to investigate the effects of varying ON length, LNA content, and fatty acid modification on <i>HTT</i> expression. Altering the length did not significantly influence the ON potency, while LNA content was critical for activity. Utilization of palmitoyl-modified LNA monomers enhanced the ON activity relatively to the corresponding nonmodified LNA under serum starvation conditions. Furthermore, the number of palmitoylated LNA monomers and their positioning greatly affected ON potency. In addition, we performed RNA sequencing analysis, which showed that the anti-gene ONs affect the \"immune system process, mRNA processing, and neurogenesis.\" Furthermore, we observed that for repeat containing genes, there is a higher tendency for antisense off-targeting. Taken together, our findings provide an optimized design of anti-gene ONs that could potentially be developed as DNA-targeting therapeutics for this class of TNR-related diseases.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"33 2","pages":"117-131"},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10066784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9333519","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":"Translational Pharmacokinetic/Pharmacodynamic Model for mRNA-3927, an Investigational Therapeutic for the Treatment of Propionic Acidemia.","authors":"Husain Attarwala,&nbsp;Matthew Lumley,&nbsp;Min Liang,&nbsp;Vijay Ivaturi,&nbsp;Joe Senn","doi":"10.1089/nat.2022.0036","DOIUrl":"https://doi.org/10.1089/nat.2022.0036","url":null,"abstract":"<p><p>Propionic acidemia (PA) is an ultrarare disorder caused by deficiency of the mitochondrial enzyme, propionyl-CoA carboxylase (PCC), composed of PCCA and PCCB subunits. An enzyme replacement therapy is being developed using dual messenger RNA (mRNA) therapy composed of lipid nanoparticles (LNPs) encapsulating mRNAs encoding PCCA and PCCB subunits of the PCC enzyme. We herein report on development of a translational semimechanistic pharmacokinetic (PK) and PK/pharmacodynamic (PD) model to quantify the relationship between the mRNA components of mRNA-3927 (an LNP encapsulating PCCA and PCCB mRNAs) and dose levels; PCCA/B mRNA PK and PD responses were assessed as circulating levels of primary disease markers 2-methyl citrate, 3-hydroxypropionate, and propionyl carnitine normalized to acetyl carnitine (C3/C2 ratio) to inform the first-in-human dose range and regimen selection. The translational PK/PD model was developed using preclinical data available in mice with PA, Sprague Dawley rats, and cynomolgus monkeys at dose levels ranging from 0.2 to 9 mg/kg. PCCA/B mRNA PK in mice, rats, and monkeys was adequately described using allometric scaling of volume and clearance parameters. The interspecies preclinical model was scaled allometrically to humans to predict the dose-response relationship in adult and pediatric patients with PA to guide selection of dose range and regimen for the Phase 1 clinical trial (ClinicalTrials.gov Identifier NCT04159103).</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"33 2","pages":"141-147"},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10066765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9633753","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":"Aerosolized Pulmonary Delivery of mRNA Constructs Attenuates Severity of <i>Escherichia coli</i> Pneumonia in the Rat.","authors":"Sean D McCarthy,&nbsp;Christopher B Rohde,&nbsp;Matt Angel,&nbsp;Claire H Masterson,&nbsp;Ronan MacLoughlin,&nbsp;Juan Fandiño,&nbsp;Héctor E González,&nbsp;Declan Byrnes,&nbsp;John G Laffey,&nbsp;Daniel O'Toole","doi":"10.1089/nat.2022.0049","DOIUrl":"https://doi.org/10.1089/nat.2022.0049","url":null,"abstract":"<p><p>Acute respiratory distress syndrome (ARDS), a rapid onset inflammatory lung disease with no effective specific therapy, typically has pathogenic etiology termed pneumonia. In previous studies nuclear factor-κB (NF-κB) inhibitor α super-repressor (IκBα-SR) and extracellular superoxide dismutase 3 (SOD3) reduced pneumonia severity when prophylactically delivered by viral vector. In this study, mRNA coding for green fluorescent protein, IκBα-SR, or SOD3 was complexed with cationic lipid, passed through a vibrating mesh nebulizer, and delivered to cell culture or directly to rats undergoing <i>Escherichia coli</i> pneumonia. Injury level was then assessed at 48 h. <i>In vitro</i>, expression was observed as early as 4 h in lung epithelial cells. IκBα-SR and wild-type IκBα mRNAs attenuated inflammatory markers, while SOD3 mRNA induced protective and antioxidant effects. In rat <i>E. coli</i> pneumonia, IκBα-SR mRNA reduced arterial carbon dioxide (pCO2) and reduced lung wet/dry ratio. SOD3 mRNA improved static lung compliance and alveolar-arterial oxygen gradient (AaDO2) and decreased bronchoalveolar lavage (BAL) bacteria load. White cell infiltration and inflammatory cytokine concentrations in BAL and serum were reduced by both mRNA treatments compared to scrambled mRNA controls. These findings indicate nebulized mRNA therapeutics are a promising approach to ARDS therapy, with rapid expression of protein and observable amelioration of pneumonia symptoms.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"33 2","pages":"148-158"},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/2f/3f/nat.2022.0049.PMC10066785.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9279831","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":"Drug Metabolism and Pharmacokinetics of Antisense Oligonucleotide Therapeutics: Typical Profiles, Evaluation Approaches, and Points to Consider Compared with Small Molecule Drugs.","authors":"Hideo Takakusa,&nbsp;Norihiko Iwazaki,&nbsp;Makiya Nishikawa,&nbsp;Tokuyuki Yoshida,&nbsp;Satoshi Obika,&nbsp;Takao Inoue","doi":"10.1089/nat.2022.0054","DOIUrl":"https://doi.org/10.1089/nat.2022.0054","url":null,"abstract":"<p><p>Oligonucleotide therapeutics are attracting attention as a new treatment modality for a range of diseases that have been difficult to target using conventional approaches. Technical advances in chemical modification and drug delivery systems have led to the generation of compounds with excellent profiles as pharmaceuticals, and 16 oligonucleotide therapeutics have been marketed to date. There is a growing need to develop optimal and efficient approaches to evaluate drug metabolism and pharmacokinetics (DMPK) and drug-drug interactions (DDIs) of oligonucleotide therapeutics. The DMPK/DDI profiles of small molecule drugs are highly diverse depending on their structural and physicochemical characteristics, whereas oligonucleotide therapeutics share similar DMPK profiles within each chemistry type. Most importantly, the mechanisms and molecules involved in the distribution and metabolism of oligonucleotides differ from those of small molecules. In addition, there are considerations regarding experimental approaches in the evaluation of oligonucleotides, such as bioanalytical challenges, the use of radiolabeled tracers, materials for <i>in vitro</i> metabolism/DDI studies, and methods to study biodistribution. In this review, we attempt to summarize the DMPK characteristics of antisense oligonucleotide (ASO) therapeutics and discuss some of the issues regarding how to optimize the evaluation and prediction of the DMPK and DDI of ASOs.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"33 2","pages":"83-94"},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10066781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9333516","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}