Nucleic acid therapeutics最新文献_第2页

Addressing the Challenges of Treating Patients with Heterozygous Gain of Function Mutations. 应对治疗杂合子功能增益突变患者的挑战。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-12-01 Epub Date: 2024-09-23 DOI: 10.1089/nat.2024.0060

Stanley T Crooke

引用次数: 0

It is Time to Revisit miRNA Therapeutics. 是时候重新审视 miRNA 疗法了。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-11-21 DOI: 10.1089/nat.2024.0069

David R Corey

引用次数: 0

Levels of Exon-Skipping Are Not Artificially Overestimated Because of the Increased Affinity of Tricyclo-DNA-Modified Antisense Oligonucleotides to the Target DMD Exon. 由于三环 DNA 修饰的反义寡核苷酸对目标 DMD 外显子的亲和力增强，外显子跳转的水平不会被人为高估。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-10-01 Epub Date: 2024-07-24 DOI: 10.1089/nat.2024.0002

Mathilde Doisy, Ophélie Vacca, Amel Saoudi, Aurélie Goyenvalle

{"title":"Levels of Exon-Skipping Are Not Artificially Overestimated Because of the Increased Affinity of Tricyclo-DNA-Modified Antisense Oligonucleotides to the Target DMD Exon.","authors":"Mathilde Doisy, Ophélie Vacca, Amel Saoudi, Aurélie Goyenvalle","doi":"10.1089/nat.2024.0002","DOIUrl":"10.1089/nat.2024.0002","url":null,"abstract":"Antisense oligonucleotides (ASO) are very promising drugs for numerous diseases including neuromuscular disorders such as Duchenne muscular dystrophy (DMD). Several ASO drugs have already been approved by the US Food and Drug Administration for DMD and global efforts are still ongoing to improve further their potency, notably by developing new delivery systems or alternative chemistries. In this context, a recent study investigated the potential of different chemically modified ASO to induce exon-skipping in mouse models of DMD. Importantly, the authors reported a strong discrepancy between exon-skipping and protein restoration levels, which was mainly owing to the high affinity of locked nucleic acid (LNA) modifications to the target RNA, thereby interfering with the amplification of the unskipped product and resulting in artificial overamplification of the exon-skipped product. These findings urged us to verify whether a similar phenomenon could occur with tricyclo-DNA (tcDNA)-ASO that also display high-affinity properties to the target RNA. We thus ran a series of control experiments and demonstrate here that exon-skipping levels are not overestimated owing to an interference of tcDNA-ASO with the unskipped product in contrast to what was observed with LNA-containing ASO.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"214-220"},"PeriodicalIF":4.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141760035","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

Near Sequence Homology Does Not Guarantee siRNA Cross-Species Efficacy. 近似序列同源性并不能保证 siRNA 的跨物种功效。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-10-01 Epub Date: 2024-08-27 DOI: 10.1089/nat.2024.0030

Iris Valeria Rivera Flores, Kathryn Monopoli, Samuel Jackson, Dimas Echeverria, Daniel O'Reilly, Robert H Brown, Anastasia Khvorova

{"title":"Near Sequence Homology Does Not Guarantee siRNA Cross-Species Efficacy.","authors":"Iris Valeria Rivera Flores, Kathryn Monopoli, Samuel Jackson, Dimas Echeverria, Daniel O'Reilly, Robert H Brown, Anastasia Khvorova","doi":"10.1089/nat.2024.0030","DOIUrl":"10.1089/nat.2024.0030","url":null,"abstract":"Small interfering RNAs (siRNAs) represent a novel class of drugs capable of potent and sustained modulation of genes across various tissues. Preclinical development of siRNAs necessitates assessing efficacy and toxicity in animal models. While identifying therapeutic leads with cross-species activity can expedite development, it may compromise efficacy and be infeasible for certain gene targets. Here, we investigate whether deriving species-active siRNAs from potent human-targeting leads-an approach termed mismatch conversion-can yield potent compounds. We systematically altered potent siRNAs targeting human genes associated with diseases-SOD1 (ALS), JAK1 (inflammation), and HTT (HD)-to generate species-matching variants with full complementarity to their target in NHPs, mice, rats, sheep, and dogs. Variants potency and efficacy were measured in corresponding cell lines. We demonstrate that sequence, position, and number of mismatches significantly influence the ability to generate potent species-active compounds via mismatch conversion. Across tested sequences, mismatch conversion strategy ability to identify a species-active lead varied from 0% to 70%. For SOD1, lead compounds identified from species-focus screening in mouse and dog cells were more potent than leads obtained from mismatch conversion. Thus, a focused screening of therapeutic lead and model compounds may represent a more reliable strategy for the clinical advancement of siRNAs.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"234-244"},"PeriodicalIF":4.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11564669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073368","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

Peptide Nucleic Acid-Mediated Regulation of CRISPR-Cas9 Specificity. 多肽核酸介导的 CRISPR-Cas9 特异性调控。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-10-01 Epub Date: 2024-07-22 DOI: 10.1089/nat.2024.0007

Kelly E W Carufe, Nicholas G Economos, Peter M Glazer

{"title":"Peptide Nucleic Acid-Mediated Regulation of CRISPR-Cas9 Specificity.","authors":"Kelly E W Carufe, Nicholas G Economos, Peter M Glazer","doi":"10.1089/nat.2024.0007","DOIUrl":"10.1089/nat.2024.0007","url":null,"abstract":"Although CRISPR-Cas9 gene therapies have proven to be a powerful tool across many applications, improvements are necessary to increase the specificity of this technology. Cas9 cutting in off-target sites remains an issue that limits CRISPR's application in human-based therapies. Treatment of autosomal dominant diseases also remains a challenge when mutant alleles differ from the wild-type sequence by only one base pair. Here, we utilize synthetic peptide nucleic acids (PNAs) that bind selected spacer sequences in the guide RNA (gRNA) to increase Cas9 specificity up to 10-fold. We interrogate variations in PNA length, binding position, and degree of homology with the gRNA. Our findings reveal that PNAs bound in the region distal to the protospacer adjacent motif (PAM) site effectively enhance specificity in both on-target/off-target and allele-specific scenarios. In addition, we demonstrate that introducing deliberate mismatches between PNAs bound in the PAM-proximal region of the gRNA can modulate Cas9 activity in an allele-specific manner. These advancements hold promise for addressing current limitations and expanding the therapeutic potential of CRISPR technology.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"245-256"},"PeriodicalIF":4.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11564683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141734691","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

Rosalind Franklin Society Proudly Announces the 2023 Award Recipient for Nucleic Acid Therapeutics. 罗莎琳德-富兰克林学会自豪地宣布 2023 年核酸治疗奖得主。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-10-01 DOI: 10.1089/nat.2024.84674.rfs2023

Anastasia Khvorova

引用次数: 0

Characterization of the TLR9-Activating Potential of LNA-Modified Antisense Oligonucleotides. LNA修饰的反义寡核苷酸的TLR9激活潜力表征

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-10-01 Epub Date: 2024-07-17 DOI: 10.1089/nat.2024.0013

Irene Riera-Tur, Julia Hinterdobler, André Maaske, Anne Sadewasser, Monika Schell, Janani Sekar, Sven Michel, Richard Klar, Frank Jaschinski

{"title":"Characterization of the TLR9-Activating Potential of LNA-Modified Antisense Oligonucleotides.","authors":"Irene Riera-Tur, Julia Hinterdobler, André Maaske, Anne Sadewasser, Monika Schell, Janani Sekar, Sven Michel, Richard Klar, Frank Jaschinski","doi":"10.1089/nat.2024.0013","DOIUrl":"10.1089/nat.2024.0013","url":null,"abstract":"Early characterization of the immunostimulatory potential of therapeutic antisense oligonucleotides (ASOs) is crucial. At present, little is known about the toll-like receptor 9 (TLR9)-mediated immunostimulatory potential of third-generation locked nucleic acid (LNA)-modified ASOs. In this study, we have systematically investigated the TLR9-activating potential of LNA-modified oligonucleotides using different mouse and human cell culture systems. Although it has been reported that LNA modifications as well as cytosine methylation of 5'-cytosine-phosphate-guanine-3' (CpG) motifs can reduce TLR9 stimulation by phosphorothioate (PTO)-modified oligonucleotides, we identified CpG-containing LNA gapmers with substantial TLR9-stimulatory activity. We further identified immunostimulatory LNA gapmers without CpG motifs. Unexpectedly, methylation of cytosines only within the CpG motif did not necessarily reduce but could even increase TLR9 activation. In contrast, systematic methylation of all cytosines reduced or even abrogated TLR9 activation in most cases. Context dependently, the introduction of LNA-modifications into the flanks could either increase or decrease TLR9 stimulation. Overall, our results indicate that TLR9-dependent immunostimulatory potential is an individual feature of an oligonucleotide and needs to be investigated on a case-by-case basis.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"257-271"},"PeriodicalIF":4.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141634130","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

Antisense Oligonucleotide STK-002 Increases OPA1 in Retina and Improves Mitochondrial Function in Autosomal Dominant Optic Atrophy Cells. 反义寡核苷酸 STK-002 增加视网膜中的 OPA1 并改善常染色体显性视神经萎缩细胞的线粒体功能

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-09-12 DOI: 10.1089/nat.2024.0022

Aditya Venkatesh,Taylor McKenty,Syed Ali,Donna Sonntag,Shobha Ravipaty,Yanyan Cui,Deirdre Slate,Qian Lin,Anne Christiansen,Sarah Jacobson,Jacob Kach,Kian Huat Lim,Vaishnavi Srinivasan,Boris Zinshteyn,Isabel Aznarez,Laryssa A Huryn,Zhiyu Li,Robert B Hufnagel,Gene Liau,Karen Anderson,Jeff Hoger

{"title":"Antisense Oligonucleotide STK-002 Increases OPA1 in Retina and Improves Mitochondrial Function in Autosomal Dominant Optic Atrophy Cells.","authors":"Aditya Venkatesh,Taylor McKenty,Syed Ali,Donna Sonntag,Shobha Ravipaty,Yanyan Cui,Deirdre Slate,Qian Lin,Anne Christiansen,Sarah Jacobson,Jacob Kach,Kian Huat Lim,Vaishnavi Srinivasan,Boris Zinshteyn,Isabel Aznarez,Laryssa A Huryn,Zhiyu Li,Robert B Hufnagel,Gene Liau,Karen Anderson,Jeff Hoger","doi":"10.1089/nat.2024.0022","DOIUrl":"https://doi.org/10.1089/nat.2024.0022","url":null,"abstract":"Autosomal dominant optic atrophy (ADOA) is an inherited optic neuropathy most frequently associated with OPA1 mutations. Most variants result in haploinsufficiency, and patient cells express roughly half of the normal levels of OPA1 protein. OPA1 is a mitochondrial GTPase that is essential for normal mitochondrial function. We identified and characterized STK-002, an antisense oligonucleotide (ASO) designed to prevent the incorporation of a naturally occurring alternatively spliced nonproductive exon in OPA1. STK-002 dose dependently reduced the inclusion of this exon, and increased OPA1 protein in human cells, including ADOA patient-derived fibroblasts. ADOA patient cells manifest reduced mitochondrial respiration, and treatment with STK-002 improved the parameters of mitochondrial respiratory function in these cells. Since STK-002 increases OPA1 through the wild-type allele, we assessed retinal OPA1 in wild-type cynomolgus monkeys and rabbits after intravitreal administration of STK-002 or a rabbit-specific surrogate. Increased OPA1 protein was produced in retinal tissue in both species at 4 weeks after ASO injection and persisted in monkeys at 8 weeks. STK-002 and enhanced OPA1 immunofluorescence were visualized in retinal ganglion cells of cynomolgus monkeys treated with the ASO. Cumulatively, these data support the progression of STK-002 toward the clinic as the first potential disease-modifying treatment for ADOA.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"44 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263110","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

Screening Splice-Switching Antisense Oligonucleotides in Pancreas-Cancer Organoids. 在胰腺癌组织细胞中筛选剪接转换反义寡核苷酸

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-08-01 Epub Date: 2024-05-08 DOI: 10.1089/nat.2023.0070

Ledong Wan, Alexander J Kral, Dillon Voss, Balázs Schäfer, Kavitha Sudheendran, Mathias Danielsen, Marvin H Caruthers, Adrian R Krainer

{"title":"Screening Splice-Switching Antisense Oligonucleotides in Pancreas-Cancer Organoids.","authors":"Ledong Wan, Alexander J Kral, Dillon Voss, Balázs Schäfer, Kavitha Sudheendran, Mathias Danielsen, Marvin H Caruthers, Adrian R Krainer","doi":"10.1089/nat.2023.0070","DOIUrl":"10.1089/nat.2023.0070","url":null,"abstract":"Aberrant alternative splicing is emerging as a cancer hallmark and a potential therapeutic target. It is the result of dysregulated or mutated splicing factors, or genetic alterations in splicing-regulatory cis-elements. Targeting individual altered splicing events associated with cancer-cell dependencies is a potential therapeutic strategy, but several technical limitations need to be addressed. Patient-derived organoids are a promising platform to recapitulate key aspects of disease states, and to facilitate drug development for precision medicine. Here, we report an efficient antisense-oligonucleotide (ASO) lipofection method to systematically evaluate and screen individual splicing events as therapeutic targets in pancreatic ductal adenocarcinoma organoids. This optimized delivery method allows fast and efficient screening of ASOs, e.g., those that reverse oncogenic alternative splicing. In combination with advances in chemical modifications of oligonucleotides and ASO-delivery strategies, this method has the potential to accelerate the discovery of antitumor ASO drugs that target pathological alternative splicing.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"188-198"},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11387002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140876860","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

Preclinical Pharmacokinetics in Tumors and Normal Tissues of the Antigene PNA Oligonucleotide MYCN-Inhibitor BGA002. 抗原 PNA 寡核苷酸 MYCN 抑制剂 BGA002 在肿瘤和正常组织中的临床前药代动力学。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-08-01 Epub Date: 2024-07-03 DOI: 10.1089/nat.2024.0005

Anna Lisa Scardovi, Damiano Bartolucci, Luca Montemurro, Sonia Bortolotti, Silvia Angelucci, Camilla Amadesi, Giammario Nieddu, Sean Oosterholt, Lucia Cerisoli, Oscar Della Pasqua, Patrizia Hrelia, Roberto Tonelli

{"title":"Preclinical Pharmacokinetics in Tumors and Normal Tissues of the Antigene PNA Oligonucleotide MYCN-Inhibitor BGA002.","authors":"Anna Lisa Scardovi, Damiano Bartolucci, Luca Montemurro, Sonia Bortolotti, Silvia Angelucci, Camilla Amadesi, Giammario Nieddu, Sean Oosterholt, Lucia Cerisoli, Oscar Della Pasqua, Patrizia Hrelia, Roberto Tonelli","doi":"10.1089/nat.2024.0005","DOIUrl":"10.1089/nat.2024.0005","url":null,"abstract":"Although MYCN has been considered an undruggable target, MYCN alterations confer poor prognosis in many pediatric and adult cancers. The novel MYCN-speciﬁc inhibitor BGA002 is an antigene peptide nucleic acid oligonucleotide covalently bound to a nuclear localization signal peptide. In the present study, we characterized the pharmacokinetics (PK) of BGA002 after single and repeated administration to mice using a novel specific enzyme-linked immunosorbent assay. BGA002 concentrations in plasma showed linear PK, with dose proportional increase across the tested dose levels and similar exposure between male and female and between intravenous and subcutaneous route of administration. Repeated dosing resulted in no accumulation in plasma. Biodistribution up to 7 days after single subcutaneous administration of [14C]-radiolabeled BGA002 showed broad tissues and organ distribution (suggesting a potential capability to reach primary tumor and metastasis in several body sites), with high concentrations in kidney, liver, spleen, lymph nodes, adrenals, and bone marrow. Remarkably, we demonstrated that BGA002 concentrates in tumors after repeated systemic administrations in three mouse models with MYCN amplification (neuroblastoma, rhabdomyosarcoma, and small-cell lung cancer), leading to a significant reduction in tumor weight. Taking into account the available safety profile of BGA002, these data support further evaluation of BGA002 in patients with MYCN-positive tumors.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"173-187"},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141492887","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