Nucleic acid therapeutics最新文献

An Evaluation of First-in-Human Studies for RNA Oligonucleotides. 评估 RNA 寡核苷酸的首次人体试验研究。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-09-23 DOI: 10.1089/nat.2024.0036

Sydney Stern, Ronald L Wange, Hobart Rogers

{"title":"An Evaluation of First-in-Human Studies for RNA Oligonucleotides.","authors":"Sydney Stern, Ronald L Wange, Hobart Rogers","doi":"10.1089/nat.2024.0036","DOIUrl":"https://doi.org/10.1089/nat.2024.0036","url":null,"abstract":"Most oligonucleotide therapeutics use Watson-Crick-Franklin base-pairing hybridization to target RNA and mitigate disease-related protein production. Using targets that were previously inaccessible to small molecules and biologics, synthetic nucleotides have provided treatments for severely debilitating and life-threatening diseases. However, these therapeutics possess unique pharmacologies that require specific considerations for their distribution, clearance, and other clinical pharmacology characteristics. Namely, one hurdle in the drug development of these therapeutics remains the prediction of human dose that results in exposures comparable with or below those seen at no observed adverse effect level in animals. For first-in-human (FIH) clinical trials, this often involves allometric scaling based on body surface area (BSA) or body weight (BW). In this study, we reviewed the current literature and surveyed elements across 16 approved oligonucleotide therapeutic New Drug Applications approved by the U.S. Food and Drug Administration in the period from September 1998 to January 2024, and 89 Investigational New Drug (IND) programs with available FIH clinical trials conducted from January 2015 to January 2024, to understand dose selection in early-stage development of oligonucleotide therapeutics. The surveyed elements across these programs include study design, route of administration, dosing regimen, interspecies scaling approach, and the most sensitive species. Of 89 IND programs and 16 approved therapeutics, intravenous and subcutaneous were the most common route of administration, no observable adverse event levels were frequently derived from nonhuman primates, BSA and BW were adjusted for in similar frequencies, patients were predominantly enrolled in FIH trials, and the most common design was a single or multiple ascending dose trial.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292379","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

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 : 2024-09-23 DOI: 10.1089/nat.2024.0060

Stanley T Crooke

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":null,"pages":null},"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

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 : 2024-08-27 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":"https://doi.org/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":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mass Spectrometry as a Quantitative Tool for SpCas9 sgRNA Quality Control. 质谱法作为 SpCas9 sgRNA 质量控制的定量工具。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-08-23 DOI: 10.1089/nat.2024.0043

Juan Daniel Avila, Puzhou Wang

引用次数: 0

A Guide to Chemical Considerations for the Pre-Clinical Development of Oligonucleotides. 寡核苷酸临床前开发化学考虑因素指南》。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-08-07 DOI: 10.1089/nat.2024.0031

Daniel O'Reilly, Willeke van Roon-Mom, Annemieke Aartsma-Rus

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":null,"pages":null},"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

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":null,"pages":null},"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

mRNA Nuclear Clustering Leads to a Difference in Mutant Huntingtin mRNA and Protein Silencing by siRNAs In Vivo. mRNA 核集群导致体内 siRNAs 沉默突变型亨廷汀 mRNA 和蛋白的差异。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-08-01 Epub Date: 2024-07-18 DOI: 10.1089/nat.2024.0027

Sarah Allen, Daniel O'Reilly, Rachael Miller, Ellen Sapp, Ashley Summers, Joseph Paquette, Dimas Echeverria Moreno, Brianna Bramato, Nicholas McHugh, Ken Yamada, Neil Aronin, Marian DiFiglia, Anastasia Khvorova

{"title":"mRNA Nuclear Clustering Leads to a Difference in Mutant Huntingtin mRNA and Protein Silencing by siRNAs In Vivo.","authors":"Sarah Allen, Daniel O'Reilly, Rachael Miller, Ellen Sapp, Ashley Summers, Joseph Paquette, Dimas Echeverria Moreno, Brianna Bramato, Nicholas McHugh, Ken Yamada, Neil Aronin, Marian DiFiglia, Anastasia Khvorova","doi":"10.1089/nat.2024.0027","DOIUrl":"10.1089/nat.2024.0027","url":null,"abstract":"Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by CAG repeat expansion in the first exon of the huntingtin gene (HTT). Oligonucleotide therapeutics, such as short interfering RNA (siRNA), reduce levels of huntingtin mRNA and protein in vivo and are considered a viable therapeutic strategy. However, the extent to which they silence huntingtin mRNA in the nucleus is not established. We synthesized siRNA cross-reactive to mouse (wild-type) Htt and human (mutant) HTT in a divalent scaffold and delivered to two mouse models of HD. In both models, divalent siRNA sustained lowering of wild-type Htt, but not mutant HTT mRNA expression in striatum and cortex. Near-complete silencing of both mutant HTT protein and wild-type HTT protein was observed in both models. Subsequent fluorescent in situ hybridization analysis shows that divalent siRNA acts predominantly on cytoplasmic mutant HTT transcripts, leaving clustered mutant HTT transcripts in the nucleus largely intact in treated HD mouse brains. The observed differences between mRNA and protein levels, exaggerated in the case of extended repeats, might apply to other repeat-associated neurological disorders.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11387003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141634131","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

Phosphorothioates and Me: A Lecture About My 35 Years in Oligo-World on My Receipt of the 2023 Lifetime Achievement Award of the Oligonucleotide Therapeutics Society. 我与硫代磷酸酯寡核苷酸治疗学会 2023 年终身成就奖获得者关于我在寡核苷酸世界 35 年的演讲。

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-08-01 Epub Date: 2024-06-26 DOI: 10.1089/nat.2024.0032

Cy A Stein

引用次数: 0