Nucleic acid therapeutics最新文献

A Combined Fertility and Developmental Toxicity Study with an Antisense Oligonucleotide Targeting Murine Apolipoprotein C-III mRNA in Mice. 以小鼠载脂蛋白 C-III mRNA 为靶点的反义寡核苷酸对小鼠生育能力和发育毒性的综合研究

IF 4 2区医学

Nucleic acid therapeutics Pub Date : 2024-12-01 Epub Date: 2024-11-25 DOI: 10.1089/nat.2024.0057

Ji-Seong Jeong, Archit Rastogi, Tae-Won Kim, Scott Henry, Christine M Hoffmaster, Sang Yun Kim, Woojin Kim, Sun-Young Lee, Jeong-Dong Park, In-Su Wi, Wook-Joon Yu, Jinsoo Lee

{"title":"A Combined Fertility and Developmental Toxicity Study with an Antisense Oligonucleotide Targeting Murine Apolipoprotein C-III mRNA in Mice.","authors":"Ji-Seong Jeong, Archit Rastogi, Tae-Won Kim, Scott Henry, Christine M Hoffmaster, Sang Yun Kim, Woojin Kim, Sun-Young Lee, Jeong-Dong Park, In-Su Wi, Wook-Joon Yu, Jinsoo Lee","doi":"10.1089/nat.2024.0057","DOIUrl":"10.1089/nat.2024.0057","url":null,"abstract":"Here, we present the reproductive toxicology profile of ISIS 838707, a GalNAc-conjugated antisense oligonucleotide (ASO) targeting mouse Apolipoprotein C-III (ApoC-III) mRNA. ISIS 838707 was subcutaneously administered during the premating, mating, and gestation periods to male and female mice at 0, 5, 10, and 20 mg/kg/week. Key focus areas included fertility, reproductive cell functions, estrus cycle, tubal transport, implantation, embryo development stages, and teratogenic potential. We also investigated the toxicokinetics and target mRNA knockdown effects. The treatment was well-tolerated at all dose levels, with no overt toxicity. Treatment led to decreased total cholesterol and/or triglyceride levels at doses ≥5 mg/kg/week, concordant with effective knockdown of ApoC-III mRNA (>85% reduction at all dose levels). Toxicokinetic analysis revealed predominant distribution to the liver of parental animals and minimally to the placenta, with no detectable transfer to fetal liver. Despite these pharmacological effects, there were no discernible adverse impacts on developmental and reproductive functions. These findings suggest that ISIS 838707, while effective in modulating ApoC-III mRNA and lipid profiles, does not adversely impact on reproductive and developmental functions in mice. The study contributes insights into the safety profile of ASOs and reduction of ApoC-III expression, particularly in the context of reproductive and developmental health.","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"285-294"},"PeriodicalIF":4.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716671","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

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 : 2024-12-01 Epub 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":"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":" ","pages":"276-284"},"PeriodicalIF":4.0,"publicationDate":"2024-12-01","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

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 : 2024-12-01 Epub 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

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 : 2024-12-01 Epub Date: 2024-08-23 DOI: 10.1089/nat.2024.0043

Juan Daniel Avila, Puzhou Wang

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 : 2024-12-01 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