Technologies for Targeted RNA Degradation and Induced RNA Decay DOI Creative Commons
Sigitas Mikutis, Gonçalo J. L. Bernardes

Chemical Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 5, 2024

The vast majority of the human genome codes for RNA, but RNA-targeting therapeutics account a small fraction approved drugs. As such, there is great incentive to improve old and develop new approaches RNA targeting. For many targeting modalities, just binding not sufficient exert therapeutic effect; thus, targeted degradation induced decay emerged as powerful with pronounced biological effect. This review covers origins advanced use cases degrader technologies grouped by nature modality well mode degradation. It both well-established methods clinically successful platforms such interference, emerging recruitment quality control machinery, CRISPR, direct We also share our thoughts on biggest hurdles in this field, possible ways overcome them.

Language: Английский

RNA editing: Expanding the potential of RNA therapeutics DOI Creative Commons

Brian J. Booth,

Sami Nourreddine, Dhruva Katrekar

et al.

Molecular Therapy, Journal Year: 2023, Volume and Issue: 31(6), P. 1533 - 1549

Published: Jan. 7, 2023

RNA therapeutics have had a tremendous impact on medicine, recently exemplified by the rapid development and deployment of mRNA vaccines to combat COVID-19 pandemic. In addition, RNA-targeting drugs been developed for diseases with significant unmet medical needs through selective knockdown or modulation pre-mRNA splicing. Recently, editing, particularly antisense RNA-guided adenosine deaminase acting (ADAR)-based programmable A-to-I has emerged as powerful tool manipulate enable correction disease-causing mutations modulate gene expression protein function. Beyond correcting pathogenic mutations, technology is well suited therapeutic applications that require transient pharmacodynamic effect, such treatment acute pain, obesity, viral infection, inflammation, where it would be undesirable introduce permanent alterations genome. Furthermore, function, altering active sites enzymes interface protein-protein interactions, opens door avenues ranging from regenerative medicine oncology. These emerging RNA-editing-based toolsets are poised broadly biotechnology applications. Here, we review field highlight recent laboratory advancements, discuss key challenges path clinical development.

Language: Английский

Citations

85
Absorption, Distribution, Metabolism, and Excretion of US Food and Drug Administration–Approved Antisense Oligonucleotide Drugs DOI Open Access

Julia M. Migliorati,

Sunna Liu,

Anna Liu

et al.

Drug Metabolism and Disposition, Journal Year: 2022, Volume and Issue: 50(6), P. 888 - 897

Published: Feb. 27, 2022

Absorption, distribution, metabolism, and excretion (ADME) are the key biologic processes for determination of a drug's pharmacokinetic parameters, which have direct impacts on efficacy adverse drug reactions (ADRs). The chemical structures, dosage forms, sites routes administration principal determinants ADME profiles consequent their ADRs. Newly developed large molecule antisense oligonucleotide (ASO) drugs completely unique that is not fully defined. ASO-based single-stranded synthetic nucleic acids with diverse modes actions from induction mRNA degradation, exon skipping restoration, interactions proteins. ASO great potential to treat certain human diseases remained untreatable small molecule-based drugs. contributes set ADRs toxicity. In this review, better understand ADME, 10 US Food Drug Administration (FDA)-approved were selected: fomivirsen, pegaptanib, mipomersen, nusinersen, inotersen, defibrotide, eteplirsen, golodirsen, viltolarsen, casimersen. A meta-analysis was conducted formulation, dosage, administration, local systematic excretion. Membrane permeabilization through endocytosis nucleolytic degradation by endonucleases exonucleases major features differ small-molecule information summarized here provides comprehensive characteristics FDA-approved drugs, leading understanding therapeutic Numerous knowledge gaps, particularly cellular uptake subcellular trafficking identified, future perspectives directions discussed.

SIGNIFICANCE STATEMENT

Through analysis existing absorption, parameters review an overall view distinct ADME. This useful discovery development new as well clinical use current

Language: Английский

Citations

74
CircPVT1 promotes ER‐positive breast tumorigenesis and drug resistance by targeting ESR1 and MAVS DOI Creative Commons
Yi Jia, Lei Wang,

Guo‐sheng Hu

et al.

The EMBO Journal, Journal Year: 2023, Volume and Issue: 42(10)

Published: April 3, 2023

Abstract The molecular mechanisms underlying estrogen receptor (ER)‐positive breast carcinogenesis and endocrine therapy resistance remain incompletely understood. Here, we report that circPVT1, a circular RNA generated from the lncRNA PVT1, is highly expressed in ERα‐positive cancer cell lines tumor samples functionally important promoting tumorigenesis resistance. CircPVT1 acts as competing endogenous (ceRNA) to sponge miR‐181a‐2‐3p, expression of ESR1 downstream ERα‐target genes growth. Furthermore, circPVT1 directly interacts with MAVS protein disrupt RIGI–MAVS complex formation, inhibiting type I interferon (IFN) signaling pathway anti‐tumor immunity. Anti‐sense oligonucleotide (ASO)‐targeting inhibits growth, re‐sensitizing tamoxifen‐resistant cells tamoxifen treatment. Taken together, our data demonstrated can work through both ceRNA scaffolding promote cancer. Thus, may serve diagnostic biomarker therapeutic target for clinic.

Language: Английский

Citations

46
Non-coding RNAs as therapeutic targets and biomarkers in ischaemic heart disease DOI
Andrea Caporali, Maryam Anwar, Yvan Devaux

et al.

Nature Reviews Cardiology, Journal Year: 2024, Volume and Issue: 21(8), P. 556 - 573

Published: March 18, 2024

Language: Английский

Citations

24
Current status and trends in small nucleic acid drug development: Leading the future DOI Creative Commons
Yuxi Miao, Chen Fu, Zhaojin Yu

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(9), P. 3802 - 3817

Published: May 13, 2024

Small nucleic acid drugs, composed of nucleotides, represent a novel class pharmaceuticals that differ significantly from conventional small molecule and antibody-based therapeutics. These agents function by selectively targeting specific genes or their corresponding messenger RNAs (mRNAs), further modulating gene expression regulating translation-related processes. Prominent examples within this category include antisense oligonucleotides (ASO), interfering (siRNAs), microRNAs (miRNAs), aptamers. The emergence drugs as focal point in contemporary biopharmaceutical research is attributed to remarkable specificity, facile design, abbreviated development cycles, expansive target spectrum, prolonged activity. Overcoming challenges such poor stability, immunogenicity, permeability issues have been addressed through the integration chemical modifications drug delivery systems. This review provides an overview current status prospective trends development. Commencing with historical context, we introduce primary classifications mechanisms drugs. Subsequently, delve into advantages U.S. Food Drug Administration (FDA) approved mainly discuss encountered during Apart researching modification system efficiently deliver enrich tissues, promoting endosomal escape critical scientific question important direction siRNA Future directions field will prioritize addressing these facilitate clinical transformation

Language: Английский

Citations

18
Antisense Oligonucleotide Therapy for the Nervous System: From Bench to Bedside with Emphasis on Pediatric Neurology DOI Creative Commons

Man Amanat,

Christina L. Nemeth, Amena Smith Fine

et al.

Pharmaceutics, Journal Year: 2022, Volume and Issue: 14(11), P. 2389 - 2389

Published: Nov. 5, 2022

Antisense oligonucleotides (ASOs) are disease-modifying agents affecting protein-coding and noncoding ribonucleic acids. Depending on the chemical modification location of hybridization, ASOs able to reduce level toxic proteins, increase functional protein, or modify structure impaired protein improve function. There multiple challenges in delivering their site action. Chemical modifications phosphodiester bond, nucleotide sugar, nucleobase can structural thermodynamic stability prevent ASO degradation. Furthermore, different particles, including viral vectors, conjugated peptides, antibodies, nanocarriers, may delivery. To date, six have been approved by US Food Drug Administration (FDA) three neurological disorders: spinal muscular atrophy, Duchenne dystrophy, polyneuropathy caused hereditary transthyretin amyloidosis. Ongoing preclinical clinical studies assessing safety efficacy genetic acquired conditions. The current review provides an update underlying mechanisms, design, modifications, delivery ASOs. administration FDA-approved disorders is described, evidence other conditions, pediatric disorders, reviewed.

Language: Английский

Citations

47
Nucleic acid degradation as barrier to gene delivery: a guide to understand and overcome nuclease activity DOI
Heyang Zhang, Jo Vandesompele, Kevin Braeckmans

et al.

Chemical Society Reviews, Journal Year: 2023, Volume and Issue: 53(1), P. 317 - 360

Published: Dec. 11, 2023

Gene therapy is on its way to revolutionize the treatment of both inherited and acquired diseases, by transferring nucleic acids correct a disease-causing gene in target cells patients. In fight against infectious mRNA-based therapeutics have proven be viable strategy recent Covid-19 pandemic. Although growing number therapies been approved, success rate limited when compared large preclinical clinical trials that been/are being performed. this review, we highlight some hurdles which encounter after administration into human body, with focus acid degradation nucleases are extremely abundant mammalian organs, biological fluids as well subcellular compartments. We overview available strategies reduce biodegradation administration, including chemical modifications acids, encapsulation vectors co-administration nuclease inhibitors discuss applied for clinically approved therapeutics. final part, currently methods techniques qualify quantify integrity their own strengths limitations.

Language: Английский

Citations

40
Recent Advance of Liposome Nanoparticles for Nucleic Acid Therapy DOI Creative Commons
Yongguang Gao, Xinhua Liu,

Na Chen

et al.

Pharmaceutics, Journal Year: 2023, Volume and Issue: 15(1), P. 178 - 178

Published: Jan. 4, 2023

Gene therapy, as an emerging therapeutic approach, has shown remarkable advantages in the treatment of some major diseases. With deepening genomics research, people have gradually realized that emergence and development many diseases are related to genetic abnormalities. Therefore, nucleic acid drugs becoming a new boon (especially tumors diseases). It is conservatively estimated global market will exceed $20 billion by 2025. They simple design, mature synthesis, good biocompatibility. However, shortcomings acid, such poor stability, low bioavailability, targeting, greatly limit clinical application acid. Liposome nanoparticles can wrap internal cavities, increase stability prolong blood circulation time, thus improving transfection efficiency. This review focuses on recent advances potential applications liposome modified with (DNA, RNA, ASO) different chemical molecules (peptides, polymers, dendrimers, fluorescent molecules, magnetic nanoparticles, receptor targeting molecules). The ability deliver also discussed detail. We hope this help researchers design safer more efficient accelerate gene therapy.

Language: Английский

Citations

38
Exosomal long noncoding RNA MLETA1 promotes tumor progression and metastasis by regulating the miR-186-5p/EGFR and miR-497-5p/IGF1R axes in non-small cell lung cancer DOI Creative Commons

Xiu-Rui Hsu,

Jia-En Wu, Yi-Ying Wu

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 42(1)

Published: Oct. 26, 2023

Lung cancer is the most common and deadliest worldwide, approximately 90% of all lung deaths are caused by tumor metastasis. Tumor-derived exosomes could potentially promote metastasis through delivery metastasis-related molecules. However, function underlying mechanism exosomal long noncoding RNA (lncRNA) in remain largely unclear.Cell were purified from conditioned media differential ultracentrifugation observed using transmission electron microscopy, size distributions determined nanoparticle tracking analysis. Exosomal lncRNA sequencing (lncRNA-seq) was used to identify RNAs. Cell migration invasion wound-healing assays, two-chamber transwell assays cell mobility tracking. Mice orthotopically subcutaneously xenografted with human cells evaluate vivo. Western blot, qRT‒PCR, RNA-seq, dual-luciferase reporter performed investigate potential mechanism. The level plasma examined qRT‒PCR. MS2-tagged affinity purification (MS2-TRAP) verify lncRNA-bound miRNAs.Exosomes derived highly metastatic promoted low potential. Using lncRNA-seq, we found that a novel lncRNA, lnc-MLETA1, upregulated their secreted exosomes. Overexpression lnc-MLETA1 augmented cancer. Conversely, knockdown attenuated motility cells. Interestingly, exosome-transmitted Reciprocally, targeting an LNA suppressed exosome-induced motility. Mechanistically, regulated expression EGFR IGF1R sponging miR-186-5p miR-497-5p facilitate clinical datasets revealed tissues predicts survival patients. Importantly, levels positively correlated patients.This study identifies as critical mediates crosstalk may serve prognostic biomarker therapeutic target for diagnosis treatment.

Language: Английский

Citations

28
Nucleic acid drugs: recent progress and future perspectives DOI Creative Commons

Xiaoyi Sun,

Sarra Setrerrahmane,

Chencheng Li

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 29, 2024

Language: Английский

Citations

14