Small Drugs, Huge Impact: The Extraordinary Impact of Antisense Oligonucleotides in Research and Drug Development DOI Creative Commons
Anaïs M. Quéméner, Maria Laura Centomo,

Scott L. Sax

et al.

Molecules, Journal Year: 2022, Volume and Issue: 27(2), P. 536 - 536

Published: Jan. 15, 2022

Antisense oligonucleotides (ASOs) are an increasingly represented class of drugs. These small sequences nucleotides designed to precisely target other oligonucleotides, usually RNA species, and modified protect them from degradation by nucleases. Their specificity is due their sequence, so it possible any sequence that already known. molecules very versatile adaptable given chemistry can be custom manufactured. Based on the being used, activity may significantly change effects cell function phenotypes differ dramatically. While some will cause decay, others only bind act as a steric blocker. incredible versatility key manipulating several aspects nucleic acid well process, alter transcriptome profile specific type or tissue. For example, they used modify splicing mask sites target. The entire design rather than just essential ensuring ASO its Thus, vitally important ensure complete process drug testing taken into account. ASOs’ adaptability considerable advantage, over past decades has allowed multiple new drugs approved. This, in turn, had significant positive impact patient lives. Given current challenges presented COVID-19 pandemic, necessary find therapeutic strategies would complement vaccination efforts across globe. ASOs powerful tool virus provide paradigm. proof efficacy anti-viral agent long-standing, yet no molecule currently FDA approval. emergence widespread use vaccines during this health crisis might ideal opportunity develop first market. In review, we describe story ASOs, different characteristics chemistry, how translate research clinical tool.

Language: Английский

Adverse Drug Reactions and Toxicity of the Food and Drug Administration–Approved Antisense Oligonucleotide Drugs DOI Open Access

Feryal Alhamadani,

Kristy Zhang,

Rajvi Parikh

et al.

Drug Metabolism and Disposition, Journal Year: 2022, Volume and Issue: 50(6), P. 879 - 887

Published: Feb. 27, 2022

The market for large molecule biologic drugs has grown rapidly, including antisense oligonucleotide (ASO) drugs. ASO work as single-stranded synthetic oligonucleotides that reduce production or alter functions of disease-causing proteins through various mechanisms, such mRNA degradation, exon skipping, and ASO-protein interactions. Since the first drug, fomivirsen, was approved in 1998, U.S. Food Drug Administration (FDA) 10 to date. Although are efficacious treating some diseases untargetable by small-molecule chemical drugs, concerns on adverse drug reactions (ADRs) toxicity cannot be ignored. Illustrative this, mipomersen recently taken off due its hepatotoxicity risk. This paper reviews ADRs from FDA labeling, preclinical studies, clinical trials, postmarketing real-world studies FDA-approved fomivirsen pegaptanib, mipomersen, nusinersen, inotersen, defibrotide, eteplirsen, golodirsen, viltolarsen, casimersen. Unique common each summarized here. risk developing hepatotoxicity, kidney toxicity, hypersensitivity co-exists multiple Special precautions need place when certain administrated. Further discussion is extended studying mechanisms these evaluating existing physiologic pathologic states patients, optimizing dose route administration, formulating personalized treatment plans improve utility discovery development new with reduced ADRs.

SIGNIFICANCE STATEMENT

current review provides a comprehensive analysis unique information can help better manage severe usage currently safer

Language: Английский

Citations

74
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
Nano drug delivery systems for antisense oligonucleotides (ASO) therapeutics DOI

Thiruganesh Ramasamy,

Hima Bindu Ruttala, Shankar Munusamy

et al.

Journal of Controlled Release, Journal Year: 2022, Volume and Issue: 352, P. 861 - 878

Published: Nov. 14, 2022

Language: Английский

Citations

71
C-reactive protein: a target for therapy to reduce inflammation DOI Creative Commons
Salma A. Rizo-Téllez, Meriem Sekheri, János G. Filep

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: July 26, 2023

C-reactive protein (CRP) is well-recognized as a sensitive biomarker of inflammation. Association elevations in plasma/serum CRP level with disease state has received considerable attention, even though not specific indicator single state. Circulating levels have been monitored varying degree success to gauge severity or predict progression and outcome. Elevations implicated useful marker identify patients at risk for cardiovascular certain cancers, guide therapy context-dependent manner. Since strong associations do establish causality, the pathogenic role often over-interpreted. functions an important modulator host defense against bacterial infection, tissue injury autoimmunity. exists conformationally distinct forms, which exhibit functional properties help explaining diverse, contradictory effects attributed CRP. In particular, dissociation native pentameric into its subunits, monomeric CRP, unmasks “hidden” pro-inflammatory activities Here, we review recent advances targeting strategies, therapeutic lowering circulating development antagonists, conformation change inhibitor particular. We will also discuss their potential mitigating deleterious actions under various pathologies, including cardiovascular, pulmonary autoimmune diseases cancer.

Language: Английский

Citations

71
Targeting and engineering long non-coding RNAs for cancer therapy DOI
Michela Coan, Simon Haefliger,

Samir Ounzain

et al.

Nature Reviews Genetics, Journal Year: 2024, Volume and Issue: 25(8), P. 578 - 595

Published: Feb. 29, 2024

Language: Английский

Citations

68
Antisense oligonucleotides: a novel Frontier in pharmacological strategy DOI Creative Commons
Debora Collotta, Ilaria Bertocchi,

E. Chiapello

et al.

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Nov. 17, 2023

Antisense oligonucleotides (ASOs) are short single stranded synthetic RNA or DNA molecules, whereas double-stranded nucleotide sequences called small interfering (siRNA). ASOs bind to complementary nucleic acid impacting the associated functions of targeted acids. They represent an emerging class drugs that, through a revolutionary mechanism action, aim directly regulate disease-causing genes and their variants, providing alternative tool traditional “protein-specific” therapies. The majority designed treat orphan genetic disorders that in most cases seriously disabling still lacking adequate therapy. In order translate into clinical success, constant technological advances have been instrumental overcoming several pharmacological, toxicological formulation limitations. Accordingly, chemical structures recently implemented new bio-conjugation nanocarriers strategies explored. this work is offer overview antisense technology with comparative analysis approved by Food Drug Administration (FDA) European Medicines Agency (EMA).

Language: Английский

Citations

60
Current State of Human Gene Therapy: Approved Products and Vectors DOI Creative Commons
Aladdin Y. Shchaslyvyi,

Svitlana Antonenko,

Maksym G. Tesliuk

et al.

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(10), P. 1416 - 1416

Published: Oct. 5, 2023

In the realm of gene therapy, a pivotal moment arrived with Paul Berg’s groundbreaking identification first recombinant DNA in 1972. This achievement set stage for future breakthroughs. Conditions once considered undefeatable, like melanoma, pancreatic cancer, and host other ailments, are now being addressed at their root cause—the genetic level. Presently, therapy landscape stands adorned 22 approved vivo ex products, including IMLYGIC, LUXTURNA, Zolgensma, Spinraza, Patisiran, many more. this comprehensive exploration, we delve into rich assortment 16 drugs, from siRNA, miRNA, CRISPR/Cas9 to aptamers TRAIL/APO2L, as well 46 carriers, AAV, AdV, LNPs, exosomes naked mRNA, sonoporation, magnetofection. The article also discusses advantages disadvantages each product vector type, current challenges faced practical use its potential.

Language: Английский

Citations

53
miRNAs: The Road from Bench to Bedside DOI Open Access
Giuseppe Iacomino

Genes, Journal Year: 2023, Volume and Issue: 14(2), P. 314 - 314

Published: Jan. 25, 2023

miRNAs are small noncoding RNAs that control gene expression at the posttranscriptional level. It has been recognised miRNA dysregulation reflects state and function of cells tissues, contributing to their dysfunction. The identification hundreds extracellular in biological fluids underscored potential field biomarker research. In addition, therapeutic is receiving increasing attention numerous conditions. On other hand, many operative problems including stability, delivery systems, bioavailability, still need be solved. this dynamic field, biopharmaceutical companies increasingly engaged, ongoing clinical trials point anti-miR miR-mimic molecules as an innovative class for upcoming applications. This article aims provide a comprehensive overview current knowledge on several pending issues new opportunities offered by treatment diseases early diagnostic tools next-generation medicine.

Language: Английский

Citations

48
Splice-Modulating Antisense Oligonucleotides as Therapeutics for Inherited Metabolic Diseases DOI Creative Commons
Suxiang Chen, Saumya Nishanga Heendeniya, Bao T. Le

et al.

BioDrugs, Journal Year: 2024, Volume and Issue: 38(2), P. 177 - 203

Published: Jan. 22, 2024

The last decade (2013-2023) has seen unprecedented successes in the clinical translation of therapeutic antisense oligonucleotides (ASOs). Eight such molecules have been granted marketing approval by United States Food and Drug Administration (US FDA) during decade, after first ASO drug, fomivirsen, was approved much earlier, 1998. Splice-modulating ASOs also developed for therapy inborn errors metabolism (IEMs), due to their ability redirect aberrant splicing caused mutations, thus recovering expression normal transcripts, correcting deficiency functional proteins. feasibility treating IEM patients with splice-switching supported FDA permission (2018) "N-of-1" study milasen, an investigational drug Batten disease. Although IEM, owing rarity individual disease and/or pathogenic mutation, only a low number may be treated that specifically suppress pattern mutant precursor mRNA (pre-mRNA), represent superior individualized molecular therapeutics IEM. In this work, we summarize technology respect its mechanisms action, chemical modifications nucleotides, rational design modified oligonucleotides; following that, precisely provide review current understanding developing splice-modulating ASO-based concluding section, suggest potential ways improve optimize development targeting

Language: Английский

Citations

25
Amphiphilic Block Copolymer Nanostructures as a Tunable Delivery Platform: Perspective and Framework for the Future Drug Product Development DOI
Gaurav Sinsinbar, Anivind Kaur Bindra, Shaoqiong Liu

et al.

Biomacromolecules, Journal Year: 2024, Volume and Issue: 25(2), P. 541 - 563

Published: Jan. 19, 2024

Nanoformulation of active payloads or pharmaceutical ingredients (APIs) has always been an area interest to achieve targeted, sustained, and efficacious delivery. Various delivery platforms have explored, but loading APIs challenging because the chemical structural properties these molecules. Polymersomes made from amphiphilic block copolymers (ABCPs) shown enormous promise as a tunable API platform confer multifold advantages over lipid-based systems. For example, COVID booster vaccine comprising polymersomes encapsulating spike protein (ACM-001) recently completed Phase I clinical trial provides case for developing safe drug products based on ABCP platforms. However, several limitations need be resolved before they can reach their full potential. In this Perspective, we would like highlight such aspects requiring further development translating ABCP-based proof concept viable commercial product.

Language: Английский

Citations

17