A perspective on oligonucleotide therapy: Approaches to patient customization

Frontiers in Pharmacology, Год журнала: 2022, Номер 13

Опубликована: Окт. 19, 2022

It is estimated that the human genome encodes 15% of proteins are considered to be disease-modifying. Only 2% these possess a druggable site approved clinical candidates target. Due this disparity, there an immense need develop therapeutics may better mitigate disease or disorders aroused by non-druggable and enzymes. The recent surge in oligonucleotide (OT) indicates imminent potential therapies. Oligonucleotide-based intermediate size with much-improved selectivity towards target fewer off-target effects than small molecules. OTs include Antisense RNAs, MicroRNA (MIR), interfering RNA (siRNA), aptamers, which currently being explored for their use neurodegenerative disorders, cancer, even orphan diseases. present review congregated effort past current efforts make plausible future therapeutics. provides updated literature on challenges bottlenecks OT advancements drug delivery. Further, deliberates newly emerging approach personalized treatment patients rare fatal diseases OT.

Язык: Английский

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RNA‐based medicine: from molecular mechanisms to therapy

The EMBO Journal, Год журнала: 2023, Номер 42(21)

Опубликована: Сен. 20, 2023

Abstract RNA‐based therapeutics have the potential to revolutionize treatment and prevention of human diseases. While early research faced setbacks, it established basis for breakthroughs in drug design that culminated extraordinarily fast development mRNA vaccines combat COVID‐19 pandemic. We now reached a pivotal moment where RNA medicines are poised make broad impact clinic. In this review, we present an overview different strategies generate novel therapeutics, including antisense RNAi‐based mechanisms, mRNA‐based approaches, CRISPR‐Cas‐mediated genome editing. Using three rare genetic diseases as examples, highlight opportunities, but also challenges wide‐ranging applications class drugs.

Язык: Английский

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Nucleic acid degradation as barrier to gene delivery: a guide to understand and overcome nuclease activity

Chemical Society Reviews, Год журнала: 2023, Номер 53(1), С. 317 - 360

Опубликована: Дек. 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.

Язык: Английский

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Enhancing the Effectiveness of Oligonucleotide Therapeutics Using Cell-Penetrating Peptide Conjugation, Chemical Modification, and Carrier-Based Delivery Strategies

Pharmaceutics, Год журнала: 2023, Номер 15(4), С. 1130 - 1130

Опубликована: Апрель 3, 2023

Oligonucleotide-based therapies are a promising approach for treating wide range of hard-to-treat diseases, particularly genetic and rare diseases. These involve the use short synthetic sequences DNA or RNA that can modulate gene expression inhibit proteins through various mechanisms. Despite potential these therapies, significant barrier to their widespread is difficulty in ensuring uptake by target cells/tissues. Strategies overcome this challenge include cell-penetrating peptide conjugation, chemical modification, nanoparticle formulation, endogenous vesicles, spherical nucleic acids, smart material-based delivery vehicles. This article provides an overview strategies efficient oligonucleotide drugs, as well safety toxicity considerations, regulatory requirements, challenges translating from laboratory clinic.

Язык: Английский

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Conjugation of antimicrobial peptides to enhance therapeutic efficacy

European Journal of Medicinal Chemistry, Год журнала: 2023, Номер 259, С. 115680 - 115680

Опубликована: Июль 25, 2023

Язык: Английский

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Nucleic acid drugs: recent progress and future perspectives

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Ноя. 29, 2024

Язык: Английский

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Metabolic Stability and Targeted Delivery of Oligonucleotides: Advancing RNA Therapeutics Beyond The Liver

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Янв. 8, 2025

Oligonucleotides have emerged as a formidable new class of nucleic acid therapeutics. Fully modified oligonucleotides exhibit enhanced metabolic stability and display successful clinical applicability for targets formerly considered "undruggable". Accumulating studies show that conjugation to targeting modalities stabilized oligonucleotides, especially small interfering RNAs (siRNAs), has enabled robust delivery intended cells/tissues. However, the major challenge in field been targeted (siRNAs antisense (ASOs)) extrahepatic tissues. In this Perspective, we review chemistry innovations emerging approaches revolutionized oligonucleotide drug discovery development. We explore findings from both academia industry highlight potential indications involving different organs─including skeletal muscles, brain, lungs, skin, heart, adipose tissue, eyes. all, continued advances coupled with conjugation-based or novel administration routes will further advance

Язык: Английский

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Emerging landscape of cell-penetrating peptide-mediated nucleic acid delivery and their utility in imaging, gene-editing, and RNA-sequencing

Journal of Controlled Release, Год журнала: 2021, Номер 341, С. 166 - 183

Опубликована: Ноя. 22, 2021

Язык: Английский

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Chemical optimization of siRNA for safe and efficient silencing of placental sFLT1

Molecular Therapy — Nucleic Acids, Год журнала: 2022, Номер 29, С. 135 - 149

Опубликована: Июнь 22, 2022

Язык: Английский

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Biological Membrane-Penetrating Peptides: Computational Prediction and Applications

Frontiers in Cellular and Infection Microbiology, Год журнала: 2022, Номер 12

Опубликована: Март 25, 2022

Peptides comprise a versatile class of biomolecules that present unique chemical space with diverse physicochemical and structural properties. Some classes peptides are able to naturally cross the biological membranes, such as cell membrane blood-brain barrier (BBB). Cell-penetrating (CPPs) barrier-penetrating (B3PPs) have been explored by biotechnological pharmaceutical industries develop new therapeutic molecules carrier systems. The computational prediction peptides’ penetration into membranes has emerged an interesting strategy due their high throughput low-cost screening large libraries. Structure- sequence-based information peptides, well atomistic biophysical models, in computer-assisted discovery strategies classify identify structures pharmacokinetic properties related translocation through biomembranes. Computational predict permeability biomembranes include cheminformatic filters, molecular dynamics simulations, artificial intelligence algorithms, statistical choice most adequate method depends on purposes investigation. Here, we exhibit discuss some principles applications these methods widely used biomembranes, exhibiting applications.

Язык: Английский

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