RNAi-based drug design: considerations and future directions

Nature Reviews Drug Discovery, Год журнала: 2024, Номер 23(5), С. 341 - 364

Опубликована: Апрель 3, 2024

Язык: Английский

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Nucleic Acid Therapeutics: Successes, Milestones, and Upcoming Innovation

Nucleic Acid Therapeutics, Год журнала: 2024, Номер 34(2), С. 52 - 72

Опубликована: Март 20, 2024

Nucleic acid-based therapies have become the third major drug class after small molecules and antibodies. The role of nucleic has been strengthened by recent regulatory approvals tremendous clinical success. In this review, we look at obstacles that hindered field, historical milestones achieved, what is yet to be resolved anticipated soon. This review provides a view key innovations are expanding acid capabilities, setting stage for future therapeutics.

Язык: Английский

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JAK inhibitor selectivity: new opportunities, better drugs?

Nature Reviews Rheumatology, Год журнала: 2024, Номер 20(10), С. 649 - 665

Опубликована: Сен. 9, 2024

Язык: Английский

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Multispecies-targeting siRNAs for the modulation of JAK1 in the skin

Molecular Therapy — Nucleic Acids, Год журнала: 2024, Номер 35(1), С. 102117 - 102117

Опубликована: Янв. 9, 2024

Identifying therapeutic oligonucleotides that are cross-reactive to experimental animal species can dramatically accelerate the process of preclinical development and clinical translation. Here, we identify fully chemically-modified small interfering RNAs (siRNAs) Janus kinase 1 (JAK1) in humans a large variety other species. We validated identified siRNAs silencing JAK1 cell lines skin tissues multiple is one four members JAK family tyrosine kinases mediate signaling transduction many inflammatory cytokine pathways. Dysregulation these pathways often involved pathogenesis various immune disorders, modulation enzymes an effective strategy clinic. Thus, this work may open up unprecedented opportunities for evaluating models human diseases. Further chemical engineering optimized expand utility compounds treating disorders additional tissues.

Язык: Английский

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Nanotechnology strategies to address challenges in topical and cellular delivery of siRNAs in skin disease therapy

Advanced Drug Delivery Reviews, Год журнала: 2024, Номер 207, С. 115198 - 115198

Опубликована: Фев. 9, 2024

Язык: Английский

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Vitiligo: advances in pathophysiology research and treatment development

Trends in Molecular Medicine, Год журнала: 2024, Номер 30(9), С. 844 - 862

Опубликована: Май 4, 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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JAK inhibitors for the treatment of vitiligo

Journal of Dermatological Science, Год журнала: 2024, Номер 113(3), С. 86 - 92

Опубликована: Янв. 11, 2024

Vitiligo is an autoimmune disease involving melanocyte-targeting T cells initiated by environmental and genetic factors. Steroids tacrolimus have been used as topical treatments. Recently, novel agents targeting Janus kinase (JAK), a family of tyrosine kinases that regulates cytokine signaling, emerged. Ruxolitinib the first approved in vitiligo therapy. Furthermore, ritlecitinib currently under clinical trials for oral treatment active vitiligo. In this review, we discuss possibility JAK inhibitors promising options with regard to their mechanism action, efficacy safety.

Язык: Английский

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Quantifying the activity profile of ASO and siRNA conjugates in glioblastoma xenograft tumors in vivo

Nucleic Acids Research, Год журнала: 2024, Номер 52(9), С. 4799 - 4817

Опубликована: Апрель 13, 2024

Abstract Glioblastoma multiforme is a universally lethal brain tumor that largely resists current surgical and drug interventions. Despite important advancements in understanding GBM biology, the invasiveness heterogeneity of these tumors has made it challenging to develop effective therapies. Therapeutic oligonucleotides—antisense oligonucleotides small-interfering RNAs—are chemically modified nucleic acids can silence gene expression brain. However, activity remains inadequately characterized. In this study, we developed quantitative method differentiate oligonucleotide-induced silencing orthotopic xenografts from normal tissue, used test differential diverse panel oligonucleotides. We show optimized for pharmacological tissue do not consistent xenografts. then survey multiple advanced oligonucleotide chemistries their Attaching lipid conjugates improves cells across several different classes. Highly hydrophobic cholesterol docosanoic acid enhance but at cost higher neurotoxicity. Moderately hydrophobic, unsaturated fatty amphiphilic still improve without compromising safety. These promise treating glioblastoma.

Язык: Английский

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A programmable dual-targeting siRNA scaffold supports potent two-gene modulation in the central nervous system

Nucleic Acids Research, Год журнала: 2024, Номер 52(11), С. 6099 - 6113

Опубликована: Май 10, 2024

Abstract Divalent short-interfering RNA (siRNA) holds promise as a therapeutic approach allowing for the sequence-specific modulation of target gene within central nervous system (CNS). However, an siRNA modality capable simultaneously modulating pairs would be invaluable treating complex neurodegenerative disorders, where more than one pathway contributes to pathogenesis. Currently, parameters and scaffold considerations multi-targeting nucleic acid modalities in CNS are undefined. Here, we propose framework designing unimolecular ‘dual-targeting’ divalent siRNAs co-silencing two genes CNS. We systematically adjusted original CNS-active identified that connecting sense strands 3′ 5′ through intra-strand linker enabled functional dual-targeting scaffold, greatly simplifying synthetic process. Our findings demonstrate supports at least months maximal distribution silencing mouse The is highly programmable, enabling simultaneous different disease-relevant (e.g. Huntington's disease: MSH3 HTT; Alzheimer's APOE JAK1) with similar potency mixture single-targeting against each gene. This work enhances potential disease-related using siRNA.

Язык: Английский

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