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

Gene regulation by long non-coding RNAs and its biological functions DOI Open Access
Luisa Statello, Chunjie Guo, Ling‐Ling Chen

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2020, Volume and Issue: 22(2), P. 96 - 118

Published: Dec. 22, 2020

Language: Английский

Citations

3585
Drug delivery systems for RNA therapeutics DOI Open Access
Kalina Paunovska, David Loughrey, James E. Dahlman

et al.

Nature Reviews Genetics, Journal Year: 2022, Volume and Issue: 23(5), P. 265 - 280

Published: Jan. 4, 2022

Language: Английский

Citations

820
Recent Advances in Oligonucleotide Therapeutics in Oncology DOI Open Access

Haoyu Xiong,

Rakesh N. Veedu, Sarah D. Diermeier

et al.

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(7), P. 3295 - 3295

Published: March 24, 2021

Cancer is one of the leading causes death worldwide. Conventional therapies, including surgery, radiation, and chemotherapy have achieved increased survival rates for many types cancer over past decades. However, recurrence and/or metastasis to distant organs remain major challenges, resulting in a large, unmet clinical need. Oligonucleotide therapeutics, which include antisense oligonucleotides, small interfering RNAs, aptamers, show promising outcomes disease indications such as Duchenne muscular dystrophy, familial amyloid neuropathies, macular degeneration. While no approved oligonucleotide drug currently exists any type cancer, results obtained preclinical studies trials are encouraging. Here, we provide an overview recent developments field therapeutics oncology, review current trials, discuss associated challenges.

Language: Английский

Citations

149
Alpha-Synuclein Aggregation Pathway in Parkinson’s Disease: Current Status and Novel Therapeutic Approaches DOI Creative Commons
Marija Vidović, Milena Rikalović

Cells, Journal Year: 2022, Volume and Issue: 11(11), P. 1732 - 1732

Published: May 24, 2022

Following Alzheimer’s, Parkinson’s disease (PD) is the second-most common neurodegenerative disorder, sharing an unclear pathophysiology, a multifactorial profile, and massive social costs worldwide. Despite this, no disease-modifying therapy available. PD tightly associated with α-synuclein (α-Syn) deposits, which become organised into insoluble, amyloid fibrils. As typical intrinsically disordered protein, α-Syn adopts monomeric, random coil conformation in aqueous solution, while its interaction lipid membranes drives transition of molecule part α-helical structure. The central unstructured region involved fibril formation by converting to well-defined, β-sheet rich secondary structures. Presently, most therapeutic strategies against are focused on designing small molecules, peptides, peptidomimetics that can directly target aggregation pathway. Other approaches include gene silencing, cell transplantation, stimulation intracellular clearance autophagy promoters, degradation pathways based immunotherapy In present review, we sum marise current advances related aggregation/neurotoxicity. These findings valuable arsenal for further development efficient, nontoxic, non-invasive protocols tackles onset progression future.

Language: Английский

Citations

98
Trials and Tribulations of MicroRNA Therapeutics DOI Open Access
Attila A. Seyhan

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(3), P. 1469 - 1469

Published: Jan. 25, 2024

The discovery of the link between microRNAs (miRNAs) and a myriad human diseases, particularly various cancer types, has generated significant interest in exploring their potential as novel class drugs. This led to substantial investments interdisciplinary research fields such biology, chemistry, medical science for development miRNA-based therapies. Furthermore, recent global success SARS-CoV-2 mRNA vaccines against COVID-19 pandemic further revitalized RNA-based immunotherapies, including approaches treatment. Consequently, RNA therapeutics have emerged highly adaptable modular options therapy. Moreover, advancements chemistry delivery methods been pivotal shaping landscape immunotherapy, approaches. biotechnology pharmaceutical industry witnessed resurgence incorporating immunotherapies miRNA into programs. Despite progress preclinical research, field remains its early stages, with only few progressing clinical development, none reaching phase III trials or being approved by US Food Drug Administration (FDA), several facing termination due toxicity issues. These setbacks highlight existing challenges that must be addressed broad application therapeutics. Key include establishing sensitivity, specificity, selectivity towards intended targets, mitigating immunogenic reactions off-target effects, developing enhanced targeted delivery, determining optimal dosing therapeutic efficacy while minimizing side effects. Additionally, limited understanding precise functions miRNAs limits utilization. viable treatment, they technically economically feasible widespread adoption As result, thorough risk evaluation is crucial minimize prevent overdosing, address other Nevertheless, diseases evident, future investigations are essential determine applicability settings.

Language: Английский

Citations

97
Applications, Challenges, and Outlook for PBPK Modeling and Simulation: A Regulatory, Industrial and Academic Perspective DOI
Wen Lin, Yuan Chen, Jashvant D. Unadkat

et al.

Pharmaceutical Research, Journal Year: 2022, Volume and Issue: 39(8), P. 1701 - 1731

Published: May 13, 2022

Language: Английский

Citations

96
lncExACT1 and DCHS2 Regulate Physiological and Pathological Cardiac Growth DOI Open Access
Haobo Li,

Lena Trager,

Xiaojun Liu

et al.

Circulation, Journal Year: 2022, Volume and Issue: 145(16), P. 1218 - 1233

Published: Feb. 4, 2022

The heart grows in response to pathological and physiological stimuli. former often precedes cardiomyocyte loss failure; the latter paradoxically protects enhances cardiomyogenesis. mechanisms underlying these differences remain incompletely understood. Although long noncoding RNAs (lncRNAs) are important cardiac development disease, less is known about their roles hypertrophy or cardiomyogenesis.RNA sequencing was applied hearts from mice after 8 weeks of voluntary exercise-induced cardiomyogenesis transverse aortic constriction for 2 induce failure. top lncRNA candidate overexpressed with adeno-associated virus vectors inhibited antisense locked nucleic acid-GapmeRs examine its function. Downstream effectors were identified through promoter analyses binding assays. functional a novel downstream effector, dachsous cadherin-related (DCHS2), examined transgenic overexpression zebrafish cardiac-specific deletion Cas9-knockin mice.We exercise-regulated lncRNAs, called lncExACTs. lncExACT1 evolutionarily conserved decreased exercised but increased human experimental Cardiac caused inhibition induced cardiomyogenesis, protecting against fibrosis dysfunction. functioned by regulating microRNA-222, calcineurin signaling, Hippo/Yap1 signaling DCHS2. Cardiomyocyte DCHS2 impaired regeneration, promoting scarring injury. In contrast, murine promoted cardiomyogenesis.These studies identify lncExACT1-DCHS2 as pathway acts master switch toggling between growth determine outcomes, providing potentially tractable therapeutic target harnessing beneficial effects exercise.

Language: Английский

Citations

83
RNA therapeutics: updates and future potential DOI Open Access

Caroline Zhang,

Biliang Zhang

Science China Life Sciences, Journal Year: 2022, Volume and Issue: 66(1), P. 12 - 30

Published: Sept. 8, 2022

Language: Английский

Citations

83
Current and Possible Future Therapeutic Options for Huntington’s Disease DOI Creative Commons

Mackenzie Wendy Ferguson,

Connor J. Kennedy,

Thulani H. Palpagama

et al.

Journal of Central Nervous System Disease, Journal Year: 2022, Volume and Issue: 14

Published: April 1, 2022

Huntington's disease (HD) is an autosomal neurodegenerative that characterized by excessive number of CAG trinucleotide repeats within the huntingtin gene (

Language: Английский

Citations

80
Where should siRNAs go: applicable organs for siRNA drugs DOI Creative Commons

In–Sook Ahn,

Chanhee S. Kang,

Jinju Han

et al.

Experimental & Molecular Medicine, Journal Year: 2023, Volume and Issue: 55(7), P. 1283 - 1292

Published: July 10, 2023

RNA interference mediated by small interfering RNAs (siRNAs) has been exploited for the development of therapeutics. siRNAs can be a powerful therapeutic tool because working mechanisms are straightforward. determine targets based on their sequence and specifically regulate gene expression target gene. However, efficient delivery to organ long an issue that needs solved. Tremendous efforts regarding siRNA have led significant progress in drug development, from 2018 2022, total five drugs were approved treatment patients. Although all FDA-approved hepatocytes liver, siRNA-based targeting different organs clinical trials. In this review, we introduce market candidates trials cells multiple organs. The eye, skin preferred targeted siRNAs. Three or more phase 2 3 suppress these On other hand, lungs, kidneys, brain challenging with relatively few We discuss characteristics each related advantages disadvantages strategies overcome barriers delivering organ-specific progressed

Language: Английский

Citations

78