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Chemical Reviews Feb 2024RNA-based therapies have catalyzed a revolutionary transformation in the biomedical landscape, offering unprecedented potential in disease prevention and treatment.... (Review)
Review
RNA-based therapies have catalyzed a revolutionary transformation in the biomedical landscape, offering unprecedented potential in disease prevention and treatment. However, despite their remarkable achievements, these therapies encounter substantial challenges including low stability, susceptibility to degradation by nucleases, and a prominent negative charge, thereby hindering further development. Chemically modified platforms have emerged as a strategic innovation, focusing on precise alterations either on the RNA moieties or their associated delivery vectors. This comprehensive review delves into these platforms, underscoring their significance in augmenting the performance and translational prospects of RNA-based therapeutics. It encompasses an in-depth analysis of various chemically modified delivery platforms that have been instrumental in propelling RNA therapeutics toward clinical utility. Moreover, the review scrutinizes the rationale behind diverse chemical modification techniques aiming at optimizing the therapeutic efficacy of RNA molecules, thereby facilitating robust disease management. Recent empirical studies corroborating the efficacy enhancement of RNA therapeutics through chemical modifications are highlighted. Conclusively, we offer profound insights into the transformative impact of chemical modifications on RNA drugs and delineates prospective trajectories for their future development and clinical integration.
Topics: RNA; RNA, Small Interfering; Prospective Studies; RNA Interference
PubMed: 38284616
DOI: 10.1021/acs.chemrev.3c00611 -
Chemical Communications (Cambridge,... Mar 2022Due to oxidative instability, arylboronic acids are not compatible with the solid-phase synthesis of nucleic acids. We solved this problem and, based on these findings,...
Due to oxidative instability, arylboronic acids are not compatible with the solid-phase synthesis of nucleic acids. We solved this problem and, based on these findings, developed siRNA prodrugs activated in the presence of reactive oxygen species (ROS) . These prodrugs can be used for specific targeting of ROS-rich cancer cells.
Topics: Oxidation-Reduction; Prodrugs; RNA Interference; RNA, Small Interfering; Reactive Oxygen Species
PubMed: 35297916
DOI: 10.1039/d2cc00651k -
NEJM Evidence Dec 2023BACKGROUND: Apolipoprotein C-III (APOC3) inhibits triglyceride clearance by reducing lipoprotein lipase–mediated hydrolysis and hepatocyte uptake of triglyceride-rich...
BACKGROUND: Apolipoprotein C-III (APOC3) inhibits triglyceride clearance by reducing lipoprotein lipase–mediated hydrolysis and hepatocyte uptake of triglyceride-rich lipoproteins. ARO-APOC3, a hepatocyte-targeting RNA interference therapeutic, inhibits APOC3 messenger ribonucleic acid expression, lowering triglyceride levels. The objective of this trial was to assess the safety, pharmacodynamic variables, and pharmacokinetic variables of ARO-APOC3 treatment. METHODS: Healthy participants and adults with hypertriglyceridemia were randomly assigned to receive escalating single (day 1) or repeat (days 1 and 29) doses, respectively, of subcutaneous injections of ARO-APOC3 10, 25, 50, or 100 mg or placebo; they were followed up until day 113. Additional cohorts of healthy participants and adults with chylomicronemia received repeat doses of open-label ARO-APOC3. The primary objective was to evaluate the safety and side effect profile of ARO-APOC3. Key secondary and exploratory objectives included pharmacokinetic variables and changes in serum APOC3, triglyceride, and cholesterol levels. RESULTS: Eighty-eight participants received ARO-APOC3 and 24 participants received placebo across double-blind and open-label cohorts. Treatment-emergent adverse events (AEs) of transient, mild to moderate liver transaminase changes occurred in 10 participants: 1 patient receiving ARO-APOC3 25 mg, 5 patients receiving ARO-APOC3 50 mg, and 4 participants receiving ARO-APOC3 100 mg (1 healthy participant and 3 patients with hypertriglyceridemia). These events were asymptomatic, and transaminase levels returned to near baseline by the end of the trial. No AEs related to thrombocytopenia or platelet declines were reported. In the hypertriglyceridemia cohorts, the day 113 mean changes from baseline in APOC3 at the 10-, 25-, 50-, and 100-mg doses were −62.0%, −81.7%, −90.1%, and −94.4%, respectively, compared with −1.6% with placebo. This corresponded to median changes in triglyceride levels of −65.6%, −69.9%, −81.2%, and −81.0% compared with −2.8% with placebo. CONCLUSIONS: In this small trial of short duration, ARO-APOC3 was associated with few AEs and reduced serum levels of APOC3 and triglycerides in healthy participants and patients with hypertriglyceridemia. (Funded by Arrowhead Pharmaceuticals, Inc.; ClinicalTrials.gov number, NCT03783377.)
Topics: Humans; Apolipoprotein C-III; RNA Interference; Hypertriglyceridemia
PubMed: 38320498
DOI: 10.1056/EVIDoa2200325 -
Phytopathology Sep 2023Plant viruses infect a wide range of commercially important crop plants and cause significant crop production losses worldwide. Numerous alterations in plant physiology...
Plant viruses infect a wide range of commercially important crop plants and cause significant crop production losses worldwide. Numerous alterations in plant physiology related to the reprogramming of gene expression may result from viral infections. Although conventional integrated pest management-based strategies have been effective in reducing the impact of several viral diseases, continued emergence of new viruses and strains, expanding host ranges, and emergence of resistance-breaking strains necessitate a sustained effort toward the development and application of new approaches for virus management that would complement existing tactics. RNA interference-based techniques, and more recently, clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing technologies have paved the way for precise targeting of viral transcripts and manipulation of viral genomes and host factors. In-depth knowledge of the molecular mechanisms underlying the development of disease would further expand the applicability of these recent methods. Advances in next-generation/high-throughput sequencing have made possible more intensive studies into host-virus interactions. Utilizing the omics data and its application has the potential to expedite fast-tracking traditional plant breeding methods, as well as applying modern molecular tools for trait enhancement, including virus resistance. Here, we summarize the recent developments in the CRISPR/Cas system, transcriptomics, endogenous RNA interference, and exogenous application of dsRNA in virus disease management.
Topics: CRISPR-Cas Systems; RNA Interference; Multiomics; Plant Diseases; Plant Breeding; Plants; Plant Viruses; Virus Diseases; Disease Management; Genome, Plant
PubMed: 37486077
DOI: 10.1094/PHYTO-01-23-0002-V -
Journal of Basic Microbiology Oct 2023The 3,4-dihydroxyphenylalanine (DOPA) melanin is one of the important virulence factors for Cryptococcus neoformans, which may trigger immune responses in the host....
The 3,4-dihydroxyphenylalanine (DOPA) melanin is one of the important virulence factors for Cryptococcus neoformans, which may trigger immune responses in the host. While the production of DOPA melanin is catalyzed by laccase that is predominantly encoded by LAC1 gene. Therefore, regulating the genetic expression of C. neoformans is conducive to exploring the impact of interested molecules on the host. In this work, we established two systems that were constructed quickly and easily for the knock-down/knock-out of LAC1 gene: RNA interference (RNAi) and clustered regularly interspaced short palindromic repeats CRISPR-Cas9. The RNAi system was constructed by pSilencer 4.1-CMV neo plasmid and short hairpin RNA to achieve effective transcriptional suppression. The CRISPR-Cas9 system was used the PNK003 vectors to obtain a stable albino mutant strain. The results of phenotype, quantitative real-time polymerase chain reaction, transmission electron microscope, and spectrophotometry were used to assess the ability of melanin production. As a result, the RNAi system displayed attenuation of transcriptional suppression when the transformants continuously passed on new plates. However, the transcriptional suppression of long loop in short hairpin RNA was more powerful and lasted longer. An albino strain produced by CRISPR-Cas9 was completely unable to synthesize melanin. In conclusion, strains with different capacities of melanin production were obtained by RNAi and CRISPR-Cas9 systems, which might be useful for exploring the linear relation between melanin and immunoreaction of the host. In addition, the two systems in this article might be convenient to quickly screen the possible trait-regulating genes of other serotypes of C. neoformans.
Topics: Cryptococcus neoformans; RNA Interference; CRISPR-Cas Systems; Melanins; Dihydroxyphenylalanine; RNA, Small Interfering
PubMed: 37309240
DOI: 10.1002/jobm.202300102 -
The New England Journal of Medicine Oct 2023
Topics: Humans; RNA Interference; Hypertension; Hypertension, Renal
PubMed: 37819964
DOI: 10.1056/NEJMc2310167 -
The New England Journal of Medicine Oct 2023
Topics: Humans; RNA Interference; Hypertension; Hypertension, Renal
PubMed: 37819963
DOI: 10.1056/NEJMc2310167 -
The New England Journal of Medicine Oct 2023
Topics: Humans; RNA Interference; Hypertension; Hypertension, Renal
PubMed: 37819962
DOI: 10.1056/NEJMc2310167 -
ELife Aug 2023Loss-of-function genetic tools are widely applied for validating therapeutic targets, but their utility remains limited by incomplete on- and uncontrolled off-target...
Loss-of-function genetic tools are widely applied for validating therapeutic targets, but their utility remains limited by incomplete on- and uncontrolled off-target effects. We describe artificial RNA interference (ARTi) based on synthetic, ultra-potent, off-target-free shRNAs that enable efficient and inducible suppression of any gene upon introduction of a synthetic target sequence into non-coding transcript regions. ARTi establishes a scalable loss-of-function tool with full control over on- and off-target effects.
Topics: RNA Interference; RNA, Small Interfering
PubMed: 37552050
DOI: 10.7554/eLife.84792 -
Current Opinion in Plant Biology Dec 2023Spray-induced gene silencing (SIGS) is a powerful and eco-friendly method for crop protection. Based off the discovery of RNA uptake ability in many fungal pathogens,... (Review)
Review
Spray-induced gene silencing (SIGS) is a powerful and eco-friendly method for crop protection. Based off the discovery of RNA uptake ability in many fungal pathogens, the application of exogenous RNAs targeting pathogen/pest genes results in gene silencing and infection inhibition. However, SIGS remains hindered by the rapid degradation of RNA in the environment. As extracellular vesicles are used by plants, animals, and microbes in nature to transport RNAs for cross-kingdom/species RNA interference between hosts and microbes/pests, nanovesicles and other nanoparticles have been used to prevent RNA degradation. Efforts examining the effect of nanoparticles on RNA stability and internalization have identified key attributes that can inform better nanocarrier designs for SIGS. Understanding sRNA biogenesis, cross-kingdom/species RNAi, and how plants and pathogens/pests naturally interact are paramount for the design of SIGS strategies. Here, we focus on nanotechnology advancements for the engineering of innovative RNA-based disease control strategies against eukaryotic pathogens and pests.
Topics: Animals; RNA, Small Interfering; Crop Protection; RNA Interference; Gene Silencing; Plants
PubMed: 37696727
DOI: 10.1016/j.pbi.2023.102441