Design of advanced siRNA therapeutics for the treatment of COVID-19

Niktab, Iman; Haghparast, Maryam; Beigi, Mohammad‐Hossein; Megraw, Timothy L.; Kiani, Amirkianoosh; Ghaedi, Kamran

doi:10.1016/j.mgene.2021.100910

Cited by 21 publications

(23 citation statements)

References 17 publications

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“…Several other in silico studies predicted siRNAs targeting ORF1ab [48][49][50][51], S gene [49,[51][52][53], ORF3 [49,51], E gene [49], M gene [49,51] and N gene [51,53] of SARS-CoV-2. Two in vitro studies further demonstrated a robust downregulation of S, M and N on the mRNA or protein levels by siRNAs in overexpression cell culture models [54,55].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of SARS-CoV-2 Replication by a Small Interfering RNA Targeting the Leader Sequence

Tolksdorf

Nie

Niemeyer

et al. 2021

Viruses

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected almost 200 million people worldwide and led to approximately 4 million deaths as of August 2021. Despite successful vaccine development, treatment options are limited. A promising strategy to specifically target viral infections is to suppress viral replication through RNA interference (RNAi). Hence, we designed eight small interfering RNAs (siRNAs) targeting the highly conserved 5’-untranslated region (5’-UTR) of SARS-CoV-2. The most promising candidate identified in initial reporter assays, termed siCoV6, targets the leader sequence of the virus, which is present in the genomic as well as in all subgenomic RNAs. In assays with infectious SARS-CoV-2, it reduced replication by two orders of magnitude and prevented the development of a cytopathic effect. Moreover, it retained its activity against the SARS-CoV-2 alpha variant and has perfect homology against all sequences of the delta variant that were analyzed by bioinformatic means. Interestingly, the siRNA was even highly active in virus replication assays with the SARS-CoV-1 family member. This work thus identified a very potent siRNA with a broad activity against various SARS-CoV viruses that represents a promising candidate for the development of new treatment options.

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Section: Discussionmentioning

confidence: 99%

Inhibition of SARS-CoV-2 Replication by a Small Interfering RNA Targeting the Leader Sequence

Tolksdorf

Nie

Niemeyer

et al. 2021

Viruses

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“…Several factors need to be considered to improve the effectiveness of siRNAs. Firstly, their binding targets should be highly conserved to decrease the possibility of viral escape caused by viral evolution [ 91 ]. For the treatment of SARS-CoV-2 infection, it is suggested that siRNA therapeutics that target the highly conserved region of SARS-CoV-2 could be effective [ 35 ].…”

Section: Sirna Therapy—a Potential and Promising Antiviral Therapeuticmentioning

confidence: 99%

“…Another study designed and evaluated the functions of six siRNAs with increased specificity. These siRNAs could combine SARS-CoV-2 mRNA targets, inducing greater inhibition of viral replication and reduced off-target effects ( Table 1 ) [ 91 ]. In addition, bioinformatics-based methods were also used to design siRNA targeting SARS-CoV-2 RdRp as a therapeutic agent [ 101 ].…”

Section: Sirna Therapy—a Potential and Promising Antiviral Therapeuticmentioning

confidence: 99%

Nanoparticle Delivery Platforms for RNAi Therapeutics Targeting COVID-19 Disease in the Respiratory Tract

Zhang

Almazi

Ong

et al. 2022

IJMS

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Since December 2019, a pandemic of COVID-19 disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread across the globe. At present, the Food and Drug Administration (FDA) has issued emergency approval for the use of some antiviral drugs. However, these drugs still have limitations in the specific treatment of COVID-19, and as such, new treatment strategies urgently need to be developed. RNA-interference-based gene therapy provides a tractable target for antiviral treatment. Ensuring cell-specific targeted delivery is important to the success of gene therapy. The use of nanoparticles (NPs) as carriers for the delivery of small interfering RNA (siRNAs) to specific tissues or organs of the human body could play a crucial role in the specific therapy of severe respiratory infections, such as COVID-19. In this review, we describe a variety of novel nanocarriers, such as lipid NPs, star polymer NPs, and glycogen NPs, and summarize the pre-clinical/clinical progress of these nanoparticle platforms in siRNA delivery. We also discuss the application of various NP-capsulated siRNA as therapeutics for SARS-CoV-2 infection, the challenges with targeting these therapeutics to local delivery in the lung, and various inhalation devices used for therapeutic administration. We also discuss currently available animal models that are used for preclinical assessment of RNA-interference-based gene therapy. Advances in this field have the potential for antiviral treatments of COVID-19 disease and could be adapted to treat a range of respiratory diseases.

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“…Several siRNAs developed for the SARS-COV virus could potentially be used against SARS-COV-2 ( Table 1 ). However, six designed siRNAs for most of the virus mRNAs (siRNA 1, siRNA 2, siRNA 3, siRNA 4, siRNA 5, and siRNA 6) were reported to have a fair but less than acceptable level of proliferation inhibition [ 168 ].…”

Section: Covid-19 Nucleic Acid-based Therapeuticsmentioning

confidence: 99%

Nucleic Acid-Based COVID-19 Therapy Targeting Cytokine Storms: Strategies to Quell the Storm

Abusalah

Khalifa

Al-Hatamleh

et al. 2022

JPM

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Coronavirus disease 2019 (COVID-19) has shaken the world and triggered drastic changes in our lifestyle to control it. Despite the non-typical efforts, COVID-19 still thrives and plagues humanity worldwide. The unparalleled degree of infection has been met with an exceptional degree of research to counteract it. Many drugs and therapeutic technologies have been repurposed and discovered, but no groundbreaking antiviral agent has been introduced yet to eradicate COVID-19 and restore normalcy. As lethality is directly correlated with the severity of disease, hospitalized severe cases are of the greatest importance to reduce, especially the cytokine storm phenomenon. This severe inflammatory phenomenon characterized by elevated levels of inflammatory mediators can be targeted to relieve symptoms and save the infected patients. One of the promising therapeutic strategies to combat COVID-19 is nucleic acid-based therapeutic approaches, including microRNAs (miRNAs). This work is an up-to-date review aimed to comprehensively discuss the current nucleic acid-based therapeutics against COVID-19 and their mechanisms of action, taking into consideration the emerging SARS-CoV-2 variants of concern, as well as providing potential future directions. miRNAs can be used to run interference with the expression of viral proteins, while endogenous miRNAs can be targeted as well, offering a versatile platform to control SARS-CoV-2 infection. By targeting these miRNAs, the COVID-19-induced cytokine storm can be suppressed. Therefore, nucleic acid-based therapeutics (miRNAs included) have a latent ability to break the COVID-19 infection in general and quell the cytokine storm in particular.

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Design of advanced siRNA therapeutics for the treatment of COVID-19

Cited by 21 publications

References 17 publications

Inhibition of SARS-CoV-2 Replication by a Small Interfering RNA Targeting the Leader Sequence

Inhibition of SARS-CoV-2 Replication by a Small Interfering RNA Targeting the Leader Sequence

Nanoparticle Delivery Platforms for RNAi Therapeutics Targeting COVID-19 Disease in the Respiratory Tract

Nucleic Acid-Based COVID-19 Therapy Targeting Cytokine Storms: Strategies to Quell the Storm

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