An Insight on RNA Based Therapeutics and Vaccines: Challenges and Opportunities

2021 ◽  
Vol 21 ◽  
Author(s):  
Kanisht Batra ◽  
Sushila Maan ◽  
Anju Sehrawat
Keyword(s):  
Physicochemical Characteristics ◽  
Technological Advancement ◽  
Small Interfering Rnas ◽  
Vaccine Platform ◽  
Promising Alternative ◽  
Rna Molecules ◽  
Guide Rnas ◽  
Drug Molecules ◽  
Challenges And Opportunities

: In this era, RNA molecules have provided a unique opportunity to researchers all over the world for expanding their range of targets in the development of drugs. Due to the unique pharmacological as well as physicochemical characteristics of different RNA molecules such as aptamers, small interfering RNAs (siRNA), antisense oligonucleotides (ASO) and guide RNAs (gRNA), they have emerged recently as a new class of drugs. They are used for selective action on proteins and genes that were not possible to target by conventional drug molecules. These RNA molecules like guide RNAs are also components of novel gene editing mechanisms which can modify the genome nearly in all cells. Vaccines based on RNA molecules have also provided a promising alternative to conventional live attenuated vaccines. RNA based vaccines have high potency, can be rapidly developed, and have potential for manufacturing at a cheaper rate and safe administration. However, the application of these RNAs has been restricted by the high instability and inefficient in vivo delivery. Technological advancement needs to overcome these issues so that RNA based drugs targeting several diseases can be developed. This article emphasizes the potential of RNA based drugs and the major barriers associated with the development of RNA therapeutics. Additionally, the role of RNA based vaccines and their challenges in advancing this promising vaccine platform for the prevention of infectious diseases have been discussed.

siRNA, miRNA, and shRNA: in vivo Applications

2008 ◽  
Vol 87 (11) ◽  
pp. 992-1003 ◽  
Author(s):  
P.N. Pushparaj ◽  
J.J. Aarthi ◽  
J. Manikandan ◽  
S.D. Kumar
Keyword(s):  
Metabolic Diseases ◽  
Small Interfering Rnas ◽  
Base Pairs ◽  
Rna Molecules ◽  
Rna Activation ◽  
Research Findings ◽  
Dental Diseases ◽  
Short Hairpin Rnas ◽  
Clinical Potential

RNA interference (RNAi), an accurate and potent gene-silencing method, was first experimentally documented in 1998 in Caenorhabditis elegans by Fire et al., who subsequently were awarded the 2006 Nobel Prize in Physiology/Medicine. Subsequent RNAi studies have demonstrated the clinical potential of synthetic small interfering RNAs (siRNAs) or short hairpin RNAs (shRNAs) in dental diseases, eye diseases, cancer, metabolic diseases, neurodegenerative disorders, and other illnesses. siRNAs are generally from 21 to 25 base-pairs (bp) in length and have sequence-homology-driven gene-knockdown capability. RNAi offers researchers an effortless tool for investigating biological systems by selectively silencing genes. Key technical aspects—such as optimization of selectivity, stability, in vivo delivery, efficacy, and safety—need to be investigated before RNAi can become a successful therapeutic strategy. Nevertheless, this area shows a huge potential for the pharmaceutical industry around the globe. Interestingly, recent studies have shown that the small RNA molecules, either indigenously produced as microRNAs (miRNAs) or exogenously administered synthetic dsRNAs, could effectively activate a particular gene in a sequence-specific manner instead of silencing it. This novel, but still uncharacterized, phenomenon has been termed ‘RNA activation’ (RNAa). In this review, we analyze these research findings and discussed the in vivo applications of siRNAs, miRNAs, and shRNAs.

scholarly journals Robust RNA editing via recruitment of endogenous ADARs using circular guide RNAs

2021 ◽  
Author(s):  
Dhruva Katrekar ◽  
James Yen ◽  
Yichen Xiang ◽  
Anushka Saha ◽  
Dario Meluzzi ◽  
...  
Keyword(s):  
Rna Editing ◽  
Transcript Level ◽  
Rnase H ◽  
Type I ◽  
Rna Molecules ◽  
Guide Rnas ◽  
Cellular Machinery ◽  
Dna Vectors

ABSTRACTAkin to short-hairpin RNAs and antisense oligonucleotides which efficaciously recruit endogenous cellular machinery such as Argonaute and RNase H to enable targeted RNA knockdown, simple long antisense guide RNAs (1) can recruit endogenous adenosine deaminases acting on RNA (ADARs) to enable programmable A-to-I RNA editing, without requiring co-delivery of any exogenous proteins. This approach is highly specific, however the efficiency is typically lower than observed with enzyme overexpression. Conjecturing this was due in part to the short half-life and residence times of guide RNAs, here we engineer highly stable circular ADAR recruiting guide RNAs (cadRNAs), which can be delivered not only by genetically encoding on DNA vectors, but also via transfection of RNA molecules transcribed in vitro. Using these cadRNAs, we observed robust RNA editing across multiple sites and cell lines, in both untranslated and coding regions of RNAs, vastly improved efficiency and durability of RNA editing, and high transcriptome-wide specificity. High transcript-level specificity was achieved by further engineering to reduce bystander editing. Additionally, in vivo delivery of cadRNAs via adeno-associated viruses (AAVs) enabled robust 38% RNA editing of the mPCSK9 transcript in C57BL/6J mice livers, and 12% UAG-to-UGG RNA correction of the amber nonsense mutation in the IDUA-W392X mouse model of mucopolysaccharidosis type I-Hurler (MPS I-H) syndrome. Taken together, cadRNAs enable efficacious programmable RNA editing with application across diverse protein modulation and gene therapeutic settings.

scholarly journals Tyrosine-Modification of Polypropylenimine (PPI) and Polyethylenimine (PEI) Strongly Improves Efficacy of siRNA-Mediated Gene Knockdown

Nanomaterials ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1809 ◽  
Author(s):  
Sandra Noske ◽  
Michael Karimov ◽  
Achim Aigner ◽  
Alexander Ewe
Keyword(s):  
Sirna Delivery ◽  
Nucleic Acid Delivery ◽  
Cationic Polymers ◽  
Small Interfering Rnas ◽  
Polymeric Systems ◽  
Rna Molecules ◽  
First Time ◽  
Tyrosine Modification

The delivery of small interfering RNAs (siRNA) is an efficient method for gene silencing through the induction of RNA interference (RNAi). It critically relies, however, on efficient vehicles for siRNA formulation, for transfection in vitro as well as for their potential use in vivo. While polyethylenimines (PEIs) are among the most studied cationic polymers for nucleic acid delivery including small RNA molecules, polypropylenimines (PPIs) have been explored to a lesser extent. Previous studies have shown the benefit of the modification of small PEIs by tyrosine grafting which are featured in this paper. Additionally, we have now extended this approach towards PPIs, presenting tyrosine-modified PPIs (named PPI-Y) for the first time. In this study, we describe the marked improvement of PPI upon its tyrosine modification, leading to enhanced siRNA complexation, complex stability, siRNA delivery, knockdown efficacy and biocompatibility. Results of PPI-Y/siRNA complexes are also compared with data based on tyrosine-modified linear or branched PEIs (LPxY or PxY). Taken together, this establishes tyrosine-modified PPIs or PEIs as particularly promising polymeric systems for siRNA formulation and delivery.

scholarly journals An Overview on the Development of mRNA-Based Vaccines and Their Formulation Strategies for Improved Antigen Expression In Vivo

Vaccines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 244
Author(s):  
Md. Motiar Rahman ◽  
Nan Zhou ◽  
Jiandong Huang
Keyword(s):  
Animal Models ◽  
Low Cost ◽  
Antigen Expression ◽  
Future Perspectives ◽  
Vaccine Platform ◽  
High Potency ◽  
Promising Alternative ◽  
Vaccine Approach ◽  
Technological Improvements

The mRNA-based vaccine approach is a promising alternative to traditional vaccines due to its ability for prompt development, high potency, and potential for secure administration and low-cost production. Nonetheless, the application has still been limited by the instability as well as the ineffective delivery of mRNA in vivo. Current technological improvements have now mostly overcome these concerns, and manifold mRNA vaccine plans against various forms of malignancies and infectious ailments have reported inspiring outcomes in both humans and animal models. This article summarizes recent mRNA-based vaccine developments, advances of in vivo mRNA deliveries, reflects challenges and safety concerns, and future perspectives, in developing the mRNA vaccine platform for extensive therapeutic use.

The Impact of Emerging Technologies on the Law of Armed Conflict

2019 ◽  
Keyword(s):  
Armed Conflict ◽  
New Technologies ◽  
Emerging Technologies ◽  
Legal Issues ◽  
Technological Advancement ◽  
Law Of Armed Conflict ◽  
Legal Challenges ◽  
Challenges And Opportunities ◽  
The Law ◽  
The Impact

Emerging technologies have always played an important role in armed conflict. From the crossbow to cyber capabilities, technology that could be weaponized to create an advantage over an adversary has inevitably found its way into military arsenals for use in armed conflict. The weaponization of emerging technologies, however, raises challenging legal issues with respect to the law of armed conflict. As States continue to develop and exploit new technologies, how will the law of armed conflict address the use of these technologies on the battlefield? Is existing law sufficient to regulate new technologies, such as cyber capabilities, autonomous weapons systems, and artificial intelligence? Have emerging technologies fundamentally altered the way we should understand concepts such as law-of-war precautions and the principle of distinction? How can we ensure compliance and accountability in light of technological advancement? This book explores these critical questions while highlighting the legal challenges—and opportunities—presented by the use of emerging technologies on the battlefield.

scholarly journals Baicalin Represses Type Three Secretion System of Pseudomonas aeruginosa through PQS System

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1497
Author(s):  
Pansong Zhang ◽  
Qiao Guo ◽  
Zhihua Wei ◽  
Qin Yang ◽  
Zisheng Guo ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Virulence Factors ◽  
Mammalian Cells ◽  
Secretion System ◽  
Chinese Herbs ◽  
Infection Model ◽  
Lung Pathology ◽  
Promising Alternative ◽  
The Impact

Therapeutics that target the virulence of pathogens rather than their viability offer a promising alternative for treating infectious diseases and circumventing antibiotic resistance. In this study, we searched for anti-virulence compounds against Pseudomonas aeruginosa from Chinese herbs and investigated baicalin from Scutellariae radix as such an active anti-virulence compound. The effect of baicalin on a range of important virulence factors in P. aeruginosa was assessed using luxCDABE-based reporters and by phenotypical assays. The molecular mechanism of the virulence inhibition by baicalin was investigated using genetic approaches. The impact of baicalin on P. aeruginosa pathogenicity was evaluated by both in vitro assays and in vivo animal models. The results show that baicalin diminished a plenty of important virulence factors in P. aeruginosa, including the Type III secretion system (T3SS). Baicalin treatment reduced the cellular toxicity of P. aeruginosa on the mammalian cells and attenuated in vivo pathogenicity in a Drosophila melanogaster infection model. In a rat pulmonary infection model, baicalin significantly reduced the severity of lung pathology and accelerated lung bacterial clearance. The PqsR of the Pseudomonas quinolone signal (PQS) system was found to be required for baicalin’s impact on T3SS. These findings indicate that baicalin is a promising therapeutic candidate for treating P. aeruginosa infections.

scholarly journals Aptamer Applications in Emerging Viral Diseases

2021 ◽  
Vol 14 (7) ◽  
pp. 622
Author(s):  
Arne Krüger ◽  
Ana Paula de Jesus Santos ◽  
Vanessa de Sá ◽  
Henning Ulrich ◽  
Carsten Wrenger
Keyword(s):  
Virus Assembly ◽  
Viral Diseases ◽  
Tissue Penetration ◽  
Rna Molecules ◽  
Viral Particles ◽  
Pharmacokinetic Properties ◽  
Oligonucleotide Library ◽  
In Vivo Diagnosis ◽  
Emerging Viral Diseases

Aptamers are single-stranded DNA or RNA molecules which are submitted to a process denominated SELEX. SELEX uses reiterative screening of a random oligonucleotide library to identify high-affinity binders to a chosen target, which may be a peptide, protein, or entire cells or viral particles. Aptamers can rival antibodies in target recognition, and benefit from their non-proteic nature, ease of modification, increased stability, and pharmacokinetic properties. This turns them into ideal candidates for diagnostic as well as therapeutic applications. Here, we review the recent accomplishments in the development of aptamers targeting emerging viral diseases, with emphasis on recent findings of aptamers binding to coronaviruses. We focus on aptamer development for diagnosis, including biosensors, in addition to aptamer modifications for stabilization in body fluids and tissue penetration. Such aptamers are aimed at in vivo diagnosis and treatment, such as quantification of viral load and blocking host cell invasion, virus assembly, or replication, respectively. Although there are currently no in vivo applications of aptamers in combating viral diseases, such strategies are promising for therapy development in the future.

scholarly journals Histological, Biomechanical, and Biological Properties of Genipin-Crosslinked Decellularized Peripheral Nerves

2021 ◽  
Vol 22 (2) ◽  
pp. 674
Author(s):  
Óscar Darío García-García ◽  
Marwa El Soury ◽  
David González-Quevedo ◽  
David Sánchez-Porras ◽  
Jesús Chato-Astrain ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Nerve Repair ◽  
Wistar Rat ◽  
Biomechanical Properties ◽  
Biological Properties ◽  
Suitable Alternative ◽  
Promising Alternative ◽  
Histological Pattern ◽  
The Impact

Acellular nerve allografts (ANGs) represent a promising alternative in nerve repair. Our aim is to improve the structural and biomechanical properties of biocompatible Sondell (SD) and Roosens (RS) based ANGs using genipin (GP) as a crosslinker agent ex vivo. The impact of two concentrations of GP (0.10% and 0.25%) on Wistar rat sciatic nerve-derived ANGs was assessed at the histological, biomechanical, and biocompatibility levels. Histology confirmed the differences between SD and RS procedures, but not remarkable changes were induced by GP, which helped to preserve the nerve histological pattern. Tensile test revealed that GP enhanced the biomechanical properties of SD and RS ANGs, being the crosslinked RS ANGs more comparable to the native nerves used as control. The evaluation of the ANGs biocompatibility conducted with adipose-derived mesenchymal stem cells cultured within the ANGs confirmed a high degree of biocompatibility in all ANGs, especially in RS and RS-GP 0.10% ANGs. Finally, this study demonstrates that the use of GP could be an efficient alternative to improve the biomechanical properties of ANGs with a slight impact on the biocompatibility and histological pattern. For these reasons, we hypothesize that our novel crosslinked ANGs could be a suitable alternative for future in vivo preclinical studies.

Computational study for suppression of CD25/IL-2 interaction

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Moein Dehbashi ◽  
Zohreh Hojati ◽  
Majid Motovali-bashi ◽  
Mazdak Ganjalikhani-Hakemi ◽  
Akihiro Shimosaka ◽  
...  
Keyword(s):  
Small Molecules ◽  
Cancer Progression ◽  
Immune Escape ◽  
De Novo ◽  
Computational Study ◽  
Treg Cells ◽  
Homology Search ◽  
Small Interfering Rnas

AbstractCancer recurrence presents a huge challenge in cancer patient management. Immune escape is a key mechanism of cancer progression and metastatic dissemination. CD25 is expressed in regulatory T (Treg) cells including tumor-infiltrating Treg cells (TI-Tregs). These cells specially activate and reinforce immune escape mechanism of cancers. The suppression of CD25/IL-2 interaction would be useful against Treg cells activation and ultimately immune escape of cancer. Here, software, web servers and databases were used, at which in silico designed small interfering RNAs (siRNAs), de novo designed peptides and virtual screened small molecules against CD25 were introduced for the prospect of eliminating cancer immune escape and obtaining successful treatment. We obtained siRNAs with low off-target effects. Further, small molecules based on the binding homology search in ligand and receptor similarity were introduced. Finally, the critical amino acids on CD25 were targeted by a de novo designed peptide with disulfide bond. Hence we introduced computational-based antagonists to lay a foundation for further in vitro and in vivo studies.

scholarly journals Effect of Mixing Ratio of Oppositely Charged Block Copolymers on Polyion Complex Micelles for In Vivo Application

Polymers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 5
Author(s):  
Noriko Nakamura ◽  
Yuki Mochida ◽  
Kazuko Toh ◽  
Shigeto Fukushima ◽  
Horacio Cabral ◽  
...  
Keyword(s):  
Physicochemical Characteristics ◽  
Charge Ratio ◽  
Structural Variations ◽  
Polyion Complex ◽  
Functional Capabilities ◽  
The Stability ◽  
Biological Performance ◽  
Complex Micelles ◽  
Oppositely Charged

Self-assembled supramolecular structures based on polyion complex (PIC) formation between oppositely charged polymers are attracting much attention for developing drug delivery systems able to endure harsh in vivo environments. As controlling polymer complexation provides an opportunity for engineering the assemblies, an improved understanding of the PIC formation will allow constructing assemblies with enhanced structural and functional capabilities. Here, we focused on the influence of the mixing charge ratio between block aniomers and catiomers on the physicochemical characteristics and in vivo biological performance of the resulting PIC micelles (PIC/m). Our results showed that by changing the mixing charge ratio, the structural state of the core was altered despite the sizes of PIC/m remaining almost the same. These structural variations greatly affected the stability of the PIC/m in the bloodstream after intravenous injection and determined their biodistribution.

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