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Development of m-RNA Vaccines in Covid-19 Pandemic Scenario
Published in Yashwant Pathak, Gene Delivery, 2022
There have been several concerns regarding the safety and efficiency of mRNA vaccines over the past few years, but many recent studies suggest that stability concerns have been tackled by modifications of the mRNA backbone structure. Second, optimal carrier development has been ongoing research to enhance the stability and cellular uptake efficiency of these mRNA vaccines. Another important factor to consider that can influence the effect of mRNA vaccines is the innate immunological response of these vaccines. The third but very important factor influencing the effect of mRNA therapeutics is the inherent innate immune-stimulating activity of mRNA, which can either support or hamper the therapeutic outcomes.
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
RNA is a rational drug target because it is universal and vital to all living cells, and is involved in the expression of all genes. Furthermore, as RNA is composed of four repeating building blocks (A,C,U,G), its structure is relatively simple compared to proteins which are comprised of 20 different amino acid building blocks and have complex secondary and tertiary structures. Theoretically, anti-RNA therapeutics could be created for any targets including genetic disorders and infections, and also those considered “un-druggable” by traditional small-molecule technologies.
The Emerging Field of RNA Nanotechnology
Published in Lajos P. Balogh, Nano-Enabled Medical Applications, 2020
The most challenging aspect of RNA therapeutics is the yield and cost of RNA production. Commercial RNA chemical synthesis can only offer 40 (conservative) to 80 (with low yield) nucleotides. Acetalester 2′ -OH protecting groups, such as pivaloyloxymethyl, have been reported to enhance chemical synthesis of RNA. RNase ligase II has been shown to be a good alternative over the traditional T4 DNA ligase to generate longer RNA by ligation of two shorter synthetic RNA fragments [115]. In enzymatic synthesis, heterogeneity of the 3′ -end has been an issue [116]; this can be addressed by extending the transcribed sequence beyond the intended end and then cleaving the RNA at the desired site using ribozymes, DNAzymes, or RNase H [115–117]. Large scale RNA complexes produced in bacteria escorted by a tRNA vector have also been reported [40, 41]. Based on the rapid reduction of cost over the history of DNA synthesis, it is expected that the cost of RNA synthesis will gradually decrease with the development of industrial-scale RNA production technologies.
Challenges with the discovery of RNA-based therapeutics for flaviviruses
Published in Expert Opinion on Drug Discovery, 2023
Mei-Yue Wang, Rong Zhao, Yu-Lan Wang, De-Ping Wang, Ji-Min Cao
RNA therapeutics is a newly emerging field of biotherapeutics with considerable promise. Since the viral life cycle of flaviviruses centers mainly on RNA, RNA-based therapeutics have great potential in dealing with flavivirus infections. Many therapeutic strategies are currently under investigation, such as ASOs, RNA aptamers, siRNAs, miRNAs, shRNAs, and ribozymes. Compared with traditional methods, RNA therapeutics are easier to design by utilizing base-pairing interactions once an effective viral target is identified. This characteristic provides RNA-based therapeutics with a great advantage. However, the development of these therapies is hindered by issues related to instability, delivery, toxicity, and viral resistance. Improving the stability and target selectivity, reducing the nonspecific toxicity, and decreasing the possibility of viral escape are urgent problems to be solved, while advances in delivery systems are required for all RNA-based therapeutics. Although many flavivirus genes have been successfully targeted, the small RNA sequences must be designed and selected carefully. Extensive studies are needed to better understand the biology of flaviviruses in humans, and extensive testing and clinical trials are the only methods to address the unsolved problems.
RNA therapeutics for mood disorders: current evidence toward clinical trials
Published in Expert Opinion on Investigational Drugs, 2021
Marguerite Le Marois, Eleni Tzavara, El Chérif Ibrahim, Olivier Blin, Raoul Belzeaux
The majority of RNA therapeutics used in the clinic are antisense oligonucleotides (ASOs) [15]. They are single-stranded synthetic RNA or DNA sequences, highly modified, that bind their target mRNA or pre-mRNA by complementary Watson-Crick base pairing, resulting in different splicing events, protein translation inhibition, or transcript degradation (Figure 1.1) [16]. For example, nusinersen is an 18-mer phosphorothioate 20-O-methoxyethoxy antisense oligonucleotide with all cytidines methyl-modified at the 5-position that binds to a regulatory sequence in intron 7 of the SMN2 pre-mRNA, leading to the production of the functional SMN protein [17]. To that extent, it was approved in the United States (US) and the European Union (EU) in 2017 for the treatment of spinal muscular atrophy (SMA).
RNA therapeutics for retinal diseases
Published in Expert Opinion on Biological Therapy, 2021
Michael C Gemayel, Ashay D. Bhatwadekar, Thomas Ciulla
Significant scientific and technological advancements have furthered our understanding of genetic conditions and inherited diseases, and RNA-based therapeutics have drawn great attention recently as the basis of vaccine development amidst the COVID-19 pandemic. Beyond this urgent application, however, RNA therapeutics provides a potential avenue for the treatment of genetic conditions, as well as acquired retinal diseases with genetic associations. At the forefront, therapies are in development for common conditions such as DR and AMD, targeting ncRNA as our understanding of regulatory elements and their association with the pathogenesis of these diseases grow. Additionally, RNA therapies are in development to target IRD using multiple approaches, such as shRNA targeting autosomal dominant conditions in a ‘knockdown and replace’ strategy, ASOs to restore splicing defects, and ERSGs targeting nonsense mutations. As our understanding of genetic conditions, inherited diseases, and acquired multifactorial diseases improves, RNA therapeutics provide a potential avenue for treatment, correcting genetic defects at a cellular level, potentially as permanent solutions.