In the field of nonviral gene therapy, in vitro transcribed (IVT) mRNA has emerged as a promising tool for the delivery of genetic information. Over the past few years it has become widely known that the introduction of IVT mRNA into mammalian cells elicits an innate immune response that has favored mRNA use toward immunotherapeutic vaccination strategies. However, for non-immunotherapy-related applications this intrinsic immune-stimulatory activity directly interferes with the aimed therapeutic outcome, because it can seriously compromise the expression of the desired protein. This review presents an overview of the immune-related obstacles that limit mRNA advance for non-immunotherapy-related applications.
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Revolutionizing Heart Failure Therapy: Harnessing IVT mRNA and Fusion Protein Technology to Prolong rhBNP Half-Life.
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Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Purpose: Recombinant human B-type natriuretic peptide (rhBNP) has been extensively proven to be an effective mean of heart failure (HF) therapy, but its clinical application is limited by its very short half-life. This study aims to combine in vitro transcribed mRNA (IVT mRNA) and fusion protein technology to develop a rhBNP-Fc mRNA drug with long half-life, high efficiency and few side effects to treat HF.
Methods: The rhBNP-Fc fusion mRNA with IgG4-Fc sequence was produced by IVT technology.
5' terminal nucleotide determines the immunogenicity of IVT RNAs.
Nucleic Acids Res
December 2024
International Institute of Molecular and Cell Biology in Warsaw, Ksiecia Trojdena 4, 02-109 Warsaw, Poland.
In vitro transcription (IVT) is a technology of vital importance that facilitated the production of mRNA therapeutics and drove numerous breakthroughs in RNA biology. T7 polymerase-produced RNAs can begin with either 5'-triphosphate guanosine (5'-pppG) or 5'-triphosphate adenosine (5'-pppA), generating potential agonists for the RIG-I/type I interferon response. While it is established that IVT can yield highly immunogenic double-stranded RNA (dsRNA) via promoterless transcription, the specific contribution of initiating nucleosides to this process has not been previously reported.
View Article and Find Full Text PDFDeveloping messenger RNA (mRNA) vaccines for COVID-19 renewed and intensified the interest in using mRNA for disease prevention and treatment. Despite their efficacy, linear mRNA molecules are short-lived in the human body, primarily due to enzymatic degradation at the free ends. In contrast, circular RNA (circRNA) exhibits enhanced stability and resistance to exonuclease degradation.
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J Chromatogr A
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Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, CMU - Rue Michel Servet 1, 1211, Geneva, Switzerland; School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland. Electronic address:
The rapid development of mRNA-based therapeutics, especially post-COVID-19, has necessitated the precise characterization of mRNA quality attributes, including sequence integrity. Ion-pairing reversed-phase liquid chromatography (IP-RPLC) has been widely accepted as a reference method for the characterization of small oligonucleotides. Some studies have already investigated the use of IP-RPLC for RNA, but no systematic approach has been developed to assess the impact of ion-pairing agents (IPAs) on the separation of large RNA molecules.
View Article and Find Full Text PDFRemoving immunogenic double-stranded RNA impurities post in vitro transcription synthesis for mRNA therapeutics production: A review of chromatography strategies.
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Downstream Processing, Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, #06-01 Centros, Singapore 138668, Republic of Singapore. Electronic address:
Messenger RNA (mRNA) vaccines and therapeutics hold immense potential for a wide range of clinical applications. However, the in vitro transcription (IVT) process used to synthesize mRNA also results in the generation of a by-product, double-stranded RNA (dsRNA), which can trigger innate immune activation and reduce translation activity. Although various efforts have been made to optimize IVT synthesis to minimize dsRNA formation, dsRNA impurities still cannot be fully resolved.
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