干旱区生态环境知识资源中心(Arid): Immunogenicity of In Vitro-Transcribed RNA

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DOI	10.1021/acs.accounts.1c00521
	Immunogenicity of In Vitro-Transcribed RNA
	Mu, Xin; Hur, Sun
通讯作者	Mu, X (corresponding author), Tianjin Univ, Sch Pharmaceut Sci & Technol, Tianjin 300072, Peoples R China. ; Mu, X (corresponding author), Tianjin Univ, Tianjin Univ & Hlth Biotech United Grp Joint Lab, Tianjin 300072, Peoples R China. ; Hur, S (corresponding author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. ; Hur, S (corresponding author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.
来源期刊	ACCOUNTS OF CHEMICAL RESEARCH
ISSN	0001-4842
EISSN	1520-4898
出版年	2021
卷号	54 期号:21 页码:4012-4023
英文摘要	CONSPECTUS: In vitro-transcribed RNAs are emerging as new biologics for therapeutic innovation, as exemplified by their application recently in SARS-CoV-2 vaccinations. RNAs prepared by in vitro transcription (IVT) allow transient expression of proteins of interest, conferring safety over DNA- or virus-mediated gene delivery systems. However, in vitro-transcribed RNAs should be used with caution because of their immunogenicity, which is in part triggered by double-stranded RNA (dsRNA) byproducts during IVT. Cellular innate immune response to dsRNA byproducts can lead to undesirable consequences, including suppression of protein synthesis and cell death, which in turn can detrimentally impact the efficacy of mRNA therapy. Thus, it is critical to understand the nature of IVT byproducts and the mechanisms by which they trigger innate immune responses. Our lab has been investigating the mechanisms by which the innate immune system discriminates between self and nonself RNA, with the focus on the cytoplasmic dsRNA receptors retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated 5 (MDA5). We have biochemically and structurally characterized critical events involving RNA discrimination and signal transduction by RIG-I or MDA5. We have used in vitro-transcribed RNAs as tools to investigate RNA specificity of RIG-I and MDA5, which required optimization of the IVT reaction and purification processes to eliminate the effect of IVT byproducts. In this Account, we summarize our current understanding of RIG-I and MDA5 and IVT reactions and propose future directions for improving IVT as a method to generate both research tools and therapeutics. Other critical proteins in cellular innate immune response to dsRNAs are also discussed. We arrange the contents in the following order: (i) innate immunity sensors for nonself RNA, including the RIG-Ilike receptors (RLRs) in the cytosol and the toll-like receptors (TLRs) in the endosome, as well as cytoplasmic dsRNA-responding proteins, including protein kinase R (PKR) and 2',5'-oligoadenylate synthetases (OASes), illustrating the feature of protein-RNA binding and its consequences; (ii) the immunogenicity of IVT byproducts, specifically the generation of dsRNA molecules during IVT; and (iii) methods to reduce IVT RNA immunogenicity, including optimizations of RNA polymerases, reagents, and experimental conditions during IVT and subsequent purification.
类型	Review
语种	英语
收录类别	SCI-E
WOS记录号	WOS:000714106300004
WOS关键词	DOUBLE-STRANDED-RNA ; INITIATION-FACTOR 2 ; PROTEIN-KINASE PKR ; MESSENGER-RNA ; NUCLEOSIDE MODIFICATIONS ; AUTOANTIBODY PRODUCTION ; ENHANCES TRANSLATION ; SIGNAL-ACTIVATION ; STRUCTURAL BASIS ; BINDING DOMAIN
WOS类目	Chemistry, Multidisciplinary
WOS研究方向	Chemistry
资源类型	期刊论文
条目标识符	http://119.78.100.177/qdio/handle/2XILL650/368070
作者单位	[Mu, Xin] Tianjin Univ, Sch Pharmaceut Sci & Technol, Tianjin 300072, Peoples R China; [Mu, Xin] Tianjin Univ, Tianjin Univ & Hlth Biotech United Grp Joint Lab, Tianjin 300072, Peoples R China; [Hur, Sun] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA; [Hur, Sun] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA
推荐引用方式 GB/T 7714	Mu, Xin,Hur, Sun. Immunogenicity of In Vitro-Transcribed RNA[J],2021,54(21):4012-4023.
APA	Mu, Xin,&Hur, Sun.(2021).Immunogenicity of In Vitro-Transcribed RNA.ACCOUNTS OF CHEMICAL RESEARCH,54(21),4012-4023.
MLA	Mu, Xin,et al."Immunogenicity of In Vitro-Transcribed RNA".ACCOUNTS OF CHEMICAL RESEARCH 54.21(2021):4012-4023.