The potential of long noncoding RNA therapies. (April 2022)

• Record Type: Journal Article
• Authors: Mercer, Tim R.; Munro, Trent; Mattick, John S.
• Is Part Of: Trends in pharmacological sciences. Volume 43:Number 4(2022)
• Page Start: 269
• Page End: 280
• Publication Date: 2022-04
• Subjects: long-noncoding RNAs -- RNA therapies -- developmental -- synthetic biology, disease; Pharmacology -- Periodicals; Pharmacology -- trends -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Electronic journals; Periodicals; 615.1
• DOI: 10.1016/j.tips.2022.01.008
• Languages: English
• ISSNs: 0165-6147

Abstract

Abstract : The human genome expresses vast numbers of long noncoding RNAs (lncRNA) that fulfil diverse roles in gene regulation, cell biology, development, and human disease. These roles are often mediated by sequence motifs and secondary structures bound by proteins and can regulate epigenetic, transcriptional, and translational pathways. These functional domains can be further optimised and engineered into RNA devices that are widely used in synthetic biology. We propose that natural lncRNA structures can be explored and exploited for the rational design and assembly of synthetic RNA therapies. This potential has been enabled by advances in the stability, immunogenicity, manufacture, and delivery of other RNA-based therapies, from which we can anticipate the pharmacological properties of lncRNA therapies that have not yet otherwise entered clinical trials. Highlights: Advances in long noncoding RNA (lncRNA) biology have identified sequence motifs and secondary structures that bind DNA, RNA, or protein targets. An understanding of these structures and their function is needed for the rational and programmable design of lncRNA therapies. LncRNAs contribute to diverse disease aetiologies and may be targeted using small molecules and antisense oligonucleotides. Advances in RNA chemistry, including sequence optimisation and nucleotide modifications, have improved the stability and reduced the immunogenicity of RNA therapies. Formulation of RNA therapies with delivery vehicles, such as lipid nanoparticles, improves stability and enables delivery to target cells and tissues at sufficient dosage. Cellular reprogramming using synthetic mRNAs has demonstrated the ability to modulate gene expression and affect cellular phenotype. Studies have demonstrated the effectiveness of synthetic lncRNA therapies in treating animal disease models.