Innovative approaches in transforming microRNAs into therapeutic tools

Abstract

MicroRNA (miRNA) is regarded as a prominent genetic regulator, as it can fine-tune an entire biological pathway by targeting multiple target genes. This characteristic makes miRNAs promising therapeutic tools to reinstate cell functions that are disrupted as a consequence of diseases. Currently, miRNA replacement by miRNA mimics and miRNA inhibition by anti-miRNA oligonucleotides are the main approaches to utilizing miRNA molecules for therapeutic purposes. Nevertheless, miRNA-based therapeutics are hampered by major issues such as off-target effects, immunogenicity, and uncertain delivery platforms. Over the past few decades, several innovative approaches have been established to minimize off-target effects, reduce immunostimulation, and provide efficient transfer to the target cells in which these molecules exert their function. Recent achievements have led to the testing of miRNA-based drugs in clinical trials, and these molecules may become next-generation therapeutics for medical intervention. Despite the achievement of exciting milestones, the dosage of miRNA administration remains unclear, and ways to address this issue are proposed. Elucidating the current status of the main factors of therapeutic miRNA would allow further developments and innovations to achieve safe therapeutic tools. This article is categorized under: RNA in Disease and Development > RNA in Disease Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action K E Y W O R D S artificial miRNA, clinical trials, miRNA inhibition therapy, miRNA replacement therapy, miRNA therapeutics 1 | INTRODUCTION MicroRNAs (miRNAs) are noncoding RNAs 20 nucleotides in length that exist in mammals, plants, and viruses.According to miRBase version 22, the human genome is estimated to contain 2300 true human mature miRNAs, 1115 of which are currently annotated (Alles et al., 2019). Each miRNA can repress from ten to hundreds of genes, regulating almost every cellular and metabolic process (Friedman et al., 2009;Fuchs Wightman et al., 2018;Kilikevicius et al., 2021). miRNA has been recognized as an essential molecule for gene regulation since its discovery in 1993 (Lee et al., 1993). miRNA is synthesized through either canonical or noncanonical pathways. In the canonical pathway, the

Discovery of novel microRNA mimic repressors of ribosome biogenesis

“…Additionally, microRNA mimic therapeutics are a promising avenue in oncology (163), though roadblocks including delivery and dosage have impeded achieving success in the clinic (164).…”

“…Additionally, microRNA mimic therapeutics are a promising avenue in oncology (163), though roadblocks including delivery and dosage have impeded achieving success in the clinic (164). Combining mimics and small molecules may enable inhibition of multiple targets or decrease required microRNA dose (164), as seen in clinical trials for hepatitis C (165, 166).…”

“…Additionally, microRNA mimic therapeutics are a promising avenue in oncology (163), though roadblocks including delivery and dosage have impeded achieving success in the clinic (164). Combining mimics and small molecules may enable inhibition of multiple targets or decrease required microRNA dose (164), as seen in clinical trials for hepatitis C (165, 166). Given that cancer cells often hyperactivate ribosome production (24), our study underscores the potential of harnessing conserved microRNAs for chemotherapy as standalone therapeutics or in concert with other potent small molecule inhibitors of RB like BMH-21 to simultaneously target pre-rRNA transcription and processing.…”

“…We emphasize the enrichment of the hits' targets for involvement in the cell cycle, which is tightly intertwined with RB, nucleolar formation, and tumorigenesis (25,54,157). Additionally, microRNA mimic therapeutics are a promising avenue in oncology (158), though roadblocks including delivery and dosage have impeded achieving success in the clinic (159). Combining mimics and small molecules may enable inhibition of multiple targets or decrease required microRNA dose (159), as seen in clinical trials for hepatitis C (160,161).…”

microRNAs‐based diagnostic and therapeutic applications in liver fibrosis

“…RNA therapy refers to the use of RNA-based molecules to treat or prevent disease. Currently, as a novel vaccination, mRNA therapy serves as one of the powerful and effective tools (Samad & Kamaroddin, 2022), even to address the COVID-19 pandemic outbreaks (Thompson et al, 2021). The unprecedented effectiveness, flexibility, and speed of mRNA vaccines have rekindled interest in RNA-based therapies.…”