RNAa: Mechanisms, therapeutic potential, and clinical progress

Abstract

RNA activation (RNAa), a gene regulatory mechanism mediated by small activating RNAs (saRNAs) and microRNAs (miRNAs), has significant implications for therapeutic applications. Unlike small interfering RNA (siRNA), which is known for gene silencing in RNA interference (RNAi), synthetic saRNAs can stably upregulate target gene expression at the transcriptional level through the assembly of the RNA-induced transcriptional activation (RITA) complex. Moreover, the dual functionality of endogenous miRNAs in RNAa (hereafter referred to as mi-RNAa) reveals their complex role in cellular processes and disease pathology. Emerging studies suggest saRNAs' potential as a novel therapeutic modality for diseases such as metabolic disorders, hearing loss, tumors, and Alzheimer's. Notably, MTL-CEBPA, the first saRNA drug candidate, shows promise in hepatocellular carcinoma treatment, while RAG-01 is being explored for non-muscle-invasive bladder cancer, highlighting clinical advancements in RNAa. This review synthesizes our current understanding of the mechanisms of RNAa and highlights recent advancements in the study of mi-RNAa and the therapeutic development of saRNAs.

Keywords: MT: Oligonucleotides: Therapies and Applications; RNAa; delivery systems; gene activation; miRNA; oligonucleotides; saRNA.

Graphical abstract

Figure 1

Mechanistic model of saRNA-mediated RNAa (A) When an saRNA (double stranded) is recognized and loaded by AGO (e.g., AGO2), the passenger strand is cleaved and discarded in the cytoplasm and the guide strand of the saRNA is retained to form an saRNA-AGO complex, which is imported into the nucleus in an undefined pathway. (B) saRNA guides AGO2 to the promotor target site. (C) At the promotor, key components such as RHA, CTR9, and RNAP II are convened by the AGO2/saRNA complex to assemble the RITA complex, thereby stimulating transcription.

Figure 2

A mechanistic model of miR-34a-mediated mi-RNAa (A) miR-34a is imported to the nucleus by interacting with the AGO2/TNRC6A complex. (B) Inside the nucleus, DDX21 and CDK9 are released and activated by binding with the AGO2-miR-34a-TNRC6A complex. (C) The complex, now including DDX21 and CDK9, binds to paRNAs overlapping the ZMYND10 promoter. (D) The complex’s presence at the ZMYND10 promoter enables the release and activation of paused RNA polymerase II (RNA pol II), leading to transcription activation of the ZMYND10 gene.