Perspectives in MicroRNA Therapeutics

The authors provide further insight into microRNA biology, and the simplicity of anti-miR oligonucleotide drug delivery.
May 01, 2011
Volume 2011 Supplement, Issue 3

RNA-based therapeutics hold significant potential as promising treatment options for human disease. In the past 20 years, advances in the RNA field have identified several novel RNA-based therapies that are currently under clinical investigation, including antisense oligonucleotides, small interfering RNA (siRNA), and microRNA. By targeting RNA and modulating human biology at the molecular level, these new technologies have allowed drug-discovery efforts to focus on a broad range of disease targets once deemed to be "undruggable."

Figure 1: The RNA therapeutics opportunity. MicroRNAs represent a new set of drug targets capable of regulating an entire network of related genes. (ALL FIGURES COURTESY OF THE AUTHORS)
Leading RNA biotechnology companies have since expanded the target space and generated multiple clinical candidates characterized by improved target specificity, improved drug safety, and demonstrated efficacy in patients. These companies have traditionally focused on targeting specific genes relevant to the disease indication through the control of protein synthesis at the RNA level. More recently, drug discovery researchers are attempting to regulate entire networks of genes through the modulation of a single microRNA. Targeting microRNAs with either oligonucleotide inhibitors, namely anti-miRs, or miR-mimics (double-stranded oligonucleotides that replace microRNA function), provides a novel class of therapeutics and a unique approach to treating disease by modulating entire biological pathways (see Figure 1).

Targeting specific genes using antisense oligonucleotides and siRNA

Figure 2: MicroRNAs are key regulators of the genome. Hybridization of microRNAs (red) to their target seed sequence in mRNAs regulates and directs the expression of an entire network of genes. AGO is Argonaute protein, DGCR8 is DiGeorge critical region 8, miR is microRNA, RISC is RNA induced silencing complex.
Antisense oligonucleotides and siRNA have great potential to become mainstream therapeutic entities. This is due, in part, to their high specificity and wide therapeutic target space in the genome. The antisense approach targets a specific gene and interrupts the translation phase of the protein production process by preventing the mRNA from reaching the ribosome (1). Antisense drugs are short (15–23mer) chemically modified nucleotide chains that hybridize to a specific complementary area of mRNA. On hybridization, the mRNA is recognized as a RNA-DNA hybrid and degraded through an RNase H cleavage mechanism and not translated by the ribosome into a functional protein (see Figure 2). By inhibiting the production of proteins involved in disease, antisense drugs can create pharmacologic benefit for patients.

Table I: Overview of the current RNA-based drug-discovery platform.
RNA interference (RNAi) is a highly conserved sequence-dependent eukaryotic process for regulating gene expression. Small stretches of double-stranded RNA ranging from 19 to 25 base pairs, and known as siRNA, utilize the RNA induced silencing complex (RISC) pathway to target a specific gene and bind to its homologous mRNA. This results in site-specific mRNA cleavage and protein degradation (see Table I) (2). The presence of the RNAi cellular components, combined with silencing, specificity, and efficacy makes it an attractive mechanism for targeting dysregulated gene expression in human disease.

lorem ipsum