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."
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).
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)
Targeting specific genes using antisense oligonucleotides and siRNA
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.
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.
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.
Table I: Overview of the current RNA-based drug-discovery platform.