Targeting noncoding RNAs in disease

Abstract

Many RNA species have been identified as important players in the development of chronic diseases, including cancer. Over the past decade, numerous studies have highlighted how regulatory RNAs such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) play crucial roles in the development of a disease state. It is clear that the aberrant expression of miRNAs promotes tumor initiation and progression, is linked with cardiac dysfunction, allows for the improper physiological response in maintaining glucose and insulin levels, and can prevent the appropriate integration of neuronal networks, resulting in neurodegenerative disorders. Because of this, there has been a major effort to therapeutically target these noncoding RNAs. In just the past 5 years, over 100 antisense oligonucleotide-based therapies have been tested in phase I clinical trials, a quarter of which have reached phase II/III. Most notable are fomivirsen and mipomersen, which have received FDA approval to treat cytomegalovirus retinitis and high blood cholesterol, respectively. The continued improvement of innovative RNA modifications and delivery entities, such as nanoparticles, will aid in the development of future RNA-based therapeutics for a broader range of chronic diseases. Here we summarize the latest promises and challenges of targeting noncoding RNAs in disease.

Figure 1. The complexity of noncoding RNA gene networks.

In this scenario, four genes are transcribed. However, only the splice variants mRNA-1 and mRNA-2 encoded by gene A are translated into protein products. These protein products can be regulated by noncoding RNAs (ncRNAs) that are encoded by genes B, C, and D, which interact with gene A at the RNA level in what is referred to as an RNA language or RNA network. Gene B encodes miRNA, which can interact with mRNAs at their 3′-UTR. Gene C encodes long noncoding RNA (lncRNA), which can interact with the protein products of gene A or serve as a decoy for certain miRNAs. Gene D encodes circular RNA (circRNA), which can sponge or serve as a decoy for any RNA binding event that indirectly regulates gene A protein products, such as lncRNA or miRNA interactions.

Figure 2. Oligoribonucleotide modifications for therapeutic delivery.

(A) Various oligoribonucleotide (ORN) modifications have been developed to improve RNA stability, including (i) substitutions of the 2′-OH of the ribose sugar, such as 2′-O-methyl (2′-OMe, light blue), 2′-O-methoxyethyl (2′-MOE, yellow), and 2′-fluoro (2′-F) substitutions (red); (ii) replacement of the phosphodiester linkage with a phosphorothioate (dark blue); (iii) locking of the conformation of the backbone with a methylene bridge using LNA modification (green); and (iv) DNA modification of the ribose sugar to a deoxyribose sugar (purple). (B) Examples of current modifications used in anti-miRNA ORN therapeutic strategies. Figure adapted with permission from Silence (ref. ; Creative Commons user license available at http://creativecommons.org/licenses/by/2.0).

Figure 3. Delivery vehicles/carriers for ncRNAs.

The images depict the various delivery methodologies described in Table 1. Peptide nucleic acid (PNA) approaches (A) and lipid-based nanocarriers (B) are the most well-characterized delivery methods for RNA. Recently, new carriers have been developed, including poly(lactic-co-glycolic acid)–coated (PLGA-coated) nanoparticles (C), poly(amine-co-esters) such as PACE (D), and pH-sensitive peptides such as pHLIP (E).