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Functional RNAs, e.g., aptamers (Lee et al., 2005; Que-Gewirth & Sullenger, 2007), ribozymes (Malhbacher et al., 2010), antisense oligonucleotides (Hnik et al., 2009), and double-stranded RNA (dsRNA) (Watts & Corey, 2010), hold promise for use as RNA drugs in the near future. However, the linear form of RNA without chemical modifications is rapidly degraded in both human serum and cell extracts due to endogenous nucleases. Therefore, it will likely be necessary to chemically modify these RNA drugs (Pestourie et al., 2005; Watts et al., 2008) to protect them from nuclease-dependent degradation. In fact, the recently developed aptamer drug pegaptanib sodium (Macugen®; Pfizer) for use against macular degradation consists of 2'-For 2'-OCH3-substituted nucleotides, thus preventing its rapid degradation in the ocular environment. Although at present it is the only commercially available RNA drug, we infer from the selling price of Macugen® that similar novel chemically modified RNA drugs are likely to be expensive because production of a chemically modified RNA molecule and scaling up the production yield of the RNA are expensive in principle. Therefore, the development of not only inexpensive but also durable RNA drugs will facilitate the widespread use of easily administered RNA drugs. To address the problems outlined above, our research group has considered in vivo circular RNA expression as a model for inexpensive RNA drug production because circular RNA molecules are resistant to exoribonucleases without any chemical modifications under cellular conditions. Therefore, the circular form of RNA would be a promising RNA drug candidate without requiring chemical modification.

In Vivo Circular RNA Expression by the Permuted Intron-Exon Method