Fraunhofer Institute for Toxicology and Experimental Medicine
Circular RNAs (circRNAs) form a distinct class of endogenous RNA molecules that are particularly stable against enzymatic degradation due to their covalently closed ring structure. In natural biological systems, circRNAs are predominantly non-coding and play regulatory roles in controlling gene expression. This principle – enhanced stability through circularity – forms the basis of new RNA therapeutic approaches. Researchers at Fraunhofer ITEM and the Hannover Medical School have applied this concept to a therapeutically relevant, protein-coding messenger RNA (mRNA) (DOI: 10.1111/acel.70240).
For this purpose, the mRNA of human telomerase reverse transcriptase (hTERT) was specifically circularized to achieve prolonged intracellular persistence and more sustained protein expression. Telomerase is essential for maintaining telomere length and plays a central role in regeneration, cellular aging, and the development of fibrotic diseases such as pulmonary fibrosis.
In cell culture models, the circularized hTERT mRNA proved significantly more stable than its linear counterpart. While linear modified mRNA was rapidly degraded, the circRNA remained detectable even after 48 hours and mediated sustained telomerase activity. This was associated with functional effects: reduced DNA damage and senescence markers as well as improved proliferation of human fibroblasts and primary alveolar type II epithelial cells. Moreover, the circular hTERT RNA – unlike the linear form – led to a measurable elongation of telomeres. In an ex-vivo model of precision-cut lung slices (PCLS), established at Fraunhofer ITEM, treatment of native tissue slices from patients with advanced pulmonary fibrosis with hTERT circRNA induced increased telomerase expression while simultaneously reducing pro-inflammatory cytokines (IL-6, IL-8) and fibrotic markers such as TGF-β and collagen-1.
Overall, these results demonstrate that circularization of mRNA significantly enhances the duration and efficacy of protein expression, thereby influencing key processes such as senescence, telomere shortening, and fibrotic signaling pathways. This nature-derived structural principle of circRNA thus expands the potential of RNA-based therapeutics, particularly for diseases where prolonged protein expression is therapeutically advantageous.
