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Efforts of RNA aptamers as a new therapeutic modality are limited by their readiness to degradation and immunogenicity. A previous study has demonstrated that synthetic short double-stranded circular RNAs (ds-cRNAs) have minimal immunogenicity, targeting protein kinase R (PKR) activated by dsRNA.
On April 23, 2024, Lingling Chen's team from the Center for Excellence in Molecular and Cell Science, Chinese Academy of Sciences (Institute of Biochemistry and Cell Biology) published a paper titled "Therapeutic application of circular RNA aptamers in a mouse model of psoriasis" online in Nature Biotechnology The study reveals the therapeutic application of circular RNA aptamers in a mouse model of psoriasis.
The study tested the therapeutic potential of ds-cRNAs in a mouse model of pizimod-induced psoriasis. Genetic supplementation of ds-cRNAs results in inhibition of PKR, resulting in a reduction in downstream interferon-α and dsRNA signaling and attenuation of the psoriasis phenotype. Delivery of ds-cRNAs to the spleen via lipid nanoparticles attenuates PKR activity in the examined splenocytes, resulting in a decrease in epidermal thickness. These findings suggest that ds-cRNAs represent a promising approach to attenuate overactivation of PKRs for therapeutic purposes.
Several RNA-based drug modalities have received regulatory approval, including small interfering RNAs, antisense oligonucleotides, mRNA vaccines, and RNA aptamers. Compared with other classes of RNA drugs, RNA aptamers face greater challenges due to their susceptibility and immunogenicity to RNases, as well as their unclear mechanism of action. Covalently closed circular RNAs (circRNAs) have been shown to have high stability, unique conformation, and low immunogenicity compared to linear RNAs with great pharmaceutical potential.
Overactivation of double-stranded RNA (dsRNA)-activated protein kinase R (PKR) has been associated with autoinflammatory diseases, such as systemic lupus erythematosus (SLE), suggesting that blocking PKR activation holds promise in treating such diseases. While chemical inhibitors of PKR can produce off-target effects and reduce in vivo activity, the activity of PKR can be modulated by RNA duplexes, such as ectopic plasmid-mediated short double-stranded circular RNAs (ds-cRNAs) in SLE-derived peripheral blood mononuclear cells (PBMCs), and ds-cRNAs with low immunogenicity synthesized in cultured cells.
EPIC与PKR在动力学上的高亲和力（Credit: Nature Biotechnology）
Psoriasis is a chronic papulosquamous skin disease characterized by chronic plaques or psoriasis vulgaris. Decreased expression of endogenous circRNAs, skin lesions affected by lupus erythematosus and chronic inflammatory skin diseases such as psoriasis and atopic dermatitis were observed in PBMCs of patients. These observations led to the study of the link between decreased circular RNAs and increased inflammation, and to explore whether ds-cRNAs could inhibit overactive PKR-associated inflammation in psoriasis mice.
The study optimized a user-friendly intron-exon alignment (PIE) strategy to generate RNA loops with high yields and low immunogenicity. In a mouse model of imiquimod (IMQ)-induced psoriasis, these ds-cRNAs with high PKR-binding capacity can reduce inflammation by reducing pathological PKR activity, suggesting that RNA aptamers have therapeutic potential. These findings suggest that ds-cRNAs represent a promising approach to attenuate overactivation of PKRs for therapeutic purposes.
Link to original article
https://www.nature.com/articles/s41587-024-02204-4
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文章来源|“ iNature"
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