Peptide Nucleic Acids Are Potent Modulators of Endogenous Pre-mRNA Splicing of the Murine Interleukin-5 Receptor-α Chain
2001; American Chemical Society; Volume: 40; Issue: 26 Linguagem: Inglês
10.1021/bi010263l
ISSN1943-295X
AutoresJames G. Karras, Martin A. Maier, Tao Lü, Andrew T. Watt, Muthiah Manoharan,
Tópico(s)Cytokine Signaling Pathways and Interactions
ResumoAntisense oligonucleotides (ASOs) that bind target pre-mRNA with high affinity have been shown to alter splicing patterns and offer promise as therapeutics. Previous studies have shown that ASOs fully modified with 2'-O-methoxyethyl (2'-O-MOE) sugar residues redirect constitutive and alternative splicing of the murine interleukin-5 receptor-α (IL-5Rα) chain pre-mRNA in cells, resulting in inhibition of the membrane-bound isoform and enhanced expression of the soluble isoform. Here, we show that antisense peptide nucleic acids (PNAs) alter splicing of the IL-5Rα pre-mRNA in a fashion similar to their 2'-O-MOE-modified counterparts of the same sequence. Moreover, using PNA as the splicing modulator, the length of the antisense oligomer could be shortened from 20 to 15 nucleobase units to obtain a comparable effect. Treatment of cells with antisense PNA resulted in dose-dependent, specific downregulation of IL-5Rα membrane isoform mRNA expression and enhanced levels of the soluble IL-5Rα isoform transcript, with an EC50 equivalent to that observed in parallel with the corresponding 2'-O-MOE ASO. The pronounced activity of antisense PNAs in modulating IL-5Rα mRNA splicing observed in our study identifies these compounds as a promising new class of lower molecular weight splicing modulators.
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