Antisense modulation of IL7R splicing to control sIL7R expression in human CD4+ T cells.

Gaddiel Galarza-Muñoz, Debbie Kennedy-Boone, Geraldine Schott, Shelton S Bradrick, Mariano A Garcia-Blanco

RNA (New York, N.Y.) 2022 Aug

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The interleukin 7 receptor (IL7R) is strongly associated with increased risk to develop multiple sclerosis (MS), an autoimmune disease of the central nervous system, and this association is likely driven by up-regulation of the soluble isoform of IL7R (sIL7R). Expression of sIL7R is determined by exclusion of the alternative exon 6 from IL7R transcripts, and our previous work revealed that the MS risk allele of the SNP rs6897932 within this exon enhances the expression of sIL7R by promoting exclusion of exon 6. sIL7R potentiates the activity of IL7, leading to enhanced expansion of T cells and increased disability in the experimental autoimmune encephalomyelitis (EAE) murine model of MS. This role in modulating T cell-driven immunity positions sIL7R as an attractive therapeutic target whose expression could be reduced for treatment of MS or increased for treatment of cancers. In this study, we identified novel antisense oligonucleotides (ASOs) that effectively control the inclusion (anti-sIL7R ASOs) or exclusion (pro-sIL7R ASOs) of this exon in a dose-dependent fashion. These ASOs provided excellent control of exon 6 splicing and sIL7R secretion in human primary CD4+ T cells. Supporting their potential for therapeutic targeting, we showed that lead anti-sIL7R ASOs correct the enhanced exon 6 exclusion imposed by the MS risk allele of rs6897932, whereas lead pro-sIL7R ASOs phenocopy it. The data presented here form the foundation for future preclinical studies that will test the therapeutic potential of these ASOs in MS and immuno-oncology. © 2022 Galarza-Muñoz et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

Citation

Gaddiel Galarza-Muñoz, Debbie Kennedy-Boone, Geraldine Schott, Shelton S Bradrick, Mariano A Garcia-Blanco. Antisense modulation of IL7R splicing to control sIL7R expression in human CD4+ T cells. RNA (New York, N.Y.). 2022 Aug;28(8):1058-1073