Chiara Agostinis

Anti-miRNA therapeutics for uterine fibroids

Uterine leiomyomas arise from altered uterine smooth muscle cell proliferation in the myometrium. Available treatments are limited and fraught with major side effects. Here, we leveraged data from a high-throughput screening using human microRNA mimics and selected miR-148a-3p as a therapeutic target. The study aimed to assess the therapeutic potential of a miR-148a-3p inhibitor in suppressing the proliferation of uterine leiomyoma cells and in a xenograft mouse model. Clinical samples of uterine leiomyoma were used to isolate primary uterine leiomyoma cells and develop a subcutaneous xenograft mouse model. Cells were transfected with both miR-148a-3p mimic and anti-miR-148a-3p to assess the effect of miR-148a-3p on-cell proliferation. Animals were administered anti-miR-148a-3p-LNA via both local (intra-tumoral) and systemic (intraperitoneal) routes. Tumor volume was measured using ultrasonography, followed by histological and immunofluorescence staining, and target gene expression analysis. Transfection of primary cells with miR-148a-3p mimic resulted in increased smooth-muscle cell proliferation, whereas anti-miR-148a-3p LNA reduced their proliferation. Both local and systemic delivery of anti-miR-148a-3p LNA reduced tumor volume and cell proliferation. Anti-miR-148a-3p LNA also led to reduced levels of miR-148a-3p in vivo, paralleled by the up-regulation of its target genes TXNIP and Nrp1. Anti-miR-148a-3p LNA inhibits the proliferation of patient-derived leiomyoma cells and tumor growth in vivo, by suppressing miR-148a-3p levels and increasing TXNIP and Nrp1 gene expression. The highest therapeutic effect was observed with systemic administration, positioning miR-148a-3p inhibition as a promising therapeutic strategy for uterine leiomyoma in humans.