Anti-miRNA therapeutics for uterine fibroids

Background: 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. Methods: 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. Results: 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. Conclusion: 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.