RGLS4326 (RG4326) is a short oligonucleotide inhibitor of microRNA-17 (miR-17), with a pioneering role in its class. This compound, with a research focus on autosomal dominant polycystic kidney disease (ADPKD), effectively suppresses the activity of miR-17 in HeLa cells, displaying an EC50 value of 28.3 nM.

RGLS4326, a chemically modified, single-stranded oligonucleotide of 9 nucleotides (nt) fully complementary to the miR-17 seed sequence, effectively inhibits the adverse functions associated with the miR-17 family of microRNAs (miRNAs) in autosomal dominant polycystic kidney disease (ADPKD)[1]. This inhibition extends to the function of miR-17 in cultured kidney collecting duct cells, where its activity is significantly reduced, as evidenced by the miR-17 PD-Sig, with an efficacy concentration (EC 50) of approximately 77.2 ± 20.2 nM[1]. Additionally, RGLS4326 demonstrates the capability to suppress the growth of primary human ADPKD cysts[1]. In a Cell Proliferation Assay conducted on primary cysts within a 3D Matrigel environment at various concentrations (5, 20, 100, and 300 nM) over nine days, it was observed that RGLS4326 leads to a decrease in the proliferation of cyst epithelial cells[1].

RGLS4326 exhibits a preference for targeting kidney tubules and cysts. Administered as a single subcutaneous (SC) injection at 30mg/kg, it achieves rapid plasma absorption with a peak concentration (T max) of ≤1 hour, a maximum concentration (C max) of 8.5μg/mL, and a short half-life of <4 hours in wild-type mice[1]. This compound notably increases the levels of Pkd1 and Pkd2 genes, direct targets of miR-17, upon in vivo administration[1]. In a study involving Pkd2 knockout (Pkd2 -KO) mice[1] treated with 20mg/kg RGLS4326 via SC injection, a marked difference was observed in polycystic kidneys when compared to non-cystic control kidneys. Specifically, in the placebo (PBS)-treated Pkd2-KO mice, there was a progressive, age-dependent increase in miR-17 activity, as evidenced by a drop in miR-17 pharmacodynamic signal (PD-Sig), correlating with disease progression. Conversely, treatment with RGLS4326 led to a reversal of this trend, effectively indicating sustained functional inhibition of miR-17.