PYC-003, a Peptide-Conjugated Oligonucleotide for the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Background: ADPKD is a severe disease that causes kidney failure, affecting 1 in 1,000 people. Roughly 80% of ADPKD cases are caused by mutations in one copy of the PKD1 gene leading to deficient PC1 protein. Addressing the root cause, PYC-003 is designed to upregulate PC1 expression. Methods: PYC-003 effects on PC1 protein was determined by western blot and cyst shrinkage tested in 3D patient-derived models. A PYC-003 mouse surrogate molecule was intravenously injected into B6 mice where drug distribution was measured after 3 days using miRNAscope. Results: PYC-003 raises PC1 protein in HEK293 cells to 1.6-fold. PYC-003 prevented cyst formation and reduces cyst area. A single dose of the PYC-003 mouse surrogate showed uniform renal distribution. Conclusion: PYC-003 shows potential to be a treatment for ADPKD by increasing PC1 protein, preventing the formation of cysts in vitro and exhibiting enhanced renal delivery. PYC-003 is undergoing IND-enabling studies in preparation for anticipated clinical trials scheduled to begin in Q1 2025. Funding: Commercial Support - PYC TherapeuticsPC1 fold-change over untreated (normalized to total protein) in HEK293 cells at day 3 following treatment of PYC-003. Mean + S.D (n=2)ADPKD 3D cyst shrinkage after 2 treatments of PYC-003 in two patients. Nuclei (blue) and cytoskeleton (red), x4 magnification