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Kidney Week

Abstract: SA-PO443

Targeting Lysophosphatidic Acid Receptor 1 (LPAR1) with siRNA-Lipid Nanoparticles (siRNA-LNP) Is a Potential Therapeutic Approach for CKD -Associated Kidney Fibrosis

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Yu, Xing-Xian (Scott), Nitto BioPharma Inc, San Diego, California, United States
  • Liu, Yun, Nitto BioPharma Inc, San Diego, California, United States
  • Xia, Fengcheng, Nitto BioPharma Inc, San Diego, California, United States
  • Quimbo, Alistair Joseph C., Nitto BioPharma Inc, San Diego, California, United States
  • Harborth, Jens, Nitto BioPharma Inc, San Diego, California, United States
  • Lee, Jingyuan, Nitto BioPharma Inc, San Diego, California, United States
  • Clamme, Jean-Pierre, Nitto BioPharma Inc, San Diego, California, United States
Background

LPAR1 plays an important role in tissue fibrosis. Its expression is upregulated in kidneys (K) of different injuries. To explore if siRNA inhibition of its expression could be a therapeutic approach for K fibrosis, we developed a K-targeting LPAR1 siRNA-LNP.

Methods

A series of LPAR1 siRNAs were designed and screened in vitro. The activity of the selected lead siRNA was confirmed in vivo. A series of LNP formulations for delivery of siRNA to K were designed and screened in vivo. Cell distribution of siRNA in K was analyzed with different approaches. The selected lead LPAR1 siRNA-LNP was used to treat mice of DKD or rats of Adriamycin-induced CKD. LPAR1 gene knockdown, serum creatinine, uACR, K hydroxyproline (HP) and histological changes were determined.

Results

In vitro screen identified a lead LPAR1 siRNA of an IC50 ~10pM. The activity was confirmed in vivo. A lead LNP formulation was identified by showing >50% LPAR1 mRNA reduction in mouse K after a dose of 4 mpk and a higher siRNA accumulation in K than in liver or other tissues 24 hr after dosing. FACS analysis found that siRNA was delivered to majority of K cells including podocytes, mesangial cells, endothelial cells in glomeruli, and epithetical and non-epithetical cells in non-glomerulus part. Treatment (Tx) of mice with a single dose of a podocin siRNA-LNP significantly reduced podocin mRNA, further demonstrating the siRNA was delivered into podocytes. RNAscope analysis found that LPAR1 siRNA reduced LPAR1 mRNA level in different K cells. Tx of STZ-induced diabetic mice with LPAR1 siRNA at 4 mpk once a wk for 4 wks lowered K HP levels, and improved K fibrosis and tubular degeneration. Tx of BTBR ob/ob mice caused ~20% and 45% reduction in uACR after 3 and 9 wks of Tx, respectively. Tx of rats of Adriamycin-induced CKD at 2 mpk/wk for 4 wks normalized serum creatinine, lowered uACR by 60%, improved glomerulosclerosis, stopped worsening of glomerular atrophy, and reversed glomerular effacement and tubular dilation. The Tx effect lasted for >11 wks.

Conclusion

Above data demonstrated that siRNA inhibition of LPAR1 expression improves K fibrosis accompanied by an improved K function in multiple CKD models. Therefore, the siRNA-LNP could be a potential therapeutic for K fibrosis.