Small molecule PGE1 shows promise for nephronophthisis treatment in vitro and in vivo

Prostaglandin E1 (PGE1) treatment in nephronophthisis (NPH) patient urine-derived epithelial cell lines (URECs) rescued ciliary deficits. In a knockout mouse model of NPH, treatment improved renal tubular dilatations.

NPH is an autosomal recessive ciliopathy that causes up to 15% of paediatric cases of end-stage kidney disease. Pathologically, it is characterised by severe renal fibrosis cortical cysts. There are over 25 genes involved in NPH, making early diagnosis and treatment challenging in the clinic. Prof. Sophie Saunier (Inserm, France) researches the genetic and molecular basis of NPH [1].

In a genetic analysis of 834 patients with NPH, the most frequently mutated gene was NPHP1 (52.8%). To understand cellular and molecular changes with NPHP1 mutations, URECs from NPH patients with NPHP1 mutations were created. Compared with URECs from control patients, there were significantly fewer ciliated cells in the NPHP1 URECs.

Prof. Saunier’s group also investigates small molecules for potential NPH therapies. They screened 1,120 compounds from the Prestwick Chemical Library on Nphp1 knockdown cell lines. Of 51 compounds that rescued ciliogenesis and migration phenotypes, they evaluated 11 of their hits in the NPHP1-mutated patient URECs and validated 1 compelling compound: PGE1/alprostadil. PGE1 is an analogue of prostaglandin E2. Treating NPHP1-mutated patient URECs with PGE1 led to significant increases in the percentage of ciliated cells. PGE1 also increased actin cytoskeletal remodelling [2].

In addition to the in vitro exploration of PGE1 treatment on NPH phenotype, Prof. Saunier wanted to assess the drug’s efficacy in vivo. Using a CRISPR/Cas9 homozygous deletion of the NPHP1 start codon, the researchers generated Nphp1 knockout mice. The knockout mice presented with significant renal tubular dilatations at 2 months and 5 months. The animals were treated with 80 µg/kg of PGE1 or saline intraperitoneally daily between months 1 and 5, and found that PGE1 treatment decreased the number of severe tubular dilatations. PGE1 may thus be an interesting candidate for clinical trials of NPH.

1. Saunier S. Ciliary Disease and Potential Therapeutic Mechanisms. ASN Kidney Week 2023, 2–5 November, Philadelphia, PA, USA.
2. Garcia H, et al. Proc Natl Acad Sci USA. 2022;119(18):e2115960119.

 

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Posted on 28 November 202328 November 2023