Kidney Week

Abstract: TH-OR049

A Novel Strategy to Identify an Effective Treatment for Juvenile Nephronophthisis

Session Information

• Cystic Kidney Diseases: Genes, Mechanisms, Interventions
  November 02, 2017 | Location: Room 390, Morial Convention Center
  Abstract Time: 06:06 PM - 06:18 PM

Category: Genetic Diseases of the Kidney

• 801 Cystic Kidney Diseases

Authors

• Garcia, Hugo, INSERM UMR1163, Paris, France

Hugo Garcia, MD



• Silbermann, Flora, INSERM UMR1163, Paris, France

Flora Silbermann,

• Porée, Esther, INSERM UMR1163, Paris, France

Esther Porée,

• Mahaut, Clementine, Alexion R&D France, Paris, France

Clementine Mahaut,

• Deleglise, Berangere Maud, Alexion R&D France, Paris, France

Berangere Maud Deleglise,

• Rodriguez, Pamela C, Alexion R&D France, Paris, France

Pamela C Rodriguez,

• Sin-Monnot, Soraya, Alexion R&D France, Paris, France

Soraya Sin-Monnot,

• Briseno-Roa, Luis, Alexion R&D France, Paris, France

Luis Briseno-Roa,

• Annereau, Jean-Philippe Michel, Alexion R&D France, Paris, France

Jean-Philippe Michel Annereau,

• Antignac, Corinne, INSERM UMR1163, Paris, France

Corinne Antignac,

• Salomon, Remi, INSERM UMR1163, Paris, France

Remi Salomon,

• Delous, Marion H., INSERM UMR1163, Paris, France

Marion H. Delous,

• Saunier, Sophie, INSERM UMR1163, Paris, France

Sophie Saunier,

Background

Nephronophthisis (NPH) is an autosomal recessive tubulointerstitial nephropathy and the most common cause of hereditary end-stage renal disease in children and young adults. No specific treatment is currently available. Almost all the 21 identified NPHP genes encode proteins localized in the primary cilium.

Methods

We designed an in vitro high-throughput drug-screen strategy based on the Prestwick Chemical Library that includes more than 1120 compounds (mostly FDA-approved). We first evaluated migration and ciliogenesis in mammalian renal epithelial cells invalidated for either Nphp1 or Nphp4, the two main genes involved in juvenile NPH, and identified 78 modulating drugs in these models. Then we selected 30 molecules based on pharmacodynamics and assessed their effect on ciliogenesis of immortalized renal tubular cells derived from urine samples of NPHP1-deleted patients (URECs).

Results

We validated the positive effects of one compound (ARDF006) that increases the percentage of ciliated cell from and normalizes cilia length distribution. A similar rescue was observed when using specific agonists and antagonists targeting ARDF006 receptors. These G protein–coupled receptors partially localize at primary cilia. We could confirm in vivo effects of ARDF006 and a structural analog by using the nphp4-ATG morphant zebrafish model, which present a classical ciliopathy-related phenotype: body curvature and pronephric cysts. By using semi-automated imaging and analysis tools, we observed that ARDF006 treatment of morphant embryos does not have a significative impact on body curvature; however, it leads to a 27% relative reduction of pronephric cysts formation and an increase of ciliated cells percentage and cilia length in the distal part of the pronephros.

Conclusion

URECs and zebrafish represent useful and fast models to recapitulate patients’ ciliogenesis defects and implement a pharmacologic approach for genetic deletion-related disease such as NPH.

Funding

• Commercial Support – Alexion Pharmaceuticals