Nephronophthisis: a promising molecule

For more than 25 years, the Hereditary Kidney Diseases laboratory has identified some 30 genes responsible for three rare kidney diseases that particularly affect children: cystinosis, cortico-resistant nephrotic syndrome and nephronophthisis. Nephronophthisis belongs to the family of 'ciliopathies', diseases caused by mutations in genes coding for proteins of the primary cilium, a kind of antenna present on the surface of most of our cells.

"Nephronophthisis is the leading genetic cause of end-stage renal disease in children," says Sophie Saunier, director of the laboratory. In these patients, the functional unit of the kidney that filters blood and produces urine - the nephron - is altered. The disease affects the tubules of the nephron that concentrate urine and reabsorb sodium, leading to the development of kidney fibrosis, cysts and inflammation. The symptoms are severe fatigue, anaemia, stunted growth and progressive deterioration of kidney function. Eventually, the destruction of the kidneys is inevitable as there is no treatment. Children must then undergo repeated dialysis or a kidney transplant, with unequal progress in each case.

In a new study published in the journal PNAS, Sophie Saunier and her team - in particular the first co-authors, Hugo Garcia, Alice Sérafin and Flora Silbermann - in partnership with the start-up Medetia, hosted by the Institut Imagine, have identified a signalling pathway and a series of promising molecules for the treatment of nephronophthisis [1].

Stimulating cilium regrowth, a promising strategy

"In the majority of cases, this disease is due to mutations in the NPHP1 gene encoding a protein located in the primary cilium. This results in defects in the formation and/or function of the cilia in the nephron cells, followed by a progressive alteration in the function of the nephron," explains Sophie Saunier. "For a long time, biologists thought that this type of cilium was just an evolutionary relic of little use. But researchers have realised that it actually plays an essential role in cell signalling and the function of many organs (kidneys, retina, bones, brain)," adds Alexandre Benmerah, a researcher in the laboratory.

And for good reason, the cilium is a mechanical and biochemical sensor enabling the cell to get informations from its immediate environment. This observation gave rise to the idea of restoring the primary cilium in children with nephronophthisis. "To achieve this, we analysed the effect of 1,120 compounds approved by various medical agencies (FDA, EMA and others) in vitro on cells with the NPHP1 mutation. The result: 51 had a beneficial effect on ciliogenesis, i.e. the regrowth of primary cilium,' explains Sophie Saunier. What remained was to identify the most effective and relevant one. 

Prostaglandin E1: the most effective molecule

Medetia played a key role in this work by providing expertise to evaluate the efficacy of the first candidate compounds as pharmacological agents. Together, the two teams showed that a molecule called prostaglandin E1 (PGE1) was particularly effective in restoring ciliogenesis and/or cilia length both in cells derived from patient urine and in animal models such as zebrafish and mice. Furthermore, they showed that prostaglandin derivatives could decrease nephron tubule damage but also improve retinal degeneration in animals, a clinical manifestation also observed in humans.

"We believe that this discovery could benefit not only nephronophthisis patients but also other patients with ciliopathy affecting the eye," said Jean-Philippe Annereau, CEO and co-founder of Medetia.

"This discovery is the result of a real synergy between our teams and those of Sophie Saunier. It's a great example of a public-private partnership in the sense that we've really been working together every day, every week, since August 2015, building on our complementarity," explain Jean-Philippe Annereau and Luis Briseño-Roa, co-founders of Medetia.

The next step? To demonstrate the effectiveness of this molecule on the symptoms of nephronophthisis by developing models that are even closer to the disease observed in patients. The laboratory is thus developing innovative models : organoids, a kind of miniature nephrons produced in vivo from patients' stem cells. These 3D mini-organs are a godsend because they partly reproduce the complexity of the functioning of a real diseased kidney, with typical lesions of nephronophthisis (lack of reabsorption of solutes, development of fibrosis and/or renal cysts). "This makes it a robust model for testing both the toxicity and efficacy of PGE1," predicts Sophie Saunier. So we'll keep an eye on it !

[1] H.Garcia, A.Serafin, F. Silbermann et al., PNAS, 2022