Published on 16.03.2021
Nephronophthisis, a renal ciliopathy, the main genetic cause of renal failure in children
Ciliopathies have in common a dysfunction of the primary cilia, cellular sensory antennae enriched in sensors (receptors). These cilia are found on the surface of almost all the cells of the organism, they perceive signals (growth factors, morphogens, light, urine flow, etc.) allowing them to analyze the external environment and thus coordinate cellular responses during development and the proper functioning of tissues in adults. They are present in particular on the cells of the kidney, liver, cartilage, visual cells of the retina, neurons, and control the functioning of these organs. If the spectrum of clinical manifestations of ciliopathies is wide, one of the most frequent manifestations and the main cause of mortality is the deterioration of renal function, inevitably leading to end-stage renal failure requiring renal transplantation.
Affecting about 1 in 50,000 births, nephronophthisis (NPH) is the leading genetic cause of end-stage renal disease in children and young adults. It can be isolated or associated with extra-renal abnormalities, including retinal dystrophy (Senior-Loken syndrome), cerebellar abnormalities (Joubert syndrome), skeletal abnormalities (Jeune syndrome) and/or laterality defects.
Identifying the genetic causes and understanding the physiopathological mechanisms
The "Molecular basis of hereditary renal diseases" research team, directed by Dr. Sophie Saunier at Institut Imagine, has specialized for more than 20 years in the study of renal ciliopathies, and in particular nephronophthisis (NPH). Composed of researchers with expertise in genetics, cell biology and pathophysiology, as well as nephrologists and geneticists, the team identified in 1997 the first gene (NPHP1) whose mutations are the main cause of NPH. Based on large patient cohorts from a multicenter clinical network, and thanks to the development of innovative exome sequencing approaches, the team has since participated directly or in collaboration in the discovery of 13 of the 23 NPHP genes known to date. Most of these genes code for proteins localized at the level of the primary cilium, highlighting the major role of the cilium in these diseases. The mutations present in patients lead to defects in cilia formation and/or function, confirming the key role of NPHP in these processes. For more information.
NPH, like other ciliopathies, is a genetically very heterogeneous disease (23 NPHP genes) and to date, no genetic mutation could be identified in 30% of patients. Using high throughput genome sequencing approaches, functional studies and pre-clinical in vitro and in vivo models, Sophie Saunier's team hopes to identify new NPHP genes, or new types of mutations, and to highlight the deregulated cellular signaling pathways at the origin of NPH and other associated manifestations in syndromic forms (retina, liver, etc.).
Developing therapeutic approaches
The only possible 'treatment' for NPH is dialysis and then, inevitably, renal transplantation. The laboratory's objective is therefore to identify new therapeutic avenues by targeting the altered signaling pathways in the patients' cells, through the use of molecules capable of compensating for these biological defects. The identification of molecules already approved and used for other pathologies would accelerate the implementation of therapeutic trials for NPH. In parallel, a complementary approach of the team seeks to identify, through the screening of a large number of molecules, compounds that would be able to restore functional cilia in patient cells. The cellular and animal models developed by the laboratory play a major role in this strategy. Renal tubular cells collected from patients' urine have allowed the identification of certain molecules with interesting properties that will then be tested in animal models such as zebrafish and mice, as well as organoid cultures generated from patients' induced stem cells (mini kidneys generated in vitro).
Recent studies have characterized a promising molecule capable of restoring ciliary defects in NPHP1 patient cells and renal and retinal defects in a mutant mouse model. This molecule, developed in collaboration with the start-up Medetia, housed at Institut Imagine, could enter clinical trials in 2024. For more information. This is a real hope for patients. Moreover, since the function of the cilium is very similar in different organs, the team hopes to be able to restore renal, retinal and hepatic functions with the same molecule, as observed in mice.
Finding diagnostic and prognostic markers
Another major goal of the team is to identify biomarkers, both for diagnosis and prognosis. At present, it remains difficult to detect the first signs of NPH, which can go undetected for years, to predict whether kidney damage will develop in patients with other damage (visual or skeletal), and when the first signs of NPH are observed, when the patient will enter into end-stage renal failure. Multiscale or omics analyses allow the analysis of gene and protein expression as well as metabolites secreted by the cells or present in the urine or blood in the different available models. This could provide indicators of the presence of a NPHP gene mutation, a pre-symptomatic signature of renal function, and markers for monitoring the degradation of renal function, and thus, to propose treatments. Biomarkers of response to treatment are also being developed, notably through in vitro models generated from patient cells. The research carried out in the laboratory covers a global approach aiming to better understand the mechanisms of the diseases, to diagnose and identify patients at risk of renal damage, and to allow their follow-up.
Towards the medicine of the future for ciliopathies with kidney damage
Institut Imagine concentrates a unique expertise in the world on ciliopathies by bringing together specialists in these pathologies, particularly in the fields of kidney, eyes, bones, and bioinformatics and data science*.
In this context, the Institute and the research team led by Sophie Saunier are coordinating the RHU (University Hospital Research - Investissements d'Avenir Program) C'IL-LICO project "Medicine of the future for ciliopathies with renal involvement". This program aims to develop innovative and revolutionary approaches to diagnosis, prognosis and personalized treatment for patients suffering from ciliopathies, in particular ciliopathies leading to renal failure. It relies on disruptive informational technologies (artificial intelligence), state-of-the-art experimental approaches (renal organoids derived from induced patient stem cells, multi-omics, high-throughput sequencing) and clinical resources developed over several years.
The program is led by a consortium that brings together a unique network of clinicians, biologists and computer scientists from Institut Imagine, Inserm, APHP, the University Hospitals of Strasbourg and the École Polytechnique. For more information.
* Several teams at Institut Imagine and Hôpital Necker-Enfants malades AP-HP are working on ciliopathies, in particular the team of Dr Sophie Saunier, Dr Jean-Michel Rozet, Prof Valérie Cormier-Daire, Prof Tania Attié-Bitach and Dr Sophie Thomas, Nicolas Garcelon's Data Science platform, Dr Antonio Rausell's clinical bioinformatics laboratory, and Patrick Nitschké's bioinformatics platform...