Recherche de cibles thérapeutiques dans le cadre de la néphronophtise et des ciliopathies rénales associées (NPH1)
Recherche de cibles thérapeutiques dans le cadre de la néphronophtise et des ciliopathies rénales associées - NPH_1
Nephronophthisis (NPH) is an autosomal recessive, genetically heterogeneous disease, with mutations identified in over 20 genes (notably NPHP1 and NPHP4).
These genetic defects are associated with reduced urine concentration, chronic tubulointerstitial nephritis, etc., and progress to end-stage renal failure before the age of 20.
Nephronophthisis may occur as an isolated pathology, but is also often associated with various extrarenal symptoms.
NPHP genes account for around 50% of the genes responsible for NPH. No effective treatment is available to date.
Studying NPHP proteins and associated signaling pathways could help identify how to circumvent the problems of protein distribution and therapeutic mRNA, and could be applicable to a broad set of NPHP mutations. To this end, Dr. Saunier's laboratory at Institut Imagine has recently identified approved drugs that correct some of the ciliary and epithelial defects found in cells with NPHP mutations.
Aperçu de l'étude
Statut
Les conditions
Description détaillée
Nephronophthisis (NPH) is an autosomal recessive, genetically heterogeneous disease, with mutations identified in over 20 genes (notably NPHP1 and NPHP4).
These genetic defects are associated with reduced urine concentration, chronic tubulointerstitial nephritis, etc., and progress to end-stage renal failure before the age of 20.
Nephronophthisis may occur as an isolated pathology, but is also often associated with various extrarenal symptoms such as retinal dystrophy, cerebellar vermis hypoplasia, skeletal dysmorphisms and/or situs/inversus. These disorders overlap phenotypically, genetically and functionally. All are thought to result from defective ciliary signaling and are classified as renal ciliopathies.
NPHP genes account for around 50% of the genes responsible for NPH. No effective treatment is available to date.
One possible therapeutic approach is to replace the defective protein; but delivery of recombinant proteins or mRNA to renal tubular cells is not currently feasible. However, each NPHP protein participates in numerous intracellular signalling pathways involving cilia functions.
Studying NPHP proteins and associated signaling pathways could help identify how to circumvent the problems of protein distribution and therapeutic mRNA, and could be applicable to a broad set of NPHP mutations. To this end, Dr. Saunier's laboratory at Institut Imagine has recently identified approved drugs that correct some of the ciliary and epithelial defects found in cells with NPHP mutations.
The global research project of which this protocol is a part seeks to identify new specific targets and develop new therapeutic agents against these targets for the treatment of NPH and other ciliopathies.
Type d'étude
Inscription (Estimé)
Phase
- N'est pas applicable
Contacts et emplacements
Lieux d'étude
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La Defense, France
- Recrutement
- Imagine Institute
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Contact:
- Sophie AF SAUNIER
- E-mail: sophie.saunier@inserm.fr
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Critères de participation
Critère d'éligibilité
Âges éligibles pour étudier
- Enfant
- Adulte
- Adulte plus âgé
Accepte les volontaires sains
Sexes éligibles pour l'étude
La description
Inclusion Criteria:
- In order to be included in the protocol, subjects will have to respect the following criteria:
Affected patients:
Suffering from nephronophthisis or renal associated ciliopathies with known genetic diagnosis or not, Having obtained the signature of the informed consent form of patient, parent(s) or legal representative No age limit is requested for these patients, who can be recruited from birth.
Healthy relatives:
Being the healthy relative (father / mother / brother / sister) of an included patient Having signed the informed consent form (patient or parent in case of minor subject) No age limit is requested for these subjects, who can be recruited from birth.
'Negative' control patients: Being unscathed of any chronic renal disease, with or without ciliopathies Having obtained the signature of the informed consent form No age limit is requested for these patients, who can be recruited from birth.
'Positive' control patients Suffering from Chronic Kidney Disease unrelated to ciliary dysfunction (such as glomerulopathy, tubulopathy…) Having obtained the signature of the informed consent form No age limit is requested for these patients, who can be recruited from birth.
Exclusion Criteria:
In order to be included in the protocol, subjects will have to fulfill none of the following criteria:
Affected patients:
Patients with a functioning kidney transplant (only for patient for who urine sample is performed. This criteria is not applicable when only blood is sampling) Patients included in a therapeutic protocol since fewer 30 days.
Healthy relatives:
No no-inclusion criteria
'Negative' control subjects: No no-inclusion criteria
'Positive' control subjects: Patients with a functioning kidney transplant
Plan d'étude
Comment l'étude est-elle conçue ?
Détails de conception
- Objectif principal: Traitement
- Répartition: Non randomisé
- Modèle interventionnel: Affectation à un seul groupe
- Masquage: Aucun (étiquette ouverte)
Armes et Interventions
Groupe de participants / Bras |
Intervention / Traitement |
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Autre: Patients with nephronophthisis/renal associated ciliopathies
Affected patients: Suffering from nephronophthisis or renal associated ciliopathies with known genetic diagnosis or not, Having obtained the signature of the informed consent form of patient, parent Intervention : blood and urine sample collection Collection of urines from patients will be followed by multiomics analyses including proteome and miRNAome profiling on EVs purified from urines by ultracentrifugation and metabolomics on unfractionated urine. Biomarkers identification for ciliopathy-induced chronic kidney disease will allow to monitor the drug response in treated urine-derived renal epithelial cells. |
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Autre: Healthy relatives of Patients
Healthy relatives: Being the healthy relative (father / mother / brother / sister) of an included patient Having signed the informed consent form (patient or parent in case of minor subject) No age limit is requested for these subjects, who can be recruited from birth. Intervention : blood and urine sample collection Collection of urines from patients will be followed by multiomics analyses including proteome and miRNAome profiling on EVs purified from urines by ultracentrifugation and metabolomics on unfractionated urine. Biomarkers identification for ciliopathy-induced chronic kidney disease will allow to monitor the drug response in treated urine-derived renal epithelial cells |
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Autre: Negative control
Being unscathed of any chronic renal disease, with or without ciliopathies Having obtained the signature of the informed consent form No age limit is requested for these patients, who can be recruited from birth. Intervention : blood and urine sample collection Collection of urines from patients will be followed by multiomics analyses including proteome and miRNAome profiling on EVs purified from urines by ultracentrifugation and metabolomics on unfractionated urine. Biomarkers identification for ciliopathy-induced chronic kidney disease will allow to monitor the drug response in treated urine-derived renal epithelial cells |
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Autre: Positive control
Suffering from Chronic Kidney Disease unrelated to ciliary dysfunction (such as glomerulopathy, tubulopathy…) Having obtained the signature of the informed consent form No age limit is requested for these patients, who can be recruited from birth. Intervention : blood and urine sample collection Collection of urines from patients will be followed by multiomics analyses including proteome and miRNAome profiling on EVs purified from urines by ultracentrifugation and metabolomics on unfractionated urine. Biomarkers identification for ciliopathy-induced chronic kidney disease will allow to monitor the drug response in treated urine-derived renal epithelial cells |
Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Délai |
|---|---|
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Confirmation positive ou négative de cibles thérapeutiques potentielles dans les cellules épithéliales rénales dérivées de l'urine de patients
Délai: 3 ans
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3 ans
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Mesures de résultats secondaires
Mesure des résultats |
Description de la mesure |
Délai |
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Identifier des biomarqueurs pour évaluer la réponse aux petites molécules pour la prise en charge du NPHP et d'autres ciliopathies rénales.
Délai: 3 ans
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3 ans
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Experimental transcriptomics data package from in vitro tubule cell model perturbed with disease network modifying agents
Délai: 3 years
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The experimental design and data will be formatted for Bayesian analytics. |
3 years
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A rank ordered list of specific druggable nodes within the NPHP disease module that could be targeted by biologic or chemical entities.
Délai: 3 years
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A rank ordered list of specific druggable nodes within the NPHP disease module that could be targeted by biologic or chemical entities. |
3 years
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Collaborateurs et enquêteurs
Parrainer
Dates d'enregistrement des études
Dates principales de l'étude
Début de l'étude (Réel)
Achèvement primaire (Estimé)
Achèvement de l'étude (Estimé)
Dates d'inscription aux études
Première soumission
Première soumission répondant aux critères de contrôle qualité
Première publication (Réel)
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Réel)
Dernière mise à jour soumise répondant aux critères de contrôle qualité
Dernière vérification
Plus d'information
Termes liés à cette étude
Termes MeSH pertinents supplémentaires
Autres numéros d'identification d'étude
- IMIS2015-05
Plan pour les données individuelles des participants (IPD)
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Informations sur les médicaments et les dispositifs, documents d'étude
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