Onderzoek naar therapeutische doelen in het kader van nefronoftise en nier-geassocieerde ciliopathieën (NPH1)
Onderzoek naar therapeutische doelen in het kader van nefronoftise en nier-geassocieerde ciliopathieën - 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.
Studie Overzicht
Toestand
Gedetailleerde beschrijving
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.
Studietype
Inschrijving (Geschat)
Fase
- Niet toepasbaar
Contacten en locaties
Studie Locaties
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La Defense, Frankrijk
- Werving
- Imagine Institute
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Contact:
- Sophie AF SAUNIER
- E-mail: sophie.saunier@inserm.fr
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Deelname Criteria
Geschiktheidscriteria
Leeftijden die in aanmerking komen voor studie
- Kind
- Volwassen
- Oudere volwassene
Accepteert gezonde vrijwilligers
Geslachten die in aanmerking komen voor studie
Beschrijving
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
Studie plan
Hoe is de studie opgezet?
Ontwerpdetails
- Primair doel: Behandeling
- Toewijzing: Niet-gerandomiseerd
- Interventioneel model: Opdracht voor een enkele groep
- Masker: Geen (open label)
Wapens en interventies
Deelnemersgroep / Arm |
Interventie / Behandeling |
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Ander: 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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Ander: 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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Ander: 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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Ander: 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 |
Wat meet het onderzoek?
Primaire uitkomstmaten
Uitkomstmaat |
Tijdsspanne |
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Positieve of negatieve bevestiging van potentiële therapeutische doelen in uit urine afkomstige nierepitheelcellen van patiënten
Tijdsspanne: 3 jaar
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3 jaar
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Secundaire uitkomstmaten
Uitkomstmaat |
Maatregel Beschrijving |
Tijdsspanne |
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Identificeer biomarkers om de respons op kleine moleculen te evalueren voor de behandeling van NPHP en andere nierciliopathieën.
Tijdsspanne: 3 jaar
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3 jaar
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Experimental transcriptomics data package from in vitro tubule cell model perturbed with disease network modifying agents
Tijdsspanne: 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.
Tijdsspanne: 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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Medewerkers en onderzoekers
Sponsor
Studie record data
Bestudeer belangrijke data
Studie start (Werkelijk)
Primaire voltooiing (Geschat)
Studie voltooiing (Geschat)
Studieregistratiedata
Eerst ingediend
Eerst ingediend dat voldeed aan de QC-criteria
Eerst geplaatst (Werkelijk)
Updates van studierecords
Laatste update geplaatst (Werkelijk)
Laatste update ingediend die voldeed aan QC-criteria
Laatst geverifieerd
Meer informatie
Termen gerelateerd aan deze studie
Aanvullende relevante MeSH-voorwaarden
Andere studie-ID-nummers
- IMIS2015-05
Plan Individuele Deelnemersgegevens (IPD)
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Informatie over medicijnen en apparaten, studiedocumenten
Bestudeert een door de Amerikaanse FDA gereguleerd geneesmiddel
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