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Therapies for Renal Ciliopathies

Project description

Advancing diagnosis and treatment of paediatric ciliopathies

Many cells feature primary cilia on their surface, which are microtubule-based antennae crucial for controlling essential signalling processes during development and tissue maintenance. Dysfunctional cilia can lead to ciliopathies, rare genetic disorders with diverse symptoms. Common morbidities associated with ciliopathies include chronic kidney disease and end-stage kidney disease, necessitating dialysis and transplantation. The EU-funded TheRaCil project, leveraging European patient databases, biocollections, robust preclinical models, and AI-based tools, aims to enhance diagnosis, prognosis, and treatment options for paediatric renal ciliopathies. The research includes repurposing therapeutic molecules and the use of antisense oligonucleotides to directly target kidney gene variants. Additionally, researchers will identify disease modifier genes and biomarkers, and refine patient stratification for improved treatment eligibility criteria.

Objective

Ciliopathies are a large group of rare and severe genetic diseases caused by dysfunction of the primary cilium, a microtubule-based cell surface antenna that controls key signaling output required during development and tissue homeostasis. Cilium dysfunction leads to complex disorders with high genetic heterogeneity and overlapping phenotypes. Despite the broad clinical spectrum, chronic kidney disease (CKD) leading to end stage kidney disease (ESKD) is a common cause of morbidity across ciliopathies. Currently, the only available standard of care for CKD is based on dialysis and transplantation. Renal ciliopathies represent a main cause of ESKD during childhood and despite the identification of more than 40 causative genes, it remains difficult to predict the severity of the disease as well as the risk of appearance (if not present at diagnosis) and the rate of progression of renal failure. TheRaCil therefore aims: (1) to improve diagnosis and prognosis of at risk pediatric renal ciliopathy patients, and (2) to implement therapeutic approaches aimed at targeting shared pathological pathways, at modifying mRNA targets of the causative or modifier genes by antisense oligonucleotides and by the repurposing of available molecules. These goals will be achieved through the federation of our unique databases of pediatric renal ciliopathies cases available across Europe, which will allow a better stratification of patients, the identification of modifier genes and markers of disease progression. Bioinformatics approaches will be used to integrate patients’ biological and genetic data as well as multi-omics and functional analyses from patients samples and preclinical models. These analyses should lead to the identification of shared targetable pathological pathways as well as of patients eligible for the identified new therapeutic approaches which will be evaluated in robust preclinical models.

Coordinator

IMAGINE INSTITUT DES MALADIES GENETIQUES NECKER ENFANTS MALADES FONDATION
Net EU contribution
€ 1 989 483,05
Address
24 BD DU MONTPARNASSE
75015 Paris
France

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Region
Ile-de-France Ile-de-France Paris
Activity type
Research Organisations
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Total cost
€ 1 989 483,05

Participants (13)

Partners (2)