Cannabinod receptor 1 inhibition for Treating ciliopathies – CaRTCil

Chronic kidney disease (CKD) is a major public health concern, affecting millions worldwide. Ciliopathies such as ADPKD, ARPKD, and nephronophthisis are genetic disorders that disrupt primary cilium function, leading to cyst formation and renal fibrosis. Current treatments offer limited efficacy in reducing disease progression, underscoring the need for novel therapeutic approaches.
The cannabinoid-1 receptor (CB1R) has emerged as a potential target in kidney diseases, with its inhibition showing promise in reducing renal fibrosis and improving kidney function in various models. Recent findings suggest that CB1R activation may also play a significant role in ciliopathies, influencing both cyst formation and fibrosis.
Therefore our objectives:
1. To demonstrate that CB1R plays a direct role in cyst formation by influencing cilium biogenesis in vitro (Partner 1)
2. To show that CB1R activation occurs across various models of ciliopathies, and that its inhibition—pharmacological or genetic—reduces renal fibrosis, immune cell infiltration, cyst formation and CKD in vivo (Partners 1 and 2)
3. To validate that CB1R activation is a significant factor in the course of human renal ciliopathies
Our preliminary results in vitro showed that CB1R inhibition increases cilia length in MDCK cells, while in vivo models like jck mice revealed elevated CB1R expression in diseased kidneys. These promising results support the hypothesis that CB1R inhibition could slow or halt disease progression in ciliopathies and are part of a patent recenlty filed by Partenr 1.
Given that CB1R inhibitors are already in Phase II clinical trials for obesity, clinical application for ciliopathies could be rapidly translated. The CaRTCil project aligns with ANR’s research themes in physiology and pathophysiology, and the expertise of Partners 1 (specialist of renal fibrosis and endocannabinoids) and Partner 2 (international expert in ciliopathy) ensures a strong foundation for success.