ANR GENESIS : Bertrand Cariou & Antoine Rimbert (2022 - 2024)

• Scientific coordinators (ITX, Team IV: Dyslipidemia and Lipotoxicity):  Bertrand Cariou (MD, PhD) and Antoine Rimbert (PhD)
• Partner 1 (HCL/CarMeN Lyon): Mathilde Di Filippo (PharmD)

Proposal context:
Despite major progress in the treatment against atherosclerotic cardiovascular disease (ASCVD), new therapeutic alternatives are needed for patients at very high ASCVD risk and/or with side effects upon available therapies. Recently, we and others reported that the G protein-coupled receptor 146 (GPR146), a member of the G-coupled protein receptors’ family (widely used in pharmaceutical targeting), is a regulator of plasma cholesterol. Compared to existing LLT-targets, GPR146 hepatic inhibition in mice has unique and promising characteristics with protective effects, not only against hypercholesterolemia and atherosclerosis, but also on liver function. Importantly, in contrast to statins and PCSK9 inhibitors, the mechanism of action of GPR146 signaling on cholesterol homeostasis occurs independently of the LDLR pathway.

Scientific aims:

The present project aims at:

1. Evaluating the druggability-potential of GPR146-inhibition in human. We will systematically look for genetic variations in GPR146 in population cohorts and familial cases of hyper- and hypocholesterolemia and assess their cardiometabolic consequences.
2. Identifying the phenotypic consequences of Gpr146 inhibition in several mouse models with cardiometabolic disorders (dyslipidemia, diabetes, NASH).
3. Refining the GPR146-natural ligand(s) and intracellular signaling pathways in hepatocytes-like cells derived from human iPSC.

Novelty and importance

By validating GPR146 as a new drug target for hypercholesterolemia, GENESIS will have a short-term impact on drug discovery in the management of cardiometabolic diseases. We feel that GPR146 discovery may be the next breakthrough in the cardiovascular research field. Indeed, GPR146 inhibition might offer at least three major advantages compared to already marketed therapies: i) a LDL-c lowering action independent of the LDLR pathway and thus potentially synergistic with statins and PCSK9 inhibitors; ii) a favourable metabolic profile beyond lipid homeostasis, with a beneficial impact on T2D and NAFLD; iii) the opportunity to find small oral molecule inhibitors that antagonize GPR146 signalling.

Consortium description:

ITX (INSERM UMR1087, CNRS UMR1087, UNIV Nantes – CHU Nantes): Bertrand Cariou (scientific coordination, patient recruitment) ; Antoine Rimbert (scientific coordination, genetic analyses) ; Cédric Le May (Lipoprotein metabolism, mouse models) ;  Amandine Caillaud (iPSC, HLCs) ; Vincent Sauzeau & Gervaise Loirand (GPRs Signalling)

HCL (Hospices Civils de Lyon) : Mathilde Di Filippo (genetic analyses) & Philippe Moulin (lipoprotein metabolism, patient recruitment)

External collaborator : Pr Jan-Albert Kuivenhoven (UMCG, The Netherlands)