Collaboration between “Institut du thorax” and HCS Pharma: improving the management of hypercholesterolemia using a relevant and innovative organoid-based in vitro liver model

Launched in 2016, the adventure is coming to an end after 5 years of work carried out within the RHU CHOPIN (CHOlesterol Personalized INnovation), and with a strong collaboration between HCS Pharma and l’Institut du thorax. This collaborative project of national scope was led by Professor Bertrand Cariou, director of the Thorax Institute at the IRS-UN (8 quai Moncousu, Nantes). It was based on a consortium of scientists and clinicians and on a public-private partnership that brought together 8 institutional partners and 6 private partners.

Familial hypercholesterolemia (FH) is an inherited genetic disease, associated to elevated blood LDL-cholesterol (LDL-c) levels from birth, regardless of lifestyle, diet, or weight. Chronic exposure to elevated LDL-c levels causes early cardiovascular events (women <60 years, men <55 years).

The objective of the CHOPIN medical-scientific project was to implement personalized management of hypercholesterolemia by:

• Identifying new functions of PCSK9 (major role in cholesterol metabolism)
• Identifying new cardiovascular protective factors in familial hypercholesterolemia
• Evaluating the long-term consequences of high LDL levels
• Identifying new genetic targets in LDL metabolism

This was successfully achieved through:

• The constitution of cohorts of patients with extremely high levels of LDL-c to identify new genes involved in cholesterol metabolism.

• The validation of therapeutic targets using an innovative cellular model: human hepatocytes derived from human induced pluripotent stem cells (hiPSCs).

In this frame, the collaboration between HCS Pharma and l’institut du Thorax has allowed to highlight a new role of PCSK9 by NODAL regulation signaling pathway and cellular proliferation in hiPSCs (cf. publication: https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(21)00539-7) and to develop a protocol of differentiation of hiPSCs into liver organoids in a 3D hydroscaffold of hyaluronic acid called BIOMIMESYS® (produced by HCS Pharma)  

A patent is being submitted and will be followed by another publication on the topic (you can see a poster with preliminary results on the right, please contact us to get a higher quality version)