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Cellular tools for metabolic diseases

Investigating the aetiology of various inherited disorders is often hampered by the lack of appropriate tools. A cell-based system could address these limitations and help resolve the impact of mutations in metabolic diseases.

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Because of its high incidence (1/300), familial hypercholesterolemia (FH) remains a public health burden. Therefore, in order to enhance patients’ care, numerous strategies are studied to decrease the cholesterol level in the bloodstream. Since the discovery of the role of PCSK9 in the regulation of cholesterol homeostasis, 12 years of fundamental and clinical research led to a beneficial feedback to the patient with the development of PCSK9 inhibitors, under the form of monoclonal antibodies directed against PCSK9. These new drugs have just been approved as they reduced LDL-cholesterol levels up to 60 % in association or not with statins in hypercholesterolemic patients. However, questions still remain unsolved. Genetic analysis of patients in the area of Nantes notably, led to the discovery of mutated forms of PCSK9 that remained trapped inside hepatocytes and induced FH through a mechanism that is still unknown. This lack of knowledge is mainly due to the fact that current research models are not suitable because they are too different from the patient patho-physiology. Therefore, scientists on the EU-funded IPSMILD (Human induced pluripotent stem cells as a model to study metabolic inherited liver diseases) project set out to develop preclinical tools and models from pluripotent stem cells generated with these specific patients in order to study PCSK9 intracellular functions. The generation of patient’s specific hiPS cells involved the use of adult cells from the patient, which are usually cells isolated from skin biopsies or blood samples. In order to simplify this procedure, the scientists used a very common, convenient and easy way to obtain human sample: the urine. In their resource article published in Disease Models and Mechanisms, the team showed how it is possible to isolate cells from urine samples, amplify them, reprogramme them into hiPS cells and then instruct them to become liver cells. Starting with urine samples of patients from the Nantes area, they showed that it was possible to model the effects of PCSK9 mutations on LDL uptake in a petri dish. The IPSMILD cellular tool is anticipated to help future research on dissecting metabolic disease mechanisms and screening potential therapeutic molecules for familial hypercholesterolemia.


Metabolic diseases, hypercholesterolemia, mutation, PCSK9, urine, induced pluripotent stem cells

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