Urine sample-derived human induced pluripotent stem cells as a model to study PCSK9-mediated autosomal dominant hypercholesterolemia

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1. The document describes research from the l’institut du thorax on proprotein convertase subtilisin/kexin type 9 (PCSK9) and its role in cholesterol regulation. 2. Gain-of-function mutations in PCSK9 are associated with hypercholesterolemia, while loss-of-function mutations are linked to lower cholesterol levels and potential cardioprotective effects. This has led to the development of a new class of cholesterol-lowering drugs. 3. The researchers generated induced pluripotent stem cells from patients with PCSK9 gain-of-function and loss-of-function mutations. Differentiating these into hepatocyte-like cells

Health & Medicine

l’institut du thorax, unité Inserm UMR 1087-CNRS UMR 6291, IRS-UN, 8 quai Moncousu, BP 70721, 44007 Nantes Cedex 1, France www.umr1087.univ-nantes.fr
Transatlantic network of Excellence
2014-2019
The proprotein convertase subtilisin/kexin type 9 PCSK9
PCSK9 Mutations : Gain-of-function -> Hypercholesterolemia
Loss-of-function -> Low level of circulant cholesterol, cardioprotector effects
-> Development of a new class of cholesterol-lowering drug
R104C/V114A
(LOF)
S127R
(GOF)
PCSK9 protein structure
Schulz & Schlüter Basic Res Cardiol (2015) 110:4
1 Episomal reprogramming of UCells isolated from a healthy donor and
the patient carrying the PCSK9-S127R Gain of function mutation
UCells UhiPSCs
2
UhiPS cells differentiate into hepatocytes recapitulate
PCSK9-GOF and LOF features in vitro3
Karim Si-Tayeb1, Méryl Roudaut1,2, Amandine Caillaud1, Aurore Girardeau1, Matthieu Pichelin1, Lucie Arnaud1,
Cédric Le May1, Nathalie Maubon2, Bertrand Cariou1
1L’institut du thorax, INSERM, CHU Nantes, Nantes France 2HCS Pharma, Lille, France
5 3D hepatic differentiation of UhiPS cells enhanced the expression of
genes involved in cholesterol metabolism regulation
3D scaffolds formed by
crosslinking of
Hyaluronic Acid with
ADH (Adipic Acid Di-
Hydrazide) to form
reticulated chains.
Control and PCSK9-S127R hepatocytes responded to pravastatin treatments
and mutated cells displayed a stronger response in accordance
with related patients clinical responses
http://dmm.biologists.org/lookup/doi/10.1242/dmm.022277
Gene expression
4
Functional tests
Si-Tayeb, Lemaigre & Duncan
Developmental Cell 2010
Differentiation
- Cytotoxicity (necrosis/apoptosis)
- Genotoxicity (gH2AX, comet…)
- Hepatoxicity (phospholipidosis,
steatosis, cholestasis…)
- Target of interest (expression,
localisation and trafficking)
- Phenotypic modification (stress,
proliferation, differenciation, …)
- Lipid (LDL-C, TG)
- Glucid metabolism
- ADME (CYP, UGT, transporters
activities…)
PharmacologyToxicology Metabolism
6 HIGH CONTENT SCREENING (HCS) – PHENOTYPIC SCREENING
Ongoing hiPSC-to-hepatocyte 3D-differentiation protocole setup
2(-DeltaCt)2(-DeltaCt)2(-DeltaCt)
2(-DeltaCt)
2(-DeltaCt)
2(-DeltaCt)
2(-DeltaCt)
2(-DeltaCt)
2(-DeltaCt)
2(-DeltaCt)2(-DeltaCt)
High throuput
differentiation

A broad range of reprogramming systems is available including mRNA reprogramming, dox-inducible human 4F2A reprogramming and lentivirus reprogramming. These technologies have been adopted and developed in close collaboration with leading iPS cell pioneers. Our extensive range of products allows for customization of individual transcription factors, cell culture conditions, and delivery systems for the optimization of reprogramming parameters. https://www.creative-bioarray.com/Services/Custom-iPS-Cell-Services.htm

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metabolic diseases upon hepatocyte-like cell (HLC) differentiation. In particular, HLCs have been used to model cholesterol metabolism regulation, by mimicking the main disease features in vitro. Human iPSCs can be generated from urine samples of patients with a well-described phenotype and carrying specific genotypes. This non-invasive approach allowed the study of LDLR- and PCSK9-mediated autosomal dominant hypercholesterolemia (ADH) as well as PCSK9-mediated familial hypobetalipoproteinemia (FHBL). While the direct link between hiPSCs and patients, as well as the abundance of HLCs provide promising advantages of such strategy, it is impaired mainly by the neonatal characteristic of HLCs as well as the difficulty to perform high throughput studies for pharmacological investigations.

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According to the Texas Department of State Health Services, there are approximately 17.7 million adults (age 18+) living in Texas, of which 1.47 million have diabetes. In 2010, 341,430 adult Texans were diagnosed with diabetes for the first time. What is the incidence of diabetes in Texas? Express your answer in units of per 1000 persons per year. Solution 191 Patients with hepatocellular carcinoma (HCC) within Milan criteria receive priority on the liver transplant(LT) waiting list(WL) and compete with non-HCC candidates. We compared dropout from the WL using a competing risks approach to assess the relative access to transplant for these two groups. The cohort consists of all candidates listed 4/14/04 - 12/31/2007 with HCC candidates identifi ed via initial exception application. Status 1 and pediatric patients were excluded. Dropouts included removals for candidate death, too sick, and for other. A multivariable waiting list analysis was performed using a Cox model of time to dropout and competing risks model. Results: Non-HCC patients had a signifi cantly higher dropout rate from the WL compared with HCC patients over one year after listing/exception. This was reproducible across all regions. Ablation had little infl uence on HCC dropout. Larger tumor size, higher MELD score and/or AFP were associated with increased dropout. Multivariable analysis with competing risks showed that MELD, log AFP, max tumor size were of signifi cance in predicting dropout for HCC patients. % dropout Days after Listing 30 60 90 180 365 Non-HCC All MELD 6.5 9 10.6 13.9 17.9 No Ablation 2.2 4 6 9.2 11.8 Ablation 1.4 3.1 4.7 8 11.2 Non-HCC MELD <21 1.4 2.9 4.4 8.1 13.1 HCC + MELD < 8 0.6 1.4 1.9 4 6.6 HCC + MELD 8-11 0.9 2.4 3.7 6.1 8.5 HCC + MELD 11-14 1 2.8 4.3 7.8 10.3 HCC + MELD >14 3.9 6.6 9.4 13.9 17.7 Tumor < 2 cm 0.9 2.6 4.9 8.2 11.2 2-2.6 1.8 3.4 5.1 8 10.4 2.6-3.3 2.3 3.8 5.2 8.4 11.1 > 3.3 2 4.4 6.3 10 13.4 AFP < 500 1.7 3.2 4.8 7.5 10.2 500-1000 2.8 6.4 9.2 15.3 18.2 >1000 4 8.3 13 21.8 27.8 Conclusions: HCC patients appear to be advantaged in the current allocation scheme as shown by lower dropout rates. This advantage is consistent through the UNOS regions. A continuous score incorporating MELD, AFP and tumor size would help prioritize HCC with non-HCC patients to help equate dropout rates and equalize the allocation scheme. Abstract# 4 Primary Outcomes from a Randomized, Phase III Study of Belatacept vs Cyclosporine in Kidney Transplant Recipients (BENEFIT Study). F. Vincenti,1 J. M. Grinyo,2 B. Charpentier,3 J. D. Medina-Pestana,4 L. Rostaing,5 Y. Vanrenterghem,6 G. B. Di Russo,7 P. Garg,7 C.-S. Lin,7 C. Larsen.8 1UCSF; 2Univ Hospital of Bellvitge; 3Hopital Bicetre; 4Hospital do Rim e Hipertensao Unifesp; 5CHU Ranguell; 6Univ Hospital Kuleuven; 7Bristol-Myers Squibb; 8Emory Univ School of Medicine. Introduction: Belatacept, a co-stimulation blocker, is being developed as an immunosuppressant for kidney transplant recipients to avoid the renal and.

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We previously showed that human pluripotent stem cells (hiPSCs) provide a suitable model to study metabolic diseases upon hepatocyte-like cell (HLC) differentiation. In particular, HLCs have been used to model cholesterol metabolism regulation, by mimicking the main disease features in vitro. Human iPSCs can be generated from urine samples of patients with a well-described phenotype and carrying specific genotypes. This non-invasive approach allowed the study of LDLR- and PCSK9-mediated autosomal dominant hypercholesterolemia (ADH) as well as PCSK9-mediated familial hypobetalipoproteinemia (FHBL). While the direct link between hiPSCs and patients, as well as the abundance of HLCs provide promising advantages of such strategy, it is impaired mainly by the neonatal characteristic of HLCs as well as the difficulty to perform high throughput studies for pharmacological investigations. Therefore, to overcome these burdens, we choose to 1. Differentiate hiPSCs into HLCs in a 3D environment instead of the classical 2D culture systems to enhance their maturation; 2. Adapt our 3D differentiation process to a 96 wells format to make it compatible for drug screening. To reach our goals, we established a partnership with HCS Pharma, which has an expertise in high content phenotypic screening and produces an innovative 3D scaffold, BiomimesysTM. This scaffold is composed of hyaluronic acid that can be functionalized with extra cellular matric derivatives, with adjustable stiffness and porosity. We setup conditions for hiPSCs seeding and differentiation to reach a new protocol adapted to a 3D environment. Our preliminary data indicate that our procedure enhanced expression of hepatic markers such as transcription factors (FOXA2, FOXA3, HNF1a, HNF1b, HNF4a), cytochrome P450 (CYP450) family members (CYP3A4, CYP2A6, CYP7A1) or cholesterol metabolism regulators (PCSK9, Lipoprotein(a)). During our presentation, we will discuss our data hiPSCs differentiation in 3D, CYP450 activities and induction, as well as their application for the study of metabolic diseases.

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