Research Pauline De Kinderen

Abstract

Chondrodysplasias refer to a large and heterogeneous group of skeletal disorders caused by primary defects in hyaline cartilage. They have a combined prevalence of about 1/4000 births and differ considerably with respect to disease severity; with some only inflicting mild joint symptoms, and others coming with severe dwarfism or even perinatal lethality. Especially the complications that arise from major growth problems (e.g. respiratory difficulties, spinal cord compression, hydrocephaly) impact significantly on the patient's quality of life. For many chondrodysplasias no therapies are on the market yet. Over the past years, endoplasmatic reticulum (ER) stress and the resulting excess of apoptosis have emerged as convincing converging chondrodysplasia pathomechanisms. This project builds further on these findings and aims to significantly improve future chondrodysplasia patient management by 1) establishing the protocols to create and study iPSC-chondrocytes as well as to use them for high-throughput drug screening approaches, with a primary focus on COL2A1 and BGN-related dysplasias, 2) investigating whether ER stress and UPR activation play a role in the etiology of BGN-related chondrodysplasia (i.e. a pathomechanistically unexplored severe form of dwarfism), and 3) developing and applying a novel iPSC-chondrocyte-based high-throughput high content assay to discover putative drug candidates that promote protein folding in ER stress-related chondrodysplasias.

Researcher(s)

• Promoter: Verstraeten Aline
• Co-promoter: Meester Josephina
• Fellow: De Kinderen Pauline

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Heterozygous missense mutations in the collagen type II-encoding gene COL2A1 explain about 95% and 70% of the hypochondrogenesis and spondyloepiphyseal dysplasia congenita patients, respectively, as well as a smaller fraction of patients with closely related phenotypes. Prior functional characterization of iPSC-derived and transdifferentiated chondrocytes of carriers of COL2A1 missense mutations revealed increased expression of endoplasmatic reticulum (ER) stress and apoptosis markers in addition to reduced levels of cartilage matrix proteins. Abnormal procollagen folding is considered a key pathogenic skeletal dysplasia mechanism, rendering chaperone-oriented therapy an interesting pharmacological avenue. Subjecting iPSC-chondrocytes of a COL2A1 glycine substitution carrier to a drug library comprising roughly 2,400 chaperone agonists and antagonists, we aim to identify a highly potent novel drug for skeletal dysplasias attributed to COL2A1 missense mutations. To evaluate the compounds' efficiency in restoring the cellular phenotype, integrated high content quantification of collagen type II as well as apoptosis and ER stress markers will be done. The most interesting compounds will be tested in knock-in COL2A1 mice to establish in vivo performance.

Researcher(s)

• Promoter: Verstraeten Aline
• Fellow: De Kinderen Pauline

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project