Chondrodysplasias

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Chondrodysplasia

Background

Chondrodysplasias are rare genetic disorders affecting the hyaline cartilage. This cartilage tissue is found in several areas of the human body, including the ears, nose, ribs, joint surfaces. It has an important function in the growth plate, the location in the bone where longitudinal growth takes place. Hyaline cartilage also forms the temporary skeleton during embryogenesis, which is gradually replaced by bone. Chondrodysplasia patients are clinically characterized by skeletal manifestations such as bone and joint deformities of the limbs, trunk, and skull as well as varying degrees of dwarfism. More than 400 different chondrodysplasias have been identified so far. In the last decade, the application of the massively parallel sequencing technology has boosted the discovery of the underlying genetic defect for many of these disorders, resulting in the identification of more than 400 different disease genes. However, to date, the downstream effects of these genetic defects remain largely unknown. Furthermore, no pharmacological treatment exists for many chondrodysplasias and current surgical treatment options (such as limb lengthening) are often highly invasive and have a major impact on a child's life. With many patients and families seeking for better treatment options, new pathomechanistic and preclinical research is urgently needed.

Goal

With our research we aim to provide new pathomechanistic insights in chondrodysplasias, and enable the development of new therapeutic strategies to treat patients with chondrodysplasias. As such we want to improve the quality of life of patients with chondrodysplasias.

Strategy

In our ongoing research projects, we use state-of the-art techniques (such as transcriptomics, interactomics, proteomics) in both mouse models and patient-specific induced pluripotent stem cell (iPSC)- derived chondrocyte models of different chondrodysplasias to gain pathomechanistic insights in these disorders. Based on these new insights, novel therapeutic targets and drug compounds are selected and tested in pre-clinical disease models.

Recently, we are also focusing on the comparison of pathomechanisms of both the vascular and skeletal system in chondrodysplasias and aneurysmal thoracic aortopathy, as increasing evidence suggests an important molecular and functional intersection between both organ systems in these phenotypically distinct disorders.

Disorders under investigation:

COL2A1-related chondrodysplasias (Stickler syndrome, spondylo-epiphyseal dysplasia congenita), BGN-related chondrodysplasia (X-linked spondyloepimetaphyseal dysplasia), Marfan syndrome

Team members:

Aline Verstraeten, Bart Loeys, Josephina Meester, Silke Peeters, Pauline De Kinderen, Anne Hebert, Laura Rabaut, Maaike Bastiaansen, Jarl Bastianen, Jolien Schippers, Sofie Daemen, Charlotte Claes

Connective Tissue Disorders (PhD Anne Hebert - ongoing)
Connective Tissue Disorders (PhD Pauline De Kinderen - ongoing)

Using human iPSC-derived models to investigate the divergent pathomechanisms underlying biglycan-related Meester-Loeys syndrome and X-linked spondyloepimetaphyseal dysplasia.
Pathogenic variants in biglycan cause two divergent phenotypes: Meester-Loeys syndrome (MRLS) and X-linked spondyloepimetaphyseal dysplasia (SEMDX). The latter is characterized by a disproportionate short stature and caused by missense variants. MRLS, on the other hand, is a syndromic form of thoracic aortic aneurysm that is caused by loss-of-function variants. Intriguingly, MRLS patients with partial biglycan deletions present with a more severe skeletal phenotype. To date, discriminative pathomechanisms explaining why certain biglycan mutations cause MRLS and others SEMDX remain elusive. This PhD project aims to answer this research question using induced pluripotent stem cells (iPSCs) of both patient groups and their respective (isogenic) controls. IPSC-based disease modeling provides a unique opportunity for pathomechanistic investigation in a patient-, variant- and cell type-specific manner. After the creation of disease-relevant patient-derived iPSC-vascular smooth muscle cells and -chondrocytes, I will identify cell type-specific differences between MRLS and SEMDX using (1) functional assays tailored to existing pathomechanistic insights, and (2) hypothesis-free transcriptomic and proteomic approaches. Finally, I will investigate the mutational effect of partial biglycan deletions to establish a specific MRLS genotype-phenotype association.
PhD student: Anne Hebert
Promotors: Josephina Meester, Bart Loeys & Aline Verstraeten
The study and therapeutic targeting of endoplasmic reticulum stress in hereditary chondrodysplasias.
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.
PhD student: Pauline De Kinderen
Promotors: Aline Verstraeten, Josephina Meester & Geert Mortier