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)
Connective Tissue Disorders (PhD Irene Valdivia Callejon - ongoing)
Connective Tissue Disorders (PhD Ivanna Fedoryshchenko - ongoing)
Connective Tissue Disorders(PhD Amira Bousbaa - ongoing)
Connective Tissue Disorders(PhD Katrien De Roeck - 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
Investigating thoracic aortic aneurysm pathogenesis at single-cell resolution.
Thoracic aortic aneurysm (TAA) is an abnormal widening of the aorta in the chest, caused by the weakening of the aortic wall. TAAs can lead to rupture or dissection, a devastating complication with a mortality rate of 50%. Despite considerable efforts to gain insights on the molecular mechanisms underlying TAAs, there is currently no therapy that effectively stops or reverses TAA development. Single-cell RNA sequencing (scRNA-seq) is emerging as a ground-breaking technology to investigate gene expression at single-cell level and is opening new avenues to discover yet unexplored disease pathways. In my project, I will apply this technique to investigate a novel TAA disorder caused by biallelic pathogenic variants in the IPO8 gene, recently discovered in our Cardiogenomics research group. I will search for differentially expressed genes (DEGs) within the different aortic cell populations from an Ipo8^-/- mouse model that recapitulates the human aortic aneurysmal phenotype. I will also investigate shared DEGs between Ipo8^-/- mice and additional TAAs mouse models to find convergent disease pathways in clinically related TAA disorders. Subsequently, I will validate the role of the identified candidate culprits in mouse TAA development in a human setting, by using CRISPR-inhibition or -activation in iPSCs derived vascular smooth muscle cells or endothelial cells. The predicted outcomes will potentially pinpoint novel TAA drivers and hence, unveil potential new therapeutic targets.
PhD student: Irene Valdivia Callejon
Promotors: Aline Verstraeten, Bart Loeys & Josephina Meester
Towards patient-specific aorta-on-a-chip models for thoracic aortic aneurysm and dissection.
Thoracic aortic aneurysm (TAA) denotes a progressive enlargement of the thoracic aorta, entailing a significant risk for life-threatening aortic dissection and/or rupture. At present, mouse models are often used to investigate and therapeutically target the molecular defects underlying TAA, as native aortic samples of patients and, especially, control individuals are hard to collect. Yet, murine in vivo studies are often lengthy and drug testing results did previously not always recapitulate in patients. With the advent of induced pluripotent stem cells (iPSCs), the field is closing in on apt solutions to faithfully model patient and control aortas in a dish. The currently available vascular smooth muscle cell (VSMC) or endothelial cell (EC) monocultures are still overly simplified, as they fail to adequately replicate the complex multilayered and multicellular structure of the aorta. Taking advantage of available iPSCs from syndromic TAA patients (FBN1 & IPO8), my project aims to 1) develop and consolidate the validity of the first iPSC-derived TAA aorta-on-a-chip models, comprising the two VSMC subtypes populating the native ascending aorta along with a layer of arterial ECs, and 2) use the established model to further investigate the disease mechanisms underlying the relatively unexplored IPO8 syndrome. The anticipated outcomes will contribute to the replacement of mouse models (3R principle) and expedite pathophysiological TAA research and drug discovery.
PhD student: Ivanna Fedoryshchenko
Promotors: Aline Verstraeten, Bart Loeys, Ilse Luyck
Thoracic aortic aneurysm (TAA) refers to progressive enlargement of the thoracic aorta. It often remains unnoticed until aortic dissection or rupture occur, which are associated with high mortality rates. Available drug therapies slow down TAA progression but fail to prevent the associated lethal complications. TAA is a hallmark of Loeys-Dietz syndrome (LDS), a rare connective tissue disorder characterized by an early onset and aggressive TAA course.
Leveraging the in-house expertise in induced pluripotent stem cell (iPSC)-based disease modeling and both clinical and pathophysiological LDS research, I aim to be the first to develop an LDS iPSC-derived aorta-on-a-chip (AoC) model, which comprises both endothelial cells and vascular smooth muscle cells, and mimics the concentric-layered structure of the native aorta. Following establishing and validating a control proof-of-concept model, I will demonstrate exhibition of the known LDS pathomechanisms and drug responses in SMAD3 patient AoCs. Moreover, I will investigate if the LDS-AoCs can accurately recapitulate between-patient variability in TAA severity. This novel pre-clinical tool will enable the exploration and therapeutic targeting of LDS mechanisms in a human setting that mimics the native aorta better than ever before. Additionally, the expected outcomes will hold a broader significance for aortic diseases, as the AoC expertise developed within this project can be extended to other TAA conditions and/or aortopathies.
Thoracic aortic aneurysm (TAA) is a life-threatening disease characterized by progressive aortic dilation and risk of dissection or rupture for which no true cure exists. Phenotypic severity varies among carriers of the same mutation and/or within single families. Sex is an important determinant of clinical heterogeneity, with men developing TAA earlier and more frequently, while affected women show faster progression and worse outcomes. Hitherto, these sex-dependent mechanisms in TAA remain poorly understood. This project aims to contribute to the elucidation of the cellular and molecular underpinnings of sex differences in TAA using single-cell RNA sequencing (scRNA-seq) in an Ipo8⁻/⁻ mouse model displaying significant sexual dimorphism. To assess the phenotypic and molecular contribution of sex hormones to disease development, gonadectomy will be combined with longitudinal echocardiography and scRNA-seq. Via genetic or pharmacological modulation, the top candidate sex-dependent modifying pathway’s causal link with TAA development will be validated.
Overall, this project establishes fundamental sex‑dependent mechanisms in TAA in mouse models, providing a basis for subsequent translation to human disease and, if confirmed, ultimately enabling more precise, sex‑informed therapeutic strategies.
PhD student: Katrien De Roeck
Promotors: Aline Verstraeten en Bart Loeys