This project unites leading experts in CRISPR engineering, synthetic biology, cartilage tissue engineering and translational OA models. This project aims to directly addresses the challenges of cell therapy (donor-to-donor variation, cell phenotype instability, lack of potency in inflammatory microenvironment) by integrating precise gene editing with “sense-and-response” gene circuits and allogenic MSCs and chondrocyte cell sources. Through extensive genotype and phenotype profiling and preclinical validation, we will establish the therapeutic efficacy of engineered cells, standardize the cell production, and design a scalable manufacturing pipeline for future clinical translation to produce an accessible and reliable therapy to tackle this recalcitrant disease.
By deploying precise genome editing tools, this project aims to model clinically observed single-nucleotide variants associated with different cartilage-related disorders in articular chondrocytes to determine how these mutations impact chondrocyte function and cartilage tissue properties. By identifying these variant-specific effects, the project can provide information about the pathogenic mechanisms behind different genetic diseases affecting cartilage, but also about overall cartilage biology. Additionally, the work will relate to osteoarthritis pathology, since the cellular pathways in mutation-driven cartilage disorders can overlap with mechanisms that drive the progressive cartilage degeneration in osteoarthritis.
Intestinal dysbiosis has been recently implicated in the pathogenesis of myriad of diseases. However, the mechanisms how intestinal dysbiosis could result in a disease pathogenesis is mostly unknown. Therefore our aim is to elucidate how bacteria derived products, in particular lipolysaccharides (LPS) activate the immune system, and the mechanisms how our body limits the proinflammatory impact of the large LPS load originating from the terminal ileum and large intestine, mouth and skin. We also search for means to target these mechanisms for therapeutic purposes. Areas of particular interest include the role of different LPS structures in immune activation in joints and in arterial wall, and the mechanisms of desensitization to lipopolysaccharides. To study the significance of metabolic endotoxemia in human diseases we take advantage of unique large cohorts of healthy persons and patients with Osteoarthritis and rheumatic diseases.