The aim of this thesis was to work towards pre-clinical proof-of-concept for NOTCH3 cysteine corrective exon skipping as a rational therapeutic approach for CADASIL. To address all aspects required... Show moreThe aim of this thesis was to work towards pre-clinical proof-of-concept for NOTCH3 cysteine corrective exon skipping as a rational therapeutic approach for CADASIL. To address all aspects required for therapeutic development, the work performed for this thesis included not only in vitro testing of NOTCH3 exon skipping in CADASIL patient derived vascular smooth muscle cells and studies into the function of the cysteine corrected proteins, but also the generation of a relevant humanized in vivo model, pre-clinical biomarker development, and studies defining prevalence, spectrum and characteristics of NOTCH3 mutations worldwide. Show less
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease leading to destruction of cartilage and bone. The inflammation in the joints is mainly caused by inflammatory cytokines that are... Show moreRheumatoid arthritis (RA) is a chronic inflammatory joint disease leading to destruction of cartilage and bone. The inflammation in the joints is mainly caused by inflammatory cytokines that are over-produced by various types of immune cells. Artritis is an autoimmune disease that is characterized by the presence of autoantibodies. These autoantibodies form immune complexes (IC) which are other important players in joint inflammation because they activate various immune cells by binding to Fc receptors (FcR). Binding and activation of FcRs initiates intracellular signaling that triggers activation and release of various inflammatory mediators. In this thesis we describe a variety of aspects of arthritis research that has been performed to get a better understanding of the underlying molecular and cellular disease mechanisms and to develop novel therapeutic strategies. Show less
