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Friday, 5 December, 2014 - 13:00
Prof Alain Hovnanian
Small Lecture Theatre, MSI

<p>Alain Hovnanian is full professor of Genetics and Dermatology at the new IMAGINE Institute for Genetic diseases at Necker hospital for sick children in Paris. He runs a translational clinic on genetic skin diseases of children and adults. He heads the molecular diagnostic group for genodermatosis and is the director of an INSERM research team on &ldquo;Genetic skin diseases: from molecular mechanisms to therapy&nbsp;&raquo;. His specific interests include epidermolysis bullosa, Netherton syndrome, keratinizing disorders including pachyonychia congenita and Olmsted syndrome, Darier disease and Hailey-Hailey disease. He is the coordinateor of the European GENEGRAFT project which is a phase I/II clinical trial for <em>ex vivo</em> gene therapy for recessive dystrophic epidermolysis bullosa using autologous skin equivalents genetically corrected with a safe SIN <em>COL7A1</em> retroviral vector (<br />

<p>Netherton syndrome (NS) is an orphan genetic skin disease with extensive red, scaly and itching skin, associated with severe inflammation and allergic manifestations. NS is due to loss of function mutations in <em>SPINK5</em> encoding LEKTI, a secreted multi-domain serine protease inhibitor expressed in stratified epithelia. Studies in murine models and in NS patients have established that several unopposed protease activities are involved in the disease pathophysiology, including kallikrein-related peptidases (KLKs) 5, 7 and 14, as well as elastase 2. These proteases contribute to different extend to a profound skin barrier defect through <em>stratum corneum</em> detachment, abnormal profilaggrin processing and impaired stratum corneum lipid composition. They also activate PAR-2 and pro-IL1b, leading to the production of pro-allergic and pro-inflammatory mediators which attract immune and inflammatory cells in the skin, resulting in the production of Th2 and Th-17 cytokines. The severe skin barrier defect triggers skin inflammation which aggravates the defective skin barrier. This complex network of deleterious effects initiated by loss of protease inhibition was uncovered in <em>Spink5</em> knock-out and in Tg-hKLK5 murine models, and was confirmed in NS patients. This emerging knowledge on NS pathogenesis has disclosed a central role of protease regulation in skin homeostasis, systemic inflammation and in allergy. These results have disclosed part of the complexity of the disease and hold the promise of new specific treatments</p>