Convincing evidence continues to emerge from clinical trials that gene therapy is effective for patients suffering from a wide range of diseases. The main goal of this  project consists of developing gene therapy for  major health- and life-threatening diseases, and to dissect the molecular, cellular and immunologic mechanisms that influence the outcome of these different gene therapy approaches (supported through European grants EU FP6 INTHER & EU FP7 PERSIST).

The formation of a stable blood clot is essential to maintain hemostasis and is dependent on the generation of insoluble fibrin polymers, through a complex interplay of coagulation factors in conjunction with platelet aggregation. Consequently, genetic bleeding disorders can result from either coagulation factor deficiencies (hemophilia A or B) lack of von Willebrand’s factor expression (type 3 von Willebrand’s disease)  or from platelet abnormalities (GATA-1 deficiency). We were the first to establish proof of concept that hemophilia A can be cured by gene therapy in mice suffering from this disease and are building upon this experience to develop effective ,  safe and clinically relevant gene therapy paradigms for these hereditary bleeding disorders (Awarded 2007 Royal Academy of Medicine Secq-Houssiau Prize; supported through European grants EU FP6 INTHER & EU FP7 PERSIST, UK Katherine Dormandy Trust)

Gene therapy may provide an alternative treatment to attain functional correction of the damaged heart but gene delivery into the heart has been particularly challenging and was hampered by the inability to express the therapeutic gene in a sufficient number of cells to achieve therapeutic efficacy. We have recently developed a novel means to deliver genes to the heart using a novel human AAV9 serotype resulting in highly efficient and widespread cardiac gene transfer superior to any previously described gene therapy approach which paves the way towards improved treatment for cardiac dysfunction in Duchenne muscular dystrophy (supported by AFM).

Heart disease remains one of the most prominent health challenges affecting millions worldwide despite many breakthroughs in cardiovascular medicine. Understanding the role of miRNAs in cardiac hypertrophy and heart failure has important fundamental and translational implications, and would provide important new and unique insights into the pathophysiological mechanisms of heart failure. Moreover, it may pave the way towards modulating heart function by interfering with miRNA expression, which represents a conceptually novel approach. Using AAV9 we will over-express different miRNAs and antagomirs and assess their role in cardiac remodelling after acute myocardial infarction.

The development of efficient and safe non-viral vectors would greatly facilitate clinical implementation of ex vivo and in vivo gene therapies using stem cells and other primary target cells. We have explored the use of novel engineered hyperactive transposases derived from Sleeping Beauty by in vitro evolution. These novel transposases resulted in unprecedented and robust gene transfer in CD34+ HSCs, muscle and mesenchymal stem progenitors and liver in vivo paving the way towards an attractive non-viral alternative for viral vectors (supported through European grants EU FP6 INTHER & EU FP7 PERSIST) 

Establishing long-term antigen-specific unresponsiveness in a fully immunocompetent host is required to effectively to prevent or suppress cellular and/or humoral immune responses following allogeneic transplantation and gene therapy and to treat autoimmune diseases and allergy. We are exploring novel strategies to establish immune tolerance towards clinically relevant antigens (eg. clotting factors, allergens) by modulating intracellular signalling pathways using gene transfer (Awarded International  Bayer Hemophilia Award)