Gene therapy for thrombotic thrombocytopenic purpura (TTP)

Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening microangiopathic disorder caused by a severe deficiency in the plasma metalloprotease ADAMTS13 (A Disintegrin and Metalloprotease with Thrombospondin Type 1 repeats, member 13). This disease is characterized by von Willebrand factor (VWF)- and platelet-rich microthrombi, thrombocytopenia and haemolytic anemia with schistocytes.

In about 5% of the TTP patients, the ADAMTS13 deficiency is caused by bi-allelic mutations in the ADAMTS13 gene (congenital TTP). The use of plasma infusion therapy has increased the survival rate of these patients remarkably. However, lifelong treatment with plasma products is inconvenient, not always effective, expensive and can cause serious complications for these patients. Therefore, gene therapy would be a promising alternative for plasma infusions.

Long-term expression of ADAMTS13 and subsequent prevention of congenital TTP in mice by Sleeping Beauty (SB) transposon-mediated gene therapy has been demonstrated. In this approach, the SB transposon construct was delivered by hydrodynamic injections by our group. Hydrodynamic gene delivery is, however, impractical in patients. Therefore, more clinically relevant gene therapy approaches for congenital TTP will be developed in this PhD project.