Cell-based therapy for Congenital Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) is a severe blood disorder characterised by the presence of microangiopathic haemolytic anaemia, thrombocytopenia and purpura caused by thrombi in the small vessels of many organs. It is caused by a deficiency of ADAMTS13, which is produced by hepatic stellate cells and released into the circulation where it cleaves von Willebrand factor (vWF) multimers secreted by endothelial cells. In the absence of ADAMTS13, ultra-large vWF multimers accumulate on the surface of blood vessels causing the formation of microthrombi. TTP can be hereditary caused by alterations in the ADAMTS13 gene or acquired due to the presence of autoantibodies that inhibit the protein activity. The hereditary form of the disease is rare with an estimated incidence of 1 case per million. Patients are treated with plasma infusions which are generally effective but can have complications, such as allergic and anaphylactic reactions and carry the risk of infection. Our project aims to develop a new therapeutic approach based on the generation of universal induced pluripotent stem cells that are invisible to the patient's immune system. The cells will be induced to become hepatocytes, stellate cells and endothelial cells with which we will generate mini livers in the laboratory. Our hypothesis is that these tissues, once transplanted, release constant therapeutic levels of functioning ADAMTS13 into the circulation protecting the patient from possible relapses. The ability of the mini livers to release the functional ADAMTS13 protein will be evaluated by transplanting them into experimental models.