Gene Therapy for Thrombotic Thrombocytopenic Purpura

Thrombotic Thrombocytopenic Purpura (TTP) is a rare (~1 case per 200,000) but life-threatening disease which is characterised by the presence of thrombi within the microvasculature, commonly within the brain, heart and kidney. Congenital TTP manifests through mutations within the ADAMTS13 gene, with symptoms presenting in early childhood (<5 years of age) or later in life. However in the majority of cases TTP is acquired during adulthood through the production of auto-antibodies against ADAMTS13 protein. ADAMTS13 is a metalloprotease enzyme which cleaves large von Willebrand factor (VWF) multimers in the plasma, reducing their size and consequently reducing their platelet-capturing potential. Reduced cleavage of thrombogenic, ultra-large VWF multimers through deficient ADAMTS13 can lead to the spontaneous, wide-spread accumulation of platelet-rich thrombi which can block arterioles and capillaries.

If these acute attacks are left untreated, thrombi accumulation within the microvasculature causes organ failure and death in 90% of cases.
Individuals with congenital and acquired TTP receive regular plasma infusions and exchanges to restore ADAMTS13 levels and to remove auto-antibodies. Individuals suffering an acute TTP attack, usually precipitated by an additional genetic or vascular insult such as pregnancy or trauma, are treated with daily plasma exchange until recovery. Despite current treatments reducing mortality rates to 20%, the high treatment burden and reliance on donor plasma warrants the development of a novel therapy for TTP. Gene therapy offers an alternative treatment which could prevent the onset of life-threatening acute TTP episodes while reducing the significant morbidity associated with donor-derived plasma exchange.

I hypothesise that pulmonary gene transfer may enable the lung to act as a factory for ADAMTS13 production. A lentiviral vector, specifically optimised for lung gene transfer, has been used previously for the production of systemic proteins in the lungs of mice, achieving therapeutic plasma protein levels and providing proof-of-principle for lung-targeted gene therapy for TTP. I will attempt to develop a treatment for TTP by restoring ADAMTS13 expression and plasma activity levels in a knockout mouse model as well as an acquired TTP mouse model. A conditional expression cassette will be developed so that ADAMTS13 expression can be induced or silenced at times when risk of acute TTP episodes are increased e.g. during pregnancy. In summary, gene therapy has the potential to significantly improve upon the limited treatment options currently available for TTP, which are associated with significant mortality and morbidity and treatment burden to patients.