Novel mechanisms of action of emerging therapies of hereditary thrombotic thrombocytopenic purpura

Abstract

Introduction: Hereditary thrombotic thrombocytopenic purpura (hTTP) is caused by deficiency of plasma ADAMTS13 activity, resulting from ADAMTS13 mutations. ADAMTS13 cleaves ultra large von Willebrand factor (VWF), thus reducing its multimer sizes. Hereditary deficiency of plasma ADAMTS13 activity leads to the formation of excessive platelet-VWF aggregates in small arterioles and capillaries, resulting in hTTP.

Areas covered: PubMed search from 1956 to 2024 using thrombotic thrombocytopenic purpura and therapy identified 3,675 articles. Only the articles relevant to the topic were selected for discussion, which focuses on pathophysiology, clinical presentations, and mechanisms of action of emerging therapeutics for hTTP. Current therapies include infusion of plasma, or coagulation factor VIII, or recombinant ADAMTS13. Emerging therapies include anti-VWF A1 aptamers or nanobody and gene therapies with adeno-associated viral vector or self-inactivated lentiviral vector or a sleeping beauty transposon system for a long-term expression of a functional ADAMTS13 enzyme.

Expert opinion: Frequent plasma infusion remains to be the standard of care in most parts of the world, while recombinant ADAMTS13 has become the treatment of choice for hTTP in some of the Western countries. The success of gene therapies in preclinical models may hold a promise for future development of these novel approaches for a cure of hTTP.

Keywords: ADAMTS13; TTP/HUS; inflammation; pathogenesis; therapeutic; von Willebrand factor.

Figure. 1.. Current and novel therapeutics for hTTP.

Over the past decades, there are multiple therapeutic modalities being developed for the treatment and prophylaxis of hTTP. Counterclockwise, these are: 1) The standard of care is infusion of fresh frozen plasma (FFP) which offers an episodic replacement of ADAMTS13; 2) an infusion of plasma derived FVIII concentrates, which may modestly increase ADAMTS13 activity but more importantly enhance VWF proteolysis by the residual ADAMTS13; 3) an infusion of recombinant ADAMTS13, the first and only FDA approved ADAMTS13 replacement therapy, which may achieve high levels of ADAMTS13 without concern of plasma-associated side effects; 4) anti-VWF A1 targeted therapies including aptamers and caplacizumab are approved for the treatment of iTTP but not hTTP; and 5–8) various gene therapies, which offer a long-term or more sustained correction of severe ADAMTS13 deficiency, include an in-utero gene transfer, an ex vivo transduction and transplantation of hematopoietic progenitor cells (HPCs) with a lentiviral vector encoding human full-length ADAMTS13, an intravenous injection of an adeno associated viral vector (AAV)-mediated expression of human MDTCS fragment in Adamts13^−/− mice, and a liver-specific expression of murine Adamts13 in Adamts13^−/− mice using Sleeping Beauty (SB) transposon-mediated gene expression system. The properties of each modality and the potential mechanisms of action are described in each box next to each therapy. Notes: Green (#1–3), current therapies; Orange (#4), approved therapies for iTTP, but not tested in hTTP; Yellow (#5–8), therapies in the preclinical testing, but not yet being developed for therapy for hTTP.