Academy and industry join forces to tackle TTP

Bleeding and coagulation

TTP, thrombotic thrombocytopenic purpura, is a rare and potentially life-threatening blood disease. It causes bleedings and blood clots in the small vessels at the same time. Excessive clot formation due to uncontrolled adhesion of blood platelets at sites of vascular injury may lead to organ damage or even death. Jan Voorberg: “TTP is a blood-related autoimmune disorder and therefore highly relevant to the mission of Sanquin in transfusion medicine. That’s why TTP has been subject of investigation at Sanquin for several years now. Moreover, patients are treated with plasma from donors, which is collected and processed here at Sanquin”.

ADAMTS13

Acquired TTP is caused by autoantibodies against the plasma protein ADAMTS13, the enzyme that cuts polymers of the pro-hemostatic protein Von Willebrand factor (VWF) into smaller fragments. Autoantibodies targeting ADAMTS13 prevent the processing of polymeric VWF. Platelets will stick to the ultra-large VWF polymers, which leads to blood clots, mainly consisting of platelets. Because platelets are depleted from the blood, also small bleeds presenting as petechiae on the skin can occur.

Plasma exchange

“With PROFILE we want to offer patients a better perspective”, Jan Voorberg explains. Currently, patients are treated with plasma exchange, usually in combination with immunosuppressants. With plasma exchange the autoantibodies are removed from the plasma and at the same time patients are supplied with ADAMTS13 from donor plasma. Plasma exchange is a cumbersome treatment, patients may need dozens of plasma bags during an attack.

“We want best treatment for each patient”

PROFILE hopes to improve current treatments and develop new  therapies to stop and prevent attacks, and offer new diagnostics. Jan Voorberg: “We now diagnose TTP by measuring ADAMTS13 activity. For the future, we want to develop tests that can tell us additionally which patients are prone to experience a new  attack, and when. Or predict how much donor plasma is needed. Our aim is the best treatment for each patient by developing personalized medicine approaches for patients with acquired TTP. By working together with industrial partners it will be easier to develop scientific discoveries towards novel tests and treatments”.

Where are we now?

After two years the project is halfway through. “Already a couple of papers have been published”, Jan Voorberg says. “We have developed a new assay for studying the conformation of ADAMTS13 in patients. New tests and novel therapeutic possibilities are on their way”. In 2017, the PROFILE network organized a Bootcamp in Entrepreneurial Innovations in Rare Diseases.

Three of the six PhD students of the PROFILE network are supervised by Jan Voorberg. Nuno Graca, Johana Hrdinova and Bogac Ercig spend two years at Sanquin, and two years at an industrial partner. They each have their own approach. (Photo: ESR team, www.itn-profile.eu/tag/ttp/)

Recombinant ADAMTS13 variants

Nuno started working for PROFILE in Estonia two years ago, at a company named Icosagen. This company is specialized in producing recombinant proteins. He has been making recombinant ADAMTS13 variants there. Nuno: “The idea is to design a variant that is not recognized by the patients’ antibodies, as they enhance clearance of ADAMTS13 and block the enzyme's activity. But we must be cautious with modifying the protein, as it can also lose activity due to that change alone”. Nuno started at Sanquin only recently and brought his panel of mutants. He tested them first thing when he arrived. The results are promising. “I hope I will have a variant that in the future can be applied for initial treatment and also to prevent relapses, without suppressing the entire immune system”.

Etiology of TTP

Johana focusses on deciphering the etiology of TTP. At Sanquin she investigated CD4+ T cell responses in TTP patients in order to find a specific region of ADAMTS13 that is responsible for the onset of autoimmunity. This information might help with further development of targeted TTP treatment. Currently, she is seconded at PharmaTarget in Maastricht, where she investigates ADAMTS13 protein and autoantibody structure.

Bioinformatics

Bogac is also working in Maastricht now. He is using computational approaches to design small molecule therapeutics. Bogac: ”My project is about investigating the structure and function of ADAMTS13. I am using state-of-the-art structural bioinformatics methods. I hope that together with the other ESRs within PROFILE I can come up with a candidate product which would ease the life of TTP patients".

The young scientist were all attracted to the international character of PROFILE and highly appreciate the cooperation between academy and industry. And the collaboration within Sanquin. “My colleagues from Sanquin are very nice, friendly people,”  Johana says. “I have learned to not be ashamed to ask some of my more experienced colleagues for advice. That sometimes saves a lot of time. They are always willing to help and provide me with valuable input”. Nuno is also learning a lot from his new colleagues at Sanquin: "There is so much knowledge of the immune system here.” He’s also happy with the easy access to patient samples. On 16 April the PROFILE training network will organize a seminar and workshop at Sanquin.

About PROFILE

The PROFILE Innovative Trainning Network (European Industrial Doctorates programme) aims at stratifying acquired thrombotic thrombocytopenic purpura (TTP) patients by understanding disease pathology, using new types of biomarkers and predicting their risk for relapse.

The outcome of the PROFILE project will be crucial for treatment adjustment in these patients and development of personalized medicine in the future. To stratify acquired TTP patients (or any other patients with an autoimmune disorder), a unique research approach and specialized translational training programme is needed.

Within the PROFILE network Sanquin closely collaborates with Prof. Karen Vanhoorelbeke from the KU Leuven, Belgium, Coordinator of PROFILE and supervisor of ESRs Kadri Kango, Silvia D'Angelo and Leydi Carolina Velasquez Pereira, Belgium, and from Paris, France Prof. Paul Coppo and Prof. Agnes Veyradier, TTP expert clinicians .

What is Horizon 2020?

Horizon 2020 is the biggest EU Research and Innovation program ever with nearly €80 billion of funding available over 7 years (2014 to 2020) – in addition to the private investment that this money will attract. It promises more breakthroughs, discoveries and world-firsts by taking great ideas from the lab to the market.