PROFILE (www.itn-profile.eu) is an Innovative Training Network funded by the Horizon 2020 Marie Sklodowska-Curie Actions program. Its major focus is the improvement of diagnosis, treatment, and understanding of the pathophysiology of a rare but life-threatening autoimmune disease called immune-mediated thrombotic thrombocytopenic purpura (iTTP). One year ago, we published a Q&A with three PROFILE early-stage researchers (ESRs), Kadri Kangro, Carolina Velàsquez Pereira, and Nuno Graça in HemaTopics.1 With less than one year left until the project ends, it is time for an update in the form of a short interview with the remaining 2 PROFILE ESRs, Bogac Ercig and Johana Hrdinova.
“WHAT ARE YOU CURRENTLY WORKING ON?”
Bogac: “These days, I am investigating the development of CD4+ autoreactive T-cells, which results in ADAMTS13 autoantibody production. The goal of this project is to find which part of ADAMTS13 is responsible for the onset of autoimmunity.”
Johana: “I am investigating ADAMTS13 structure and the structural changes that occur upon autoantibody binding. Furthermore, together with Bogac, we have designed peptides with potential to inhibit the binding of platelets to the von Willebrand factor (vWF) and are currently testing their efficacy.”
“How could your work benefit patients?”
Bogac: “Deciphering the major immunogenic domains in ADAMTS13 is crucial for the design of novel ADAMTS13 variants that could escape autoantibody binding and could therefore be used for iTTP therapies. We also hope that this information can help us to better understand the etiology of iTTP.”
Johana: “Having a three-dimensional (3D) structure of ADAMTS13 (or any other protein) is important because it can be used as a starting point for the computational design of novel therapeutics. ADAMTS13 structural studies are, however, extremely challenging due to its high structural flexibility. This is also the reason why, even 18 years after ADAMTS13 was described at a molecular level, we do not know its full structure. Full structural understanding, is a pre-requisite to being able to modify ADAMTS13, as Bogac has just described.”
“Why do you think there is still need to design novel iTTP therapeutics?”
“Thanks to our translational training at the Assistance Publique-Hôpitaux de Paris with Prof. Coppo and Prof. Veyradier and contact with iTTP patients, we understand that there are still many unmet needs with existing treatments. Current frontline therapy consists of plasma exchange and corticosteroids. Rituximab is also being used for treatment of patients with iTTP. Treatment with caplacizumab (a nanobody preventing the binding of platelets to vWF) has been shown to be beneficial during the acute phase of the disease. The major issue for the patients is the exhaustion associated with plasma exchange therapy and the necessity to be hospitalized. For patients with recurrent iTTP, this can make it impossible to return to the life they had before disease onset. Many patients on current therapeutics are not able to return to their job, for example. We feel that it is important to define the etiology of iTTP, which may ultimately help us to design novel therapeutic strategies that allow for the eradication of autoantibodies and the prevention of relapses in patients with iTTP. At the same time, we are also aiming to improve therapy during the acute phase of the disease by designing autoantibody-resistant ADAMTS13 variants and small compounds that limit platelet adhesion.”
“Do you already know if you will be able to achieve the goals before the PROFILE project ends?”
“We strongly hope so. However, bringing a novel therapeutic agent to the market, thus making it accessible for patients, is always a long-term project.”
“What are the next steps?”
Bogac: “We aim to reach a better understanding of the development of the disease from an immunology perspective. This is why we are currently working with TTP patient material, using state-of-the-art methods to investigate the differences between healthy donors and TTP patients at a cellular level. This research will demonstrate what risk factors actually give rise to TTP and how we can prevent them from occurring or relapsing.”
Johana: “We have finished the initial structural studies and hope that we have understood the bottleneck in obtaining a 3D structure. As we collaborate with top experts in the field of protein structural studies and have access to excellent facilities, we will improve the settings, broaden the techniques used, and hopefully get a 3D structure of ADAMTS13. Regarding the vWF-platelet inhibitory peptides, we have successfully set up and screened our first promising candidate and will move towards screening other selected candidates and their fine-tuning.”
“Which part of your study do you find the most exciting?”
“Surely the opportunity to work together with iTTP experts from academia but also industry and clinics. This helps us to broaden our perspective. Also, meeting with patients from time to time gives us an extra motivation to reach our goals. Presenting our data at a national and international level is an exciting experience, but what we would value the most is that our findings improve the current treatment of patients with iTTP.”
Are you interested in rare diseases? Then register for our Innovation Bootcamp in Rare Diseases that will be held on 4–5 November 2019 in Leuven (https://www.itn-profile.eu/bootcamp-innovation-rare-diseases).
1. Vanhoorelbeke K, Velàsquez Pereira C, Kangro K, et al. PROFILE: early-stage researchers advancing insights in TTP through a unique PhD track. HemaSphere.