Last week ESR5 (Nuno) had his first original research paper of his PhD published!
The study involved a 3.5 years work-process with participations of many of the private and public partners of the PROFILE consortium: Icosagen (Estonia), Sanquin (The Netherlands), KU Leuven (Belgium), Public-Hospitals of Paris and CNR-MAT (France) and Pharmatarget (The Netherlands). It also involved many people in one way or another (both ESRs, principal investigators, technicians and of course TTP patients).
In this paper, Nuno and co-workers show that it is possible to modify the spacer exosite-3 of full-length ADAMTS13 with aminoacid mutations to be able to effectively resist the binding of autoantibodies already existing in immune TTP patients. Concerning the types of mutations introduced, the less conservative the modifications are, the better the modified ADAMTS13 can resist those autoantibodies.
The paper also shows that these modifications in ADAMTS13 spacer exosite-3 generally lead to less activity of the mutant ADAMTS13. However, several of the most resistant full-length ADAMTS13 mutants created are capable of retaining activity levels >10% of the wild-type (up to 35%). The mutations presented in this study may serve as a template to create modified versions of ADAMTS13 that effectively resist the inhibition caused by the autoantibodies of patients, while retaining important levels of activity. Mutant versions of ADAMTS13 can therefore be further developed as innovative enzyme-replacement treatments for immune TTP patients in the future.
The paper is a full open-access publication, and is already publicly available as an epub ahead-of-print in the journal Haematologica and indexed in PubMed. You can access the paper here
We thank everyone involved in this work, especially the patients from CNR-MAT (France) for their invaluable donations of samples used for this study, as well as the European Union for funding this work.