The most severe complication in Hemophilia A treatment is the development of inhibitory antibodies towards the infused therapeutic factor, and gene mutations represent a key determinant. In principle "null mutations" should confer the highest risk. However, nonsense mutations, albeit causing severe/moderate phenotypes, appear to  be associated with a lower risk to develop inhibitory antibodies as compared with large F8 gene alterations. This might underlie traces of circulating full-length factor VIII (FVIII) resulting from the spontaneous suppression of nonsense mutations through a process named "ribosome readthrough", which is driven by miss-recognition of the nonsense triplet and incorporation of an amino acid at the nonsense position.

This basal recoding of a nonsense codon to a coding triplet, albeit occurring at low rates (less than 1% of translation events), may ensure the production of "protective" FVIII traces with potential pathophysiological implications in relation to the inhibitor risk, with high impact on quality of life of Hemophilia A patients.

The main aim of the proposed project is to investigate, through complementary studies in patients' plasma and an in-vitro expression platform, the association of F8 nonsense mutations with residual full-length FVIII protein, and the relationship with immunological complications after replacement therapy. 

Curriculum Vitae

Dr. Alessio Branchini holds a post-doc position at the Department of Life Sciences and Biotechnology at the University of Ferrara (Italy). After a BSc degree in Molecular and Cellular Biology (2004) and a MSc in Biomolecular and Cellular Sciences (2006), he received his PhD in Biochemistry, Molecular Biology and Biotechnology in 2011 with a PhD thesis on the structure/function relationships of the carboxyl-terminal region of coagulation factors VII and X.

His research activity is mainly focused on the identification and characterization of genetic defects responsible for, or models of, blood coagulation disorders including Hemophilia. The knowledge of the mechanisms underlying coagulation disorders has laid the foundation for the design of engineered variants and/or correction approaches, acting at the translational or post-translational level, based on small molecules to rescue folding-defective variants (i.e. chaperone-like compounds) or to suppress nonsense mutations (ribosome readthrough). In particular, he demonstrated the interplay between nucleotide and protein context in dictating the readthrough output in terms of secreted protein and functional features.

He has presented his works in several national and international congresses, with his research being awarded by different societies including International Society on Thrombosis and Haemostasis (young investigator awards at ISTH congresses in 2011, 2013 and 2015) and the European Haematology Association (EHA congress in 2016). He has also supervised research projects on Haemophilia and has been involved in several national and international projects as collaborator. Finally, he is also involved in teaching activities in the BSc and MSc in Biology at the University of Ferrara and serves, and has served, as reviewer for international journals and grant applications.

Contact
Department of Life Sciences and Biotechnology
University of Ferrara
Via Fossato di Mortara, 74,
44121, Ferrara, Italy
e-mail: brnlss@unife.it