Toler8: Uncovering the dynamics of cellular and molecular pathways for immune tolerance in hemophilia A

Hemophilia A (HA), a hemorrhagic disease caused mainly by mutations of the F8 gene, is intensively treated with proteins and, more recently, with GT. One of the most difficult complications is the development of inhibitory alloantibodies to the infused FVIII protein and an immune response to viral vectors and the F8 transgene according to GT.
The Toler8 project aims to unravel new ways to regulate immune tolerance to successful and durable next-generation FVIII therapies by taking advantage of innovative tools and in vivo preclinical models developed by the applicant and collaborators under this proposal. Toler8 specifically aims to:
1. improve knowledge of the mechanisms of immune tolerance and use this knowledge to develop novel approaches that optimize GT and protein therapy that work better than existing approaches.
2. identify biomarkers in preclinical models that enable a personalized approach and therapeutic regimens.
3. translate these preclinical experimental results to HA patients.

By achieving these goals, the project will provide a roadmap for improving basic and translational knowledge of the key molecular and cellular determinants of immune responses to FVIII protein and gene replacement therapies for HA and build an innovation platform that will advance the field of immune tolerance therapies in both PR and GT.