Mechanistic Insights into Factor VIII Immune Tolerance Induction via Prenatal Cell Therapy in Hemophilia A.

Abstract

Prenatal stem cell and gene therapy approaches are amongst the few therapies that can promise the birth of a healthy infant with specific known genetic diseases. This review describes fetal immune cell signaling and its potential influence on donor cell engraftment, and summarizes mechanisms of central T cell tolerance to peripherally-acquired antigen in the context of prenatal therapies for Hemophilia A. During early gestation, different subsets of antigen presenting cells take up peripherally-acquired, non-inherited antigens and induce the deletion of antigen-reactive T-cell precursors in the thymus, demonstrating the potential for using prenatal cell and gene therapies to induce central tolerance to FVIII in the context of prenatal diagnosis/therapy of Hemophilia A. Prenatal cell and gene therapies are promising approaches to treat several genetic disorders including Hemophilia A and B. Understanding the mechanisms of how FVIII-specific tolerance is achieved during ontogeny could help develop novel therapies for HA and better approaches to overcome FVIII inhibitors.