Escape or Fight: Inhibitors in Hemophilia A.

Simone Merlin,Antonia Follenzi

doi:10.3389/fimmu.2020.00476

Simone Merlin, Antonia Follenzi

Open Access

https://doi.org/10.3389/fimmu.2020.00476

Copy DOI

Abstract

Replacement therapy with coagulation factor VIII (FVIII) represents the current clinical treatment for patients affected by hemophilia A (HA). This treatment while effective is, however, hampered by the formation of antibodies which inhibit the activity of infused FVIII in up to 30% of treated patients. Immune tolerance induction (ITI) protocols, which envisage frequent infusions of high doses of FVIII to confront this side effect, dramatically increase the already high costs associated to a patient's therapy and are not always effective in all treated patients. Therefore, there are clear unmet needs that must be addressed in order to improve the outcome of these treatments for HA patients. Taking advantage of preclinical mouse models of hemophilia, several strategies have been proposed in recent years to prevent inhibitor formation and eradicate the pre-existing immunity to FVIII inhibitor positive patients. Herein, we will review some of the most promising strategies developed to avoid and eradicate inhibitors, including the use of immunomodulatory drugs or molecules, oral or transplacental delivery as well as cell and gene therapy approaches. The goal is to improve and potentiate the current ITI protocols and eventually make them obsolete.

Highlights

The major complication of replacement therapies in hemophilia A (HA) is the formation of inhibitors, anti-factor VIII (FVIII) antibodies directed against and inhibiting the function of infused FVIII
Our group recently demonstrated that targeting FVIII expression in endothelial cells, mainly liver sinusoidal endothelial cells (LSEC), using a lentiviral vector (LV) containing the endothelial-specific vascular endothelial cadherin (VEC) promoter, results in sustained expression of therapeutic levels of FVIII in HA mice without inhibitor formation, even after immunization
This study demonstrated the presence of the vector genome for more than 1 year, even though the vector copies drastically decreased after 8 weeks (>100-fold) and at the final time point, 1.5 years, were more than 400-fold lower [93]

Summary

Introduction

The major complication of replacement therapies in hemophilia A (HA) is the formation of inhibitors, anti-FVIII antibodies directed against and inhibiting the function of infused FVIII. Oral delivery of FVIII antigens was able to revert a pre-existing immunity to FVIII by significantly reducing inhibitor titers during 2–3 months of feeding, with a subsequent analysis suggesting the activation of Tregs in tolerized mice when compared to control animals [42].

Results

Conclusion