Abstract
Platelets are small anucleated blood components primarily described as playing a fundamental role in hemostasis and thrombosis. Over the last decades, increasing evidence has demonstrated the role of platelets in modulating inflammatory reactions and immune responses. Platelets harbor several specialized organelles: granules, endosomes, lysosomes, and mitochondria that can synthesize proteins with pre-stored mRNAs when needed. While the functions of platelets in the immune response are well-recognized, little is known about the potential role of platelets in immune tolerance. Recent studies demonstrate that platelet-specific FVIII gene therapy can restore hemostasis and induce immune tolerance in hemophilia A mice, even mice with preexisting anti-FVIII immunity. Here, we review the potential mechanisms by which platelet-targeted FVIII gene therapy restores hemostasis in the presence of anti-FVIII inhibitory antibodies and induces immune tolerance in hemophilia A.
Highlights
Platelets are the second most common type of cells found in blood, with approximately 1011 newly produced daily to replenish the old platelets in the body [1, 2]
Further studies by Shi et al [32] using 2bF8 transgenic mouse models showed that the preformed von Willebrand factor (VWF)/factor VIII (FVIII) complex is vital for optimal platelet gene therapy of hemophilia A with inhibitors
Without VWF, the level of platelet-FVIII significantly decreased, and while hemostatic efficacy was still maintained in hemophilia A mice in the absence of inhibitors, it was limited in the presence of anti-FVIII inhibitors. These results demonstrate that VWF is essential to platelet-targeted gene therapy in hemophilia A with inhibitors
Summary
Platelets are the second most common type of cells found in blood, with approximately 1011 newly produced daily to replenish the old platelets in the body [1, 2]. Platelets are loaded with abundant bioactive proteins and circulate in the blood, serving as both a storage “depot” and trafficking “vehicle” in circulation. Due to these characteristics, platelets may be a unique target for gene therapy of diseases. Platelet-Targeted Gene Therapy stem cells (HSCs) can induce antigen-specific immune tolerance in hemophilia A mice even with preexisting anti-FVIII immunity [22,23,24]. We discuss the potential mechanisms of platelet-targeted FVIII expression in restoring hemostasis for hemophilia A in the presence of anti-FVIII inhibitors and inducing immune tolerization after platelet-specific gene therapy
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