Recent Advances and Future Perspectives in Lentiviral Gene Therapy for Hemophilia A and B

Janka Mátrai,Thierry Vandendriessche,Marinee K L Chuah

doi:10.4172/2157-7412.s1-004

Abstract

Hemophilia A and B are rare incurable hereditary diseases due to deficiencies in clotting factor VIII (FVIII) and factor IX (FIX), respectively. These genetic defects result in potentially life-threatening, uncontrolled bleeding episodes. Current treatment by protein substitution therapy does not constitute a cure making gene therapy an attractive alternative. Lentiviral vectors (LVs) have many distinctive features that make them especially well suited for FVIII or FIX gene delivery. This includes the lack of vector-specific pre-existing immunity, their ability to permanently transduce both dividing and non-dividing cells and their capacity to readily accommodate FIX and FVIII expression cassettes, consistent with their packaging capacity of 10 kb. LVs have been used to achieve sustained therapeutic clotting factor expression levels and hemostatic correction in preclinical hemophilic mouse models. The liver has been the target organ of choice for direct in vivo LV transduction of FVIII or FIX genes, resulting in sustained therapeutic effects. Nevertheless, the potential development of neutralizing antibodies to the clotting factors following ex vivo or in vivo gene therapy with LVs can preclude long-term phenotypic correction. These risks can be minimized by preventing ectopic expression in antigen-presenting cells. LVs are well suited to deliver the clotting factor genes into hematopoietic stem/progenitor cells, allowing for stable FVIII or FIX expression upon hematopoietic reconstitution. In addition, therapeutic FVIII and FIX expression levels have been achieved in vivo after transplantation of lentivirally transduced endothelial and mesenchymal stem/progenitor cells. Current challenges relate primarily to the translation of these findings to larger preclinical animal models and ultimately to patients suffering from hemophilia.

Highlights

Hemophilia A and B are congenital bleeding disorders caused by a deficiency of functional clotting factors, factor VIII (FVIII) or factor IX (FIX), respectively, owing to mutations in the cognate genes
We demonstrated that stable therapeutic levels of FVIII could be achieved following intravenous γ-retroviral vectors (γ-RVs) injection in neonatal hemophilia A mice [44]
FVIII is more immunogenic than FIX, consistent with the higher incidence of inhibitors in patients suffering from hemophilia A (40%) than hemophilia B (5%)

Summary

Introduction

Hemophilia A and B are congenital bleeding disorders caused by a deficiency of functional clotting factors, FVIII or FIX, respectively, owing to mutations in the cognate genes. Since FVIII and FIX play a key role in the coagulation cascade, patients are suffering from uncontrolled bleeding episodes and chronic damage mostly in soft tissues, joints and muscles. Patients remain at risk for life-threatening bleeding episodes and chronic joint damage Another important drawback of the current therapy is that some patients can develop neutralizing antibodies (i.e. inhibitors) specific for the administered FVIII or FIX proteins. Patients with severe hemophilia (< 1% FVIII or FIX) either do not produce any FVIII or FIX or express dysfunctional proteins instead rendering these patient’s immune system intolerant to the therapeutic protein, appearing as neo-antigens The presence of these inhibitors can render further therapy ineffective and makes bleeding episodes extremely difficult to manage. Population-based patient-control studies revealed that FVIII levels above 150% are associated with increased thrombotic risk [8]

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