जेनेटिक सिंड्रोम और जीन थेरेपी जर्नल
खुला एक्सेस

अमूर्त

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

Janka Matrai, Marinee K. L. Chuah and Thierry VandenDriessche

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.