Hemophilia A and B are rare incurable hereditary diseases due to deficiencies in clotting factor VIII (FVIII)\r\nand factor IX (FIX), respectively. These genetic defects result in potentially life-threatening, uncontrolled bleeding\r\nepisodes. Current treatment by protein substitution therapy does not constitute a cure making gene therapy an\r\nattractive alternative. Lentiviral vectors (LVs) have many distinctive features that make them especially well suited for\r\nFVIII or FIX gene delivery. This includes the lack of vector-specific pre-existing immunity, their ability to permanently\r\ntransduce both dividing and non-dividing cells and their capacity to readily accommodate FIX and FVIII expression\r\ncassettes, consistent with their packaging capacity of 10 kb. LVs have been used to achieve sustained therapeutic\r\nclotting factor expression levels and hemostatic correction in preclinical hemophilic mouse models. The liver has been\r\nthe target organ of choice for direct in vivo LV transduction of FVIII or FIX genes, resulting in sustained therapeutic\r\neffects. Nevertheless, the potential development of neutralizing antibodies to the clotting factors following ex vivo\r\nor in vivo gene therapy with LVs can preclude long-term phenotypic correction. These risks can be minimized by\r\npreventing ectopic expression in antigen-presenting cells. LVs are well suited to deliver the clotting factor genes into\r\nhematopoietic stem/progenitor cells, allowing for stable FVIII or FIX expression upon hematopoietic reconstitution.\r\nIn addition, therapeutic FVIII and FIX expression levels have been achieved in vivo after transplantation of lentivirally\r\ntransduced endothelial and mesenchymal stem/progenitor cells. Current challenges relate primarily to the translation\r\nof these findings to larger preclinical animal models and ultimately to patients suffering from hemophilia.
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