Alternative Strategies for Gene Therapy of Hemophilia

Abstract

Hemophilia A and B are monogenic disorders that were felt to be ideal targets for initiation of gene therapy. Although the first hemophilia gene therapy trial has been over 10 years ago, few trials are currently actively recruiting. Although preclinical studies in animals were promising, levels achieved in humans did not achieve long-term expression at adequate levels to achieve cures. Transplantation as a source of cellular replacement therapy for both hemophilia A and B have been successful following liver transplantation in which the recipient produces normal levels of either factor VIII (FVIII) or factor IX (FIX). Most of these transplants have been conducted for the treatment of liver failure rather than for “curing” hemophilia. There are a variety of new strategies for delivering the missing clotting factor through ectopic expression of the deficient protein. One approach uses hematopoietic stem cells using either a nonspecific promoter or using a lineage-specific promoter. An alternative strategy includes enhanced expression in endothelial cells or blood-outgrowth endothelial cells. An additional approach includes the expression of FVIII or FIX intraarticularly to mitigate the intraarticular bleeding that causes much of the disability for hemophilia patients. Because activated factor VII (FVIIa) can be used to treat patients with inhibitory antibodies to replacement clotting factors, preclinical gene therapy has been performed using platelet- or liver-targeted FVIIa expression. All of these newer approaches are just beginning to be explored in large animal models. Whereas improved recombinant replacement products continue to be the hallmark of hemophilia therapy, the frequency of replacement therapy is beginning to be addressed through longer-acting replacement products. A safe cure of hemophilia is still the desired goal, but many barriers must still be overcome.

The gene therapy journey for hemophilia: are we there yet?

“…14 Because most trials will now include a provision for high-dose steroids if a rise in liver enzymes occurs, it will be difficult to include those who are HCV RNA viral load-positive. Strategies that target other organs, including megakaryocytes, 47,48 the joints themselves, 49 and skeletal muscle, 50,51 have been proposed, and the latter has undergone safety testing in clinical trials. 22,52 Transduction of hematopoietic cells with retroviral or lentiviral vectors expressing FVIII under the control of a platelet-specific promoter, followed by transplantation of the autologous gene-modified cells, has been carried out successfully in hemophilic mice 53 and has been shown to effect hemostasis even in mice with inhibitors.…”

Donor antigen-primed regulatory T cells permit liver regeneration and phenotype correction in hemophilia A mouse by allogeneic bone marrow stem cells

“…Gene knockout studies have recently confirmed that endothelial cells (ECs) are the principal source of plasma FVIII [ 2 , 3 ]. In treatment of HA, gene replacement therapy showed initially encouraging results in life-long correction of HA in animal models [ 4 – 6 ], although the outcome of the phase I clinical trial was not conclusive; there was a gradual loss of its potency because of the formation of inhibitors [ 7 ]. As an alternative to gene therapy, transplantation of LSECs has shown encouraging therapeutic benefits in HA mice [ 8 ].…”

Cross‐cultural adaptation and linguistic validation of age‐group‐specific haemophilia patient‐reported outcome (PRO) instruments for patients and parents

“…The main treatment available today is the infusion of concentrated plasma‐derived or recombinant clotting factor into the vein, either as prophylaxis or as on‐demand treatment . A recent Cochrane systematic review concluded that there was strong evidence that prophylaxis preserves joint function in children with haemophilia compared with on‐demand treatment .…”