Gene therapy for hemophilia

Abstract

Hemophilia A and B are X-chromosome linked recessive bleeding disorders that result from a deficiency in factor VIII (FVIII) and factor IX (FIX) respectively. Though factor substitution therapy has greatly improved the lives of hemophiliac patients, there are still limitations to the current treatment that have triggered interest in alternative treatments by gene therapy. Significant progress has recently been made in the development of gene therapy for the treatment of hemophilia A and B. These advances parallel the technical improvements of existing vector systems including MoMLV-based retroviral, adenoviral and AAV vectors, and the development of new delivery methods such as lentiviral vectors, helper-dependent adenoviral vectors and improved non-viral gene delivery methods. Therapeutic and physiologic levels of FVIII and FIX could be achieved in FVIII- and FIX-deficient mice and hemophilia dogs by different gene therapy approaches. Long-term correction of the bleeding disorders and in some cases a permanent cure has been realized in these preclinical studies. However, the induction of neutralizing antibodies often precludes stable phenotypic correction. Another complication is that certain promoters are prone to transcriptional inactivation in vivo, precluding long-term FVIII or FIX expression. Several gene therapy phase I clinical trials are currently ongoing in patients suffering from severe hemophilia A or B. No significant adverse side-effects were reported, and semen samples were negative for vector sequences by sensitive PCR assays. Most importantly, some subjects report fewer bleeding episodes and occasionally have very low levels of clotting factor activity detected. The results from the extensive preclinical studies in normal and hemophilic animal models and encouraging preliminary clinical data indicate that the simultaneous development of different strategies is likely to bring a permanent cure for hemophilia one step closer to reality.

An Adeno-Associated Virus Vector Efficiently and Specifically Transduces Mouse Skeletal Muscle

“…The skeletal muscle is a good platform for the expression of a therapeutic gene [1,2], such as a gene encoding a clotting factor [3], erythropoietin [4,5], or a hormone [6]. The systemic distribution of the transgene product from the skeletal muscle could compensate the insufficiency of the factor in the patient.…”

Haemophilia gene therapy: From trailblazer to gamechanger

“…3,42 As FVIII and FIX proteins are naturally generated by liver sinusoidal endothelial cells (LSECs) and hepatocytes, respectively, the liver is an obvious target organ for gene therapy for haemophilia. 3,42 As FVIII and FIX proteins are naturally generated by liver sinusoidal endothelial cells (LSECs) and hepatocytes, respectively, the liver is an obvious target organ for gene therapy for haemophilia.…”

“…There are several different cell types that are attractive targets to treat haemophilia by gene therapy. 3,42 As FVIII and FIX proteins are naturally generated by liver sinusoidal endothelial cells (LSECs) and hepatocytes, respectively, the liver is an obvious target organ for gene therapy for haemophilia. Both viral and nonviral gene therapy systems targeting LSECs and hepatocytes have been explored.…”

Gene therapy: reality or myth for the global bleeding disorders community?

“…Since that time, two additional clinical studies targeting haemophilia A and two human studies targeting haemophilia B have been initiated [2]. At present, none of the studies has convincingly demonstrated that they hold the key to a cure for either form of haemophilia, yet encouraging signs and substantial evidence have come out of these trials, as well as from related research, which support the optimistic view that gene therapy does indeed hold the key to a cure for haemophilia [3–6].…”