Description of the condition
Haemophilia is an X-linked bleeding disorder characterized by spontaneous or provoked, often uncontrolled, bleeding into joints, muscles and other soft tissues, causing significant pain, swelling and permanent damage if left untreated. Haemophilias are caused by a genetic deficiency of specific proteins in the blood called clotting factors. Haemophilia A is due to an inherited deficiency of factor VIII and haemophilia B is due to a deficiency of factor IX. The incidence of haemophilia A is around 1 per 5000 to 10,000 male births, and about 1 per 60,000 births for haemophilia B. Approximately 80% of affected children are born deficient in factor VIII (haemophilia A) and 20% are deficient in factor IX (haemophilia B) (Bi 1995; Wong 2011). Haemophilias are inherited in an X-linked recessive manner. Hence, haemophilias occur almost exclusively in males, but also in some carrier females due to variances in inactivation of X chromosomes.
The goal, when managing these patients, is to control both the frequency and severity of bleeding episodes and ultimately to prevent permanent joint damage and death in severe cases. Replacement of the missing clotting factor from exogenous sources is the mainstay of therapy in haemophilia. Before World War II, treatment of haemophilia was limited to the transfusion of whole blood or fresh plasma. The first clotting factor concentrate was discovered in the 1960s in the form of cryoprecipitate. In the 1970s, plasma-derived clotting factors were isolated which created a paradigm shift in the management of haemophilia (Brinkhous 1968; Webster 1965). By 1980, the commercially available freeze-dried factor VIII and IX concentrates increased the average lifespan of people with haemophilia to 60 years from a mere 27 years in the 1940s (Evatt 2006; Wong 2011). Early factor VIII and IX concentrates were derived from pooled human plasma from up to 20,000 donors.
Though hepatitis B and C were known risks of pooled human serum derived factor concentrates, they were considered acceptable due to a drastic improvement in the quality of life of people with haemophilia (Kasper 1972; Makris 1990; Mannucci 1977). In 1982 came the first reports of patients with haemophilia succumbing to acquired immune deficiency syndrome (AIDS) and only later it was realized that plasma-derived factor concentrates were responsible for transmission of the still unidentified infectious agent (Aronstam 1993; Gill 1983; Goedert 1989). Nearly 90% of Americans with severe haemophilia have been reported to be infected with HIV in the 1980s via contaminated pooled serum products (NHF 2013). HIV was isolated in early 1984 and by early 1985 heating of factor concentrates became standard practice to kill the virus before transfusion (Wong 2011). Subsequently, several safeguards were employed to prevent donor derived factor transfusion induced infections, such as: donor screening; chromatographic purification; and viral inactivation (Wong 2011). Fortunately, since 1986, there have been no reported cases of HIV transmission through factor concentrates at least in the USA (NHF 2013). The human factor IX gene was cloned in 1982, followed by the production of human rFIX in Chinese hamster ovary cells (Anson 1984; Choo 1982). Factor VIII was cloned and sequenced in 1984 (Gitschier 1984; Toole 1984) and the first recombinant factor VIII (rFVIII) product was approved for clinical use in 1992 (Wong 2011).
The initial treatment modality was episodic or 'on demand' replacement of the missing factor as needed, after the onset of bleeding. However, several studies have shown that prophylactic administration of clotting factor concentrates to prevent bleeding episodes preemptively is more beneficial than episodic administration ( Iorio 2011; Manco-Johnson 2007) The goal of clotting replacement is to keep factor activity greater than one per cent. The currently used adjuvant therapies include the use of antifibrinolytic agents (in both haemophilia A and B) and desmopressin (in mild and moderate haemophilia A only). The antifibrinolytic agents such as e-aminocaproic acid and tranexamic acid exert their effect by inhibiting the proteolytic activity of plasmin and, therefore, inhibiting fibrinolysis (Wong 2011). Desmopressin works mainly by releasing von Willebrand's factor from its storage sites and stabilizing factor VIII in the plasma (Castaman 2008; Leissinger 2001).
Description of the intervention
In gene therapy, a change is made in the genetic material in certain target cells by means of a vector (usually viruses) in such a way that the change is functional and produces an adequate end product so as to correct the defect underlying the disease. In haemophilia, recombinant genetic material is introduced into the target cells which cause production of the clotting factor which is deficient in the disease.
It was first shown in 1989 that human factor IX could be synthesized and secreted into the circulation of laboratory animals after transplantation of genetically modified human fibroblasts using a human factor IX cDNA containing retrovirus (Nathwani 2004; Palmer 1989). Since then, several translational approaches have been developed for the clinical application of gene therapy in haemophilia, but most of these have only resulted in transient benefits (Manno 2003; Manno 2006; Powell 2003; Roth 2001; VandenDriessche 1999; Xu 2003). Finally, in 2011, a new adeno-associated virus (AAV) vector for factor IX gene transduction that could directly be given to an adult by a peripheral vein infusion was developed (Nathwani 2006; Nathwani 2011; Tuddenham 2012).
Gene therapy is not without risk. Introduction of new genetic material via vector viruses may cause unpredictable outcomes due to the alteration of the genetic material (insertional mutagenesis) (Hacein-Bey-Abina 2003; Miller 2005; Nakai 2005), there is a theoretical risk that the viral vector may regain its potential to produce new viral particles, or may cause harmful immune reactions (High 2011; Manno 2003; Mingozzi 2011).
How the intervention might work
The currently available treatment for haemophilia is lifelong clotting factor replacement, a regimen which is both expensive and is not easily available (Iorio 2011; Ponder 2008). Worldwide, about 75% of haemophilia patients do not have access to adequate care (Ponder 2008). Due to the short half-life of the clotting factors in the blood, replacement is required usually every other day for haemophilia A and every two to three days for haemophilia B. The frequency and mode of administration (intravenous (IV)) of these treatment poses a huge range of challenges to people affected with haemophilia and their families (need for IV catheters and related complications such as infections and thrombosis) (Santagostino 2010).
At USD 1 per unit of recombinant factor VIII, the annual cost of on-demand factor replacement therapy for a single 50 kg adult patient of haemophilia is USD 150,000 in the United States of America (Manco-Johnson 2007; Ponder 2011). This cost increases to about USD 300,000 for prophylactic therapy. This amounts to an individual lifetime cost of over USD 20 million in factor replacement costs alone (Ponder 2011). Such an exorbitant therapy is neither available frequently, nor affordable to almost 75% of the people with haemophilia in the world who live in developing countries (Ponder 2008; Ponder 2011). These patients continue to have significant morbidities and die young.
In comparison to the above treatment modalities, gene therapy holds substantial promise. The key advantage being that it is considered to be a one time intervention and permanently curative. This intervention will lead to complete avoidance of the need for IV infusions, reduced hospital visits, a decrease in the use of other interventions and their side effects and ultimately reduced costs (Nathwani 2011). The commercial cost of gene therapy using the viral vector is projected at USD 30,000 per patient (Ponder 2011). Such a therapy would be life changing for the patients.
Why it is important to do this review
Gene therapy holds significant promise of a substantially better treatment modality. Apart from that, gene therapy offers the potential of a lifetime cure, a better quality of life and freedom from various related morbidities. Theoretically, once gene therapy is administered, the affected individual will be asymptomatic with respect to haemophilia. There are still doubts with regards to long-term sustenance of the effects, the unintended consequences or adverse effects and the costs of therapy. We aim to conduct this review in the hopes of answering some of the above questions, specifically in terms of the benefits and safety of gene therapy in comparison to standard treatment in people affected with haemophilia.