Over the past century, the development of treatments for hemophilia has seen remarkable progress. People with hemophilia in the early 1900s had a life expectancy of 13 years, while today, most patients with hemophilia can expect to live a nearly normal life (1). Back then, there was no way of storing blood and victims often died of excessive and prolonged bleeding. The discovery of blood clotting factors and a way for scientists to derive these clotting factors led to the development of a preventive treatment (1). Recent advancements include clotting factors that last longer and can be made without human or animal blood. Despite these advancements, the majority of people with hemophilia in the world receive little to no treatment, resulting in high morbidity and mortality rates (2). The development of gene therapy serves as a potential cure for hemophilia, eliminating the need for continuous treatment, thus offering hope for wider access to treatment.
Hemophilia is an inherited bleeding disorder that severely reduces the ability of blood to clot, causing prolonged external and internal bleeding. In hemophilia, the normal clotting process is disrupted due to defects in the genes responsible for producing clotting factors. These clotting factors are essential since they stop bleeding and let the wound heal. The two most common forms of the disease are hemophilia A, which is caused by a deficiency in clotting factor VIII, and hemophilia B, which is caused by a deficiency in clotting factor IX (3). The severity of hemophilia is determined by how much of the clotting factor is in the patient’s blood and can be classified as mild, moderate or severe. About 60 percent of those with hemophilia have the severe form of the condition (4). Patients with severe hemophilia have a complete absence of clotting factor VIII or IX, resulting in spontaneous bleeding that can cause permanent damage to the joints and soft tissues. Those with mild or moderate hemophilia are less likely to experience spontaneous bleeding and generally experience prolonged bleeding from injuries.
The standard treatment for people with hemophilia involves the regular administration of exogenously derived clotting factors. While this treatment has significantly improved quality of life and life expectancy for individuals with hemophilia, its effectiveness is limited due to the need for frequent infusions, the development of inhibitors and the high cost of treatment. Factor concentrates have relatively short half-lives, resulting in the need for two to three infusions administered intravenously per week. Factor VIII has a half-life of 8-12 hours, while Factor IX has a half-life of 18-24 hours (5). Patients also develop inhibitors to factor concentrates, which reduces the efficacy of infused clotting factors. An estimated one-third to one-fifth of people with severe hemophilia A develop inhibitors sometime in their lives (6). These inhibitors are a result of an immune response to the factor concentrates and destroy the foreign clotting factor before it has a chance to stop the bleeding, making treatment more difficult. Another complication is the significant financial costs associated with factor concentrates, resulting in variations in access to standard treatment around the world. One study designed to assess the cost of severe hemophilia in Europe, reveals that the average annual cost per patient across five countries in 2014 was estimated to be around $200,000 (7). The high cost and need for frequent injections explain the ineffectiveness of treatment, especially in less developed countries.
Gene therapy works by inserting a functional version of the defective gene into a cell using a viral vector, enabling the cell to produce the missing clotting factor. In terms of treating hemophilia, several different gene delivery vehicles have been tested, but the most success has been found in using a recombinant adeno-associated virus to deliver the clotting factor gene (8). These viruses have been designed to be safe since all pathogenic genes have been removed. The vector is delivered to a patient’s liver cells, since the FXIII and FIX clotting factors are naturally produced there. This then enables the liver cells to produce and secrete functional clotting factors into the bloodstream, helping prevent future bleeding (3).
The results of several clinical trials using adeno-associated virus gene therapy to treat hemophilia have been promising and have sparked a race towards a cure. At present, a handful of pharmaceutical companies have gene therapy products being assessed in phase three clinical trials, meaning it might be available as a treatment soon (8). One trial involving 15 adults with severe hemophilia A with a follow-up found that the mean annualized rate of bleeding events decreased by over 90 percent and the median use of exogenous clotting factor was reduced from 138.5 infusions to 0 infusions per year (9). Additionally, the follow-up revealed that three years after the gene therapy, sufficient levels of clotting factor XIII remained in the subjects to allow for normal clotting (9). Another trial involving 10 adults with severe hemophilia B has shown similar results with a 90 percent reduction in bleeding episodes. A long-term follow-up at six years has shown stable clotting factor IX expression and no latent toxicity in the subjects (10). These results are encouraging and have proven gene therapy can effectively treat hemophilia.
While the future of hemophilia patients looks bright, several questions still remain about the mechanisms and long-term safety of gene therapy as a novel therapeutic means. Vector-induced liver inflammation, for example, remains a challenge that is not yet fully understood, yet can be harmful to subjects (11). Liver inflammation occurs when the liver cells are attacked by a pathogen, resulting in possible liver damage and impaired liver function. Additionally, controversies about gene therapy increasing the risk of oncogenesis-a process transforming normal cells into cancerous cells-remain unresolved (11). On the bright side, these problems are not inherent to gene therapy; they are inherent to the vector. By improving the vector design, safety risks can be significantly reduced. Despite these challenges, treatments for hemophilia have come a long way and there is hope for a cure on the horizon. The most significant benefit of gene therapy would be in the developing world, where access to clotting factors is limited. How gene therapy is priced will ultimately determine its availability to patients. Nevertheless, gene therapy has led the way into a new age of groundbreaking therapeutics and has proven to be a viable and effective treatment option that can potentially be utilized to treat other diseases.
Edited by: Annie Feng
Illustrated by: Jennifer Broza