Friday, March 13, 2015

Hemophilia: Working Towards a Cure?

Hemophilia is a fairly well documented illness dating back to ancient times. In recent years, there have been enormous leaps forward in hemophilia treatment. Indeed, the hope is that with new advances in gene therapy, hemophilia will able to be completely cured within the next decade. Until that time though, researchers will continue to work towards more effective therapies for this disease.

Hemophilia is often caused by a single point mutation that stops the production of either clotting factor XIII (hemophilia A) or factor IX (hemophilia B). With hemophilia patients, it is often a race against the clock to ensure that they have sufficient levels of clotting factors at all times. Otherwise, spontaneous bleeding ensue which can be fatal if left untreated. Additionally, spontaneous bleeding can lead to serious joint degradation over time. Fortunately, we’ve come a long way in the treatment of hemophilia since the whole blood transfusions of the 1840’s. Unfortunately, we still have quite a ways to go. A parent of a child with hemophilia still must intravenous inject their child with clotting factor at least once a day in order to maintain healthy levels of factor in their blood. After 8-12 hours half of the factor VIII has been removed from the body. The half-life of factor IX is a little bit longer, about 18-24 hours. Unfortunately, hemophilia A (which lacks factor VIII) is four times as common as hemophilia B. This often spells disaster for compliance with the strict regimen of injections necessary.

There have been a number of recent advances in hemophilia research that have drastically extended the half-life of the clotting factors by interfering with the body’s ability to flush the factors away. The first two methods increase the half-lives of the clotting factors by binding themselves to proteins with a longer half-life. Immunoglobin is a naturally produced protein that is shaped like a Y. The desired clotting factor fuses to the stem of the Y (called the Fc region) and will remain in the body for as long as the immunoglobin remains. Factor VIII’s half-life increased to 3-5 days and factor IX’s half-life increased to 7-14 days with this new technique. Both of the new drugs on the market that were recently approved by the FDA utilize this method. The second method utilizes alumin which is a major protein of blood plasma and can increase the half life of factor IX to 20 days. Unfortunately, this method does not work with factor VIII. The final method uses a synthetic molecule called polyethylene glycol (PEG) which surrounds the clotting factor in a protective cloud to prevent it from being broken down and flushed out of the body. Another new technology that is in the early stages of development involves a way to bypass the factor VIII altogether. All the factor VIII really does is bring the factors IX and X together in order to clot. Researchers are working on a way to modify immunoglobin so that one factor will attach to each arm of the Y thereby completely eliminating the need for factor VIII. This method doesn't even have to be injected intravenously, it can be delivered under the skin like insulin. This is fantastic because along with extending the half-lives of these clotting factors, eliminating the need for a painful and difficult IV will encourage better compliance with drug injections and ensure that the levels of clotting factors in the blood stay higher for longer. This could lead to reduced join disease in hemophiliacs and could also make mass-producing clotting factors economically viable for pharmaceutical companies which would help control hemophilia in poorer countries.
Clotting Factors: Stretching time
Clotting factor IX: used to treat hemophilia B

Despite all of the fantastic effects of extending the half-life of the clotting factors, it is only a temporary fix. As much as it helps, it can also exacerbate larger issues such as immunicity. The biggest issue hemophiliacs face right now is the challenge of overcoming inhibitors, or antibodies that the immune system produces to neutralize the injected clotting factors which it sees as foreign bodies. Inhibitors are essentially the body’s way of fighting back against modern medicine trying to give them what they lack. Once inhibitors develop, it is close to impossible to stop a fatal hemorrhage.

Fortunately, researchers have been hard at work trying to find a way around this potentially deadly setback. One new way to get around immunicity in patients that have already developed inhibitors is by using plasma-derived (pd)-porcine VIII instead of human VIII. The two factors are similar enough that they function in essentially the same manner. However, they are still dissimilar enough to discourage an immune response. While porcine VIII can usually escape the inhibitors created to disable factor VIII, they occasionally provoke an intense immune reaction anyways that can lead to anaphylactic shock. Perhaps the most interesting advance in this area of hemophilia research comes from the extremely unlikely source of freeze dried lettuce leaves and is aimed at preventing inhibitors from even developing in the first place. Henry Daniell, director of translational research at the University of Pennsylvania School of Dental Medicine in Philadelphia, has managed to engineer chloroplasts to produce factor IX. The lettuce containing the genetically modified chloroplasts is then ground up and made into an orally administered capsule. The oral administration makes it extremely easy to use (unlike the intravenously injected current factors) and the chloroplast is actually the perfect packaging for the factor because it does not break down until it reaches the gut. Additionally proteins can be added so that the chloroplasts stick to certain regions of the gut and the factor can diffuse slowly into the bloodstream. Research has shown that the oral administration of the factor can reduce the number of inhibitors present and, in some cases, stop their formation entirely. A few other ways to get around the immune response include immunosuppresants and drugs that deplete specific immune cells. These methods have an extremely negative overall impact on the body, leaving it prone to infection. A much safer, interesting new option from Selecta Biosciences involves a nanoparticle delivery system in addition to the factor. The nanoparticles are programmed to target immune cells that induce the response and instruct them to become tolerant to the factor. The rest of the immune system is unaffected and the immune response to the factor is stopped.

While all of these new advances in hemophilia research are extremely exciting, nothing can quite beat the excitement of potentially curing the disease entirely through gene therapy. Researchers hope that within the next decade their recent work will have become mostly obsolete because hemophilia will be able to be essentially cured through gene therapy. In the mean time, these new advances have taken hemophilia treatment to previously unthinkable new heights.


Reininger, Armin, Alessandro Gringeri, Leonard Valentino, Gerald Spotts, Vadim Romanov, Robert Numerof, Friedrich Scheiflinger, and Bruce Ewenstein. "Pushing the Frontiers of Medicine: Innovations in Hemophilia Care." Scientific American (2014): 414-20. Web. 27 Feb. 2015. <>.

Savage, Neil. "Clotting Factors: Stretching Time." Scientific American (2014): Web. 27 Feb. 2015. <>.

Dolgin, Elie. "Oral Solutions." Scientific American (2014): Web. 27 Feb. 2015.


  1. Although not a long term solution, non-gene therapy treatments for hemophilia seem to have the disease under control without serious side effects. Gene therapy may provide a long term solution to hemophilia, but the risks include tumor formation, immune response, and other serious problems. Playing with the genome is a high risk, high reward venture. Would it ever really make sense to modify one's genome for an illness that is well controlled by other means?

  2. Hemophilia is truly a scary disease, and it is sad to say that there isn't a true "cure" for this debilitating illness. Replacement of clotting factors by injecting them is a huge advancement from whole blood transfusions of the past, but it seems that research surrounding this disease are in the infant stage. They focus on treating the disease instead of curing the genetic gap that causes this disorder. I think research surrounding modifying genetic material within the body safely will eventually unlock the key to all genetic disorders, hemophilia being one of the foremost important to cure.

  3. It's great to see that advances towards curing and treating hemophilia continue to be made. The potential power of genetic therapy to cure hemophilia is exciting, and I was unaware of the number of treatments in use for hemophilia in the meantime. The fact that most of the treatments compromise the immune system is sad to hear. How effective are the chloroplast-derived factors for treating hemophilia? And did that researcher find out about the use of lettuce on accident? That would be one of many scientific discoveries made on accident.