Hemophilia consists of a set of hereditary diseases responsible for a defect in blood coagulation, and therefore risk of bleeding. The main one, hemophilia A, is transmitted in an X-linked recessive way: mothers are healthy vectors and affected boys if they receive the mutated form of the coagulation factor VIII gene located on the X chromosome. affects approximately 1 in 6,000 boys.
Described a long time ago, this disease was incurable. Tsarevich Alexis was a famous victim. Rasputin, called by his mother to treat him, earned his reputation there by preventing the child from taking aspirin, which promotes bleeding! But it was only in the 1960s that the first preparations of factor VIII from the plasma of blood donors became available to treat the hemorrhages of these patients and relieve them temporarily.
It was a source of immense hope for them. This advance, however, did not prevent bleeding from occurring. Although it limited its importance, it did not prevent severe and disabling joint damage resulting from repeated bleeding within the joints. Above all, the use of factor VIII from blood donors caused in the 1980s, before the availability of screening tests, numerous contaminations by HIV and the hepatitis C virus, with dramatic consequences.
Remarkable progress
Fortunately, biotechnologies based on recombinant DNA came soon after. They make it possible to manufacture proteins of therapeutic interest in complete safety: factor VIII became available in 1992, and its use has gradually spread. Its production in quantity has made it possible to take a new step: its prophylactic use. Three injections per week greatly reduced bleeding. However, its half-life limited to twelve hours once injected into the blood means that it is not possible to completely prevent joint damage. This is where a series of remarkable advances come in, which should significantly improve the quality of life of hemophilia patients.
A first track consisted in seeking to prolong the stability of factor VIII once injected. The latest version obtained at the cost of significant modifications to the product used (in fact, a hybrid molecule with, among other things, a fragment of another protein to which factor VIII binds) extends this half-life to forty-seven hours. A weekly injection is recommended and seems to eliminate any bleeding! A second track consists in using a molecule which mimics the procoagulant action of factor VIII. It is in fact an antibody: a subcutaneous injection at an even more spaced out rate also makes it possible to obtain a very good result. These molecules are already available or will be very soon. THE New England Journal of Medicine speaks of them as “a victory for patients with hemophilia”.
Hope for a cure
Finally, the third track, gene therapy, the objective of which this time is to cure patients. Substantial progress has taken place in recent years. This involves injecting an innocuous virus (adeno-associated virus) through a vein to transport an adjusted version of the factor VIII gene and allow it to be produced by the liver. It has been shown in a well-conducted study (compared to traditional prophylactic medicine) that this treatment reduces the risk of bleeding by an average of 85% over two years. This is a remarkable result, which will allow it to be made available. However, questions arise about its duration of effectiveness, the consequences of immunizing the patient against the viral vector and the possible long-term effects.
Patients will soon have a choice between several effective strategies. It is a very good illustration of what research can bring to medicine. This is an opportunity to salute the courageous and persevering fight of patients through their associations, who were actors in this progress. But it is also an opportunity to worry about the very high prices of these innovative drugs – several hundred thousand euros per patient and per year for the first two, probably around 2.5 million euros for gene therapy. Such tariffs will inevitably jeopardize equitable access to these innovations.
Alain Fischer is president of the Academy of Sciences, professor emeritus at the Collège de France and co-founder of the Institute of Genetic Diseases (Imagine).
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