Fight against hemophilia
Maxim Rousseau, Polit.roo
Among the first news of 2020 was a message about progress in the fight against hemophilia. A long-term clinical trial has confirmed the effectiveness of gene therapy for one of the varieties of this disease.
Blood clotting in humans requires a cascade of interactions of various substances, which are called "clotting factors". There are 13 of these factors in the blood plasma, they are usually denoted by Latin numerals. A violation of the synthesis of one of them, arising from a mutation, leads to a general disorder of blood clotting - hemophilia. Therefore, hemophilia is not a single disease, but three different ones, differing in what clotting factors are missing in the patient's body.
The most common type is hemophilia A ("classical hemophilia"), caused by a lack of coagulation factor VIII, which affects up to 80% of hemophiles. It is caused by a mutation in the X chromosome, it occurs in one person out of ten thousand. About a third of cases of hemophilia A are not inherited from parents, but are caused by a spontaneous mutation that occurred for the first time.
The offspring of Queen Victoria, including members of the royal families of Russia, Spain and Germany, had hemophilia B ("royal hemophilia"). This type of hemophilia is caused by a mutation in the gene that manages the synthesis of one "coagulation factor IX". In foreign literature, it is sometimes called Christmas disease, since the first patient who had this disease described was named Stephen Christmas, and this description was published in the Christmas issue of the British Medical Journal. Hemophilia B occurs in about 20% of hemophiles and is second only to hemophilia A. The difference between these two diseases was discovered only in 1952. Hemophilia C, which occurs due to a low level of clotting factor XI, and parahemophilia associated with clotting factor V are much less common.
Until recently, the only way to help a patient with hemophilia was regular injections of the clotting factor that he lacks. With hemophilia A, for example, the introduction of coagulation factor VIII, depending on the severity of the disease, is performed two to three times a week (100-150 times a year).
But after the emergence of gene therapy, doctors had a hope to completely rid patients of the disease by correcting a mutation that causes a lack of clotting factor. In 2017, it became known about the results of the use of gene therapy for the treatment of hemophilia B. Patients received a single injection of a harmless virus that carried a working version of the desired gene. When tested after 18 months, it turned out that the level of clotting factor IX in their liver increased and averaged 34% of the norm. This was enough to prevent 9 out of 10 patients from bleeding. 8 out of 10 no longer needed daily injections of factor IX.
Now it's time for gene therapy of hemophilia A. The method was developed by the biotech company BioMarin Pharmaceutical Inc., the results of three-year clinical trials are reported in an article published by New England Journal of Medicine (Pasi et al., Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A). As in the previous case, the therapy consists in the introduction of viral particles with a functional copy of the gene (the drug is called valoctocogene roxaparvovec). Fifteen patients with a severe form of the disease participated in the trials, who received a different dose of viral particles with a therapeutic gene, depending on how much blood clotting factor VIII they had in their body.
As a result, two did not have a significant increase in the production of this factor (this happened with patients who received the smallest dose of the virus: 6×10 12 and 2×10 13 viral particles per kilogram of body weight). For the rest, the effect was significant and persisted throughout the entire trial period (seven received 6×10 13, and six received 4×10 13 viral particles per kilogram of body weight). They stopped bleeding completely and the need for coagulation factor VIII injections almost disappeared. The first seven had no need for artificial factor administration at all, whereas before the start of the study, on average, each of them received coagulation factor VIII on average 138.5 times a year. The remaining six had 0.5 cases of factor administration per year (155.5 per year before the start of the study).
In addition, 12 participants got rid of joint problems. Hemorrhages in the joints are one of the significant problems with hemophilia. They cause pain and eventually lead to the destruction of the joint ("hemophilic arthropathy"), so sometimes it is necessary to replace it with a prosthesis. The joints affected by hemophilia are called "target joints" (target joints), such a diagnosis is made if hemorrhage into the joint occurs three times in six months or more often, the cessation of inflammation of the "target joint" is considered two or less hemorrhages per year, this is the indicator achieved by 12 patients.
Regular measurements of coagulation factor VIII in the blood of participants show that the drop in its level, which often happens with gene therapy some time after the introduction of the gene, slowed down. The expression of the therapeutic gene, as the authors write, "has entered the plateau phase," which allows us to hope for an even longer-term effect.
Among the side effects of treatment, the most frequent was a temporary increase in the level of the enzyme alanine aminotransferase, which usually occurs with liver damage. Anti-inflammatory therapy returned the enzyme level to normal, there were no other signs of liver inflammation in patients.
"These data are crucial in helping the scientific and medical community understand the groundbreaking technology," says Professor John Pasi, who leads the study from the School of Medicine and Dentistry at St. Bartholomew's Hospital and The London Medical College (Barts and The London School of Medicine and Dentistry). "As an attending physician, I am inspired by the potential of gene therapy, which can significantly change the lives of people with hemophilia A."
A new method of treating hemophilia A has already attracted the favorable attention of regulatory authorities. On December 24, 2018, it became known that the European Medicines Agency had approved BioMarin Pharmaceutical's application for the use of this therapy for the treatment of adult patients in the European Union (two years earlier, the agency had approved the company's application for an accelerated review of this method). The U.S. Food and Drug Administration (FDA) will review hemophilia A gene therapy in February.
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