World Hemophilia Day | Positive treatment progress brings bright hope

April 17

World Hemophilia Day

In order to commemorate the contribution of Mr. Frank Schnabel, the founder of the World Federation of Hemophilia, a Canadian, to hemophilia patients and to arouse the public's correct understanding of hemophilia, the World Federation of Hemophilia has specially selected Schnabel's birthday, April 17, as "World Hemophilia Day" since 1989. Every year on this day, the World Federation of Hemophilia will hold activities. This year's April 17 is the 33rd "World Hemophilia Day". Without exception, hemophilia patients around the world will commemorate this day in different forms.

Hemophilia is one of the most well-known rare diseases and there is currently no cure. However, scientists and medical experts are still exploring ways to defeat hemophilia, including antibody therapy and gene therapy that have emerged in recent years.

What progress has been made in the treatment of hemophilia? Why is hope placed on gene therapy?

The British royal family's "aristocratic disease"

Hemophilia is a group of bleeding diseases caused by hereditary coagulation factor deficiency. It often develops in childhood, spontaneously or after mild trauma, with coagulation dysfunction. Bleeding cannot stop spontaneously. In severe cases, spontaneous bleeding may occur after more intense activities. It is generally incurable. The pathogenic gene of hemophilia is on the X chromosome, and it is an X-linked recessive genetic disease. If a male carries the hemophilia gene, symptoms will appear. If a female carries only one hemophilia gene and the other is normal, she will not show symptoms of hemophilia. However, the boy she gives birth to has a 50% risk of developing the disease, and the girl has a 50% chance of carrying the pathogenic gene.

Queen Victoria of the United Kingdom is the most famous carrier of the hemophilia gene. She and her husband gave birth to four sons and five daughters. The youngest son, Prince Leopold, was a hemophiliac. In 1884, when he was just over thirty years old, he accidentally slipped and injured his knee joint and bled. He hurriedly passed away the next morning. Although the five princesses were all healthy and beautiful, the second daughter, Princess Alice, and the youngest daughter, Princess Beatrice, were also carriers of the hemophilia gene. They married into the European royal family, and soon hemophilia spread to Spain, Germany, and Russia. Many members of the royal family died one after another, and hemophilia was thus awarded the title of "Royal Disease". (Click to read: How did the genes of the European royal family become corrupted? Starting from the "grandmother" Queen Victoria, the "blood curse" that cannot be escaped!)

There are 4 types of coagulation factor deficiency

Hemophilia can be divided into two types, depending on the type of clotting factor that is deficient:

(1) Hemophilia A: It is caused by a deficiency of coagulation factor VIII (FVIII), also known as hemophilia A. It is the most common hemophilia in clinical practice, accounting for about 80% to 85% of the number of hemophilia patients, and is even higher in some high-incidence areas.

(2) Hemophilia B: It is caused by a deficiency of coagulation factor IX (FIX), also known as hemophilia B. It is less common than hemophilia A clinically, accounting for about 15% of hemophilia patients.

(3) Hemophilia C: It is caused by a deficiency of coagulation factor XI (FXI). FXI deficiency is extremely rare in my country.

(4) Acquired hemophilia (i.e., acquired coagulation factor deficiency): This is often caused by one's own factors, which leads to a decrease in the level or activity of certain coagulation factors. For example, acquired coagulation factor VIII deficiency is often caused by the production of factor VIII antibodies by the individual, which leads to coagulation dysfunction and acquired hemophilia.

Great progress has been made in treatment

So far, there is no cure for hemophilia. The only way to eliminate the patient's symptoms is to increase the activity level of the patient's coagulation factor. Currently, the treatment of hemophilia mainly includes replacement therapy, preventive therapy, antibody therapy, and gene therapy that is currently in clinical trials.

Alternative treatments

That is, plasma transfusion, clotting factor, etc. are given after bleeding. Currently, the standard of care for hemophilia is to control bleeding through lifelong administration of clotting factor replacement therapy. Replacement factors are mainly recombinant (genetically engineered) or plasma-derived (from healthy blood donors) and are treated by frequent (three times a week) intravenous infusions.

Prevention and treatment

Once hemophilia is diagnosed, coagulation factors are transfused, and coagulation factors are transfused regularly before bleeding occurs. The advantage of this is that it can effectively prevent bleeding, joint damage, and joint bleeding, thereby preventing further joint dysfunction and ensuring the patient's normal work, life and study. Preventive treatment is a therapy that is highly advocated both internationally and domestically.

Antibody therapy

For a long time, hemophilia A has been mainly treated with coagulation factor replacement therapy, but it requires multiple intravenous injections per week. During the treatment of hemophilia, anti-coagulation factor antibodies (also known as hemophilia inhibitors) will be produced in the patient's body. These antibodies can neutralize coagulation factors and make the coagulation factors lose their coagulation function. It is reported that about 10% to 30% of patients will have coagulation factor VIII inhibitors. The appearance of inhibitors will greatly increase the risk of death in patients with hemophilia A.

Antibody therapy is an innovative therapy. The successful development and marketing of its therapeutic antibody Emicizumab has broken the bottleneck of clinical treatment of hemophilia. Emicizumab is a modified humanized bispecific IgG4 monoclonal antibody that can bridge activated factor IXa and factor X, thereby restoring the function of FVIII. In November 2017, the U.S. Food and Drug Administration (FDA) approved emicizumab (trade name: Hemlibra®) for routine prevention of adult and pediatric patients with hemophilia A with FVIII inhibitors to prevent or reduce the frequency of bleeding. In October 2018, the FDA approved it for routine prevention of patients with hemophilia A who do not have inhibitors, administered by weekly (or less frequent) subcutaneous injection. In other words, Emicizumab is currently the first and only drug that can be used for both severe patients with hemophilia A caused by coagulation FVIII inhibitors and patients with hemophilia A not caused by FVIII inhibitors.

Gene therapy

Although replacement therapy can significantly improve the quality of life and life expectancy of hemophilia patients, it has the following disadvantages: first, it cannot cure hemophilia, and patients are still at risk of bleeding despite treatment; second, conventional coagulation factors have a short half-life and need to be administered frequently. Although preparations that extend the half-life of coagulation factors have recently been developed, which can reduce the frequency of administration of recombinant coagulation factors, they also have certain limitations; third, some patients will produce neutralizing antibodies against coagulation factor proteins during medication, affecting the treatment effect. The above situation shows that existing treatments have certain shortcomings and are difficult to meet the needs of patients' quality of life. The emergence of hemophilia gene therapy brings an exciting prospect to patients and their families.

Gene therapy refers to the introduction of exogenous genes that normally encode coagulation factors into the patient's body through gene transfer technology, and the expression of therapeutic levels of coagulation factors, thereby achieving the goal of completely curing hemophilia. Compared with traditional treatment methods, it is a revolutionary treatment technology with high professionalism. It can be used once for lifelong treatment. It can not only avoid the production of inhibitory antibodies, but also reduce the risk of viral contamination. At present, there is no radical treatment for hemophilia A, and gene therapy is the only way to cure this disease.

With the continuous development of molecular biology technology and breakthroughs in gene and vector research, gene therapy for hemophilia has made great progress. Currently, there are multiple hemophilia gene therapy products in clinical trials. For example: In November 2020, BioMarin announced that its hemophilia A gene therapy ValRox has completed the results of Phase I/II clinical trials and obtained interim results of Phase III clinical trials. It is believed that in the near future, multiple products will be approved for marketing to meet the treatment needs of hemophilia patients.

Author: Yaohuluwa Medical Biotechnology Science Popularization Group