Biomarin's first application for gene therapy in hemophilia

Hemophilia is a rare disease with hereditary coagulation disorder Because patients lack clotting factors, minor injuries can lead to unbearable pain and life-threatening bleeding Most hemophilia patients usually can't go to school, can't play, and need to input clotting factor constantly And that's about to change Not long ago, biomarin pharmaceutical applied for the listing of gene therapy valocogene roxaparvovec in Europe and the United States This is the first gene therapy in the field of hemophilia treatment to be submitted to the market If it is approved successfully, it will bring the dawn of cure for adult patients with hemophilia A Historically, hemophilia is not a disease that has been studied early and has a great influence In just over half a century of exploration, it has become one of the rare diseases that are expected to be cured in human history Today, the content team of Wuxi apptec will review with you the history of human's cracking the "Curse of blood" from the emergence of effective therapy to the birth of the dawn of healing When it comes to hemophilia, people talk about the mysterious "blood devil" and the fetters of European royal family As a carrier of hemophilia gene, Queen Victoria passed the disease on to her offspring, and royal intermarriage spread hemophilia to more countries In Europe, hemophilia not only indirectly caused the Russian Revolution, but also became a bomb lurking in the royal blood of Spain, Germany, Britain and other countries for more than a century Therefore, people also call hemophilia "Royal disease" ▲ hemophilia family members of Queen Victoria (photo source: shakko [CC by SA (https://creativecommons.org/licenses/by-sa/4.0)]) In fact, people's understanding of hemophilia is much earlier than that of Queen Victoria In the second century A.D., people have been aware of the existence of a genetic disease with bleeding According to Hebrew records, if two boys in a family die of bleeding after circumcision, their younger brother can be exempted from surgery Since modern times, people's understanding of disease is more scientific In 1803, American doctor John Otto proposed "this is a bleeding tendency in a specific family" after studying hemophilia cases in depth, and determined that "the disease is easy to occur in men and spread through healthy women in the family" It is worth mentioning that this paper is the second one in the world to describe X-linked genetic diseases after "red green color blindness", which soon attracted more attention from the medical community In 1828, German doctors first used the word "hemophilia" to describe diseases, which was widely recognized by the medical community, hence the official name of hemophilia Before the birth of modern treatment, hemophilia was one of the most painful diseases known to the medical community at that time Most of the patients died in their childhood because of the bleeding of important organs of the body (such as cerebral hemorrhage) The surviving patients usually face the disability caused by repeated bleeding of joints, even the noble members of the royal family can not escape the fate of dying in their prime At first, it was thought that the increase of blood vessel fragility was the main cause of hemophilia patients' bleeding Until the end of the 19th century, scientists first confirmed that the coagulation speed of hemophilia was significantly lower than that of normal people in glass capillaries, people turned their attention to the defective blood By 1937, two doctors from Harvard University were the first to isolate anti hemophilia globulin (coagulation factor VIII) from human plasma Research shows that the lack of this coagulation factor is the direct cause of coagulation disorders in hemophilia It seems that human beings are infinitely close to the truth of hemophilia However, while the world was amazed at the discovery of anti hemophilia globulin, a doctor in Argentina questioned this conclusion The reason is that he accidentally found that the blood of one hemophilia patient can correct the coagulation disorder of another hemophilia patient, and vice versa As a result, he boldly speculated that there might be another coagulation abnormality unrelated to anti hemophilia globulin, fortunately, his guess was confirmed soon In 1952, Stephen Christmas, a 5-year-old boy, was admitted to hospital because of hemophilia After doctors tested his blood samples according to the Convention, they found that Chris's blood samples did have hemophilia characteristics, but the level of anti hemophilia globulin was completely normal, but the level of another unknown protein was different from that of ordinary people Soon, the researchers isolated the protein that Chris moss lacked from the normal human plasma and named it Chris moss factor (clotting factor IX) It has been proved that, like anti hemophilia globulin, the input of this factor can help a part of hemophilia patients recover their clotting ability ▲ by Dr Graham bears [CC by-sa 3.0 (https://creativecommons.org/licenses/by-sa/3.0)], from Wikimedia Commons The discovery of anti hemophilia globulin and Chris Morse factor has made scientists realize that there is more than one hemophilia In the 1960s, the formation of the "clotting waterfall" theory helped people have a more complete understanding of the clotting cascade reaction Scientists renamed clotting factors with Roman numerals The two clotting factors affecting hemophilia were named as clotting factor VIII and clotting factor IX respectively, and the corresponding two hemophilia were named as type a hemophilia and type B hemophilia In the first half of the 20th century, while scientists were busy searching for the culprit of hemophilia, they did not stop exploring better treatments besides hemostasis Doctors have found that patients with spontaneous joint and muscle bleeding, immediately after the input of plasma can effectively improve the disease So "to give patients whole blood or frozen fresh plasma to make up for the lack of clotting factors in patients" quickly became an alternative therapy for hemophilia However, the replacement therapy was not perfect at the beginning of its birth On the one hand, long-term blood transfusion brought great inconvenience to patients' lives On the other hand, for more serious patients, blood transfusion alone was not enough to resist the loss of coagulation factors Until 1960, the life expectancy of hemophilia patients was still less than 20 years old Dr Judith pool's 1965 paper on cold precipitation changed all this Her research showed that there were abundant factors VIII in the top sediments when frozen plasma melted, and the input of these sediments could make people obtain enough coagulation factors once to control serious bleeding In the 1970s, people developed a more magical clotting product, concentrated clotting factor, on the basis of cold sediment These freeze-dried powder concentrate, which can be stored at home and used at will, has changed the care of hemophilia, made patients no longer rely on hospitals, and life expectancy has begun to approach the general population Blood products benefit patients from better treatment, but also bring corresponding risks Because the production of concentrated clotting factor needs a large number of fresh blood, a batch of products even need to collect the plasma of thousands of blood donors, even if one of them carries infectious disease virus, it is enough to pollute the whole batch of products In the 1980s, the expected risks became a reality Blood products carrying HIV and HCV spread around the world, and 50% of patients in the United States alone were infected with HIV and hepatitis C The BBC's documentary "polluted blood: a fact finding" accuses the serious consequences of the incident As the magic medicine leaves the altar, the quality of blood products is pushed to the forefront In the middle and late 1980s, people began to use the method of virus inactivation by heating or chemical treatment, which made the production of coagulation factor in plasma safer In addition, in the 1990s, human clotting proteins produced in animal cells by recombinant DNA technology appeared on the market, which brought more choices to hemophilia patients On the one hand, the medication of hemophilia is getting better, and on the other hand, people have never given up the way of "once and for all" The gene therapy which came out in the 1990s has given a glimmer of hope to people who have been trapped in the disease for a long time The goal of gene therapy is to reduce or eliminate the need of patients to receive coagulation factor injection, and reduce the number of bleeding events Depending on the patient's type, doctors inject them with viral vectors that encode different genes ▲ principle of gene therapy using virus vector (picture source: [public domain]) At first, hemophilia seemed to be the ideal target of gene therapy The level of clotting protein in normal human blood varies greatly, probably from 50% to 150% of the average value Gene therapy for this disease does not need to raise clotting factor too much to produce curative effect, and researchers have known which gene should be introduced into patients' liver cells But the development of gene therapy is not smooth, immune response is a big problem of gene therapy Any time foreign bodies enter the body, they will be attacked by the immune system, and cells modified by gene therapy are no exception, which makes the therapeutic effect reduced To find an appropriate amount of virus injection: it can not only avoid the attack of the immune system, but also greatly improve the level of coagulation factors, which has become the direction of scientists' efforts The transfer came from a special patient Scientists found that an Italian man carried a gene mutation that allowed his cells to produce factor IX at 12 times the normal level The researchers realized they could use the mutated gene in a viral vector to treat patients with hemophilia B The advantage of this method is that they don't need to use so many virus vectors, and low-dose viruses are less likely to cause the immune system to attack them Using this method, spark developed gene therapy spk-9001 The elevated level of IX coagulation factor was maintained for 7-22 weeks in four patients who were initially treated If they were treated with traditional alternative therapy, they would need to receive more than 100 infusions in the same time period to supplement coagulation factor! In September 2016, spk-9001 was recognized as FDA breakthrough therapy Compared with hemophilia B, the development of gene therapy for hemophilia A A is a greater challenge The viral vectors used to carry genes into patient cells are called adeno-associated viruses They cannot carry large genes, but the genes encoding factor VIII are very large After 15 years of hard work, researchers have finally reduced the gene of factor VIII to the extent that it can be loaded into the virus vector by cutting out the unnecessary part of the gene Valoc tococogene roxaparvovec, a gene therapy developed on the basis of biomarin, recently applied for listing in Europe and the United States An experiment showed that in the course of three years of gene therapy, the bleeding rate and the use rate of coagulation factor VIII decreased by an average of 96% It is no longer a dream to get rid of the drug companion for a lifetime At present, the main method of hemophilia treatment is still to regularly supplement the coagulation factors lacking in the blood However, the preventive coagulation factor input implemented since the end of the last century has largely avoided the occurrence of patients' diseases, while the coagulation factor with extended half-life has reduced the frequency of patients receiving infusion, and improved the living conditions of patients to a certain extent For example,