Release date: 2017-07-13 Bill Maurits sat in a waiting room in Philadelphia, ready to receive intravenous injections containing trillions of viral particles. He thought in his head: "Get started! I don't want to wait anymore." Moritz suffers from hemophilia B, causing his body to fail to produce a blood coagulation protein: Factor IX, which can cause a lot of blood loss even in small wounds. Since the age of 10, he has relied on injections of "extraordinary" exaggerated alternative proteins to sustain life. His joints have been severely damaged by repeated blood stasis. Recently, his left ankle hurts. Moritz is an engineering designer. He joined a clinical trial to receive an injection of a viral vector containing a normal gene that produces the coagulation protein factor IX. During the two months after the end of treatment, he did not receive a replacement protein for factor IX. After 1 year, the effect of the treatment is still maintained. He will not bleed when he sprains his ankle or bruise. He believes: "Gene therapy works, this is the only explanation." These results are undoubtedly satisfactory for patients like Moritz and for scientists who have been working on genetic therapy for 30 years. If gene therapy is successful, catastrophic diseases like hemophilia can be cured in one dose, although its price may be high. “But it may be worth it,†said Mark Skinner, a former chairman of the World Federation of Hemophilia. Hemophilia patients face enormous challenges every day. Due to the lack of coagulation factor protein in the body, any small wounds and bruises can be dangerous, and undetected bleeding in the body can be life-threatening. Gene therapy seems to be a good choice because it may be a one-time "cure." Gene therapy for 30 years The gene therapy accepted by Moritz comes from a company called Spark. The company's president and chief scientific officer, co-founder Dr. Katherine High is a hematologist with a long-standing interest in gene therapy for genetic diseases. In 1989, Dr. Catherine, a professor at the University of Pennsylvania, studied the isolation of the Factor IX protein from dogs. In the following decade, Dr. Catherine, the director of the Cell and Molecular Therapy Center at the Children's Hospital of Philadelphia (CHOP), formed a multidisciplinary team of scientists and researchers dedicated to discovering new genes and cell therapies for genetic diseases. And promote the rapid conversion of preclinical findings into clinical applications. Gene therapy continues to effectively cure hundreds of hemophilia dogs. But attempts in the human body have encountered bottlenecks. 1999 was a tragic year in the history of gene therapy research and development. On September 17, 1999, 18-year-old Jesse Gelsinger participated in a gene therapy clinical trial at the University of Pennsylvania because of liver genetic disease, and died of multiple organ failure due to a large number of immune responses. This is the first person to die in a clinical trial of gene therapy. In the same year, 4 of the 9 infants who had undergone gene therapy for severe combined immunodeficiency (SCID) were found to have leukemia within 3 to 6 years after treatment, again reversing the field of gene therapy. After 2006, clinical success has regained the attention of researchers in gene therapy. Hemophilia is one of the important areas. In 2006, Dr. Catherine's team published a paper in the journal Nature (Reference [7]), which confirmed that gene therapy can increase the level of coagulation factor IX in patients, but this effect is quickly destroyed by the human immune response. Whenever foreign objects enter the body, the immune system attacks foreign invaders. Therefore, cells that have been corrected by gene therapy are also attacked by the immune system, which reduces the effectiveness of gene therapy. The immune response has become a major problem in gene therapy. In 2010, researchers at University College London and St. Jude's Hospital in Memphis learned from Dr. Catherine's failure. They use immunosuppressive drugs to control the efficacy of gene therapy at the right time. However, after the use of immunosuppressive drugs, the efficacy of the highest dose of gene therapy is still not strong enough. Five patients who underwent trials eventually produced 5% levels of factor IX in normal humans. This improvement is still far from being completely cured. In 2013, Dr. Catherine founded Spark with her own gene therapy research team at the Children's Hospital of Philadelphia. Soon, multinational pharmaceutical companies have regained interest in gene therapy. In 2014, Pfizer acquired the commercialization rights of Spark gene therapy, and Pfizer's own products included Factor IX (trade name BeneFix). Dr. Catherine led Spark to find an appropriate amount of viral injection: both to escape the immune system attack and to increase the level of factor IX. In order to allow the target DNA to reach the liver of the synthetic factor IX directly, they redesigned the viral vector carrying the DNA. The transfer came from a special patient. At the time, there was a report in the literature that a young man in Italy suddenly had a serious blood clot on his leg. The study found that his clotting factor IX gene was mutated, resulting in overactivity, resulting in his body's blood clotting level equivalent to 776% of normal people. His misfortune turned into an accidental surprise for Dr. Catherine's team. They used this overactive Padua gene mutation to enhance the effectiveness of hemophilia gene therapy. In Spark's lab, a shiny white corridor is on both sides of a sterile room for making viral particles. Spark can implant genes into these viral vectors. Once the virus vector is injected into the patient, it reaches the liver cell directly and unloads new foreign DNA there. In July 2016, Spark's gene therapy SPK-9001 was approved by the FDA for breakthrough therapy. The initial increase in IX clotting factor levels in four patients was maintained for 7 weeks and for up to 22 weeks. They do not need to receive an infusion to supplement the clotting factor during this observation period after receiving treatment. Be aware that if you receive traditional therapy, they will need to receive more than 100 infusions to supplement the clotting factor during the same period of time! In April 2017, Spark's latest 1/2 clinical data showed that 10 patients who received the gene therapy continued to maintain stable and long-lasting factor IX activity. Of the 10 patients, 9 patients had never received clotting factors after receiving gene therapy, and another patient had severe arthritis. After continuous joint pain, cautiously received coagulation. Factor input. According to Spark's latest follow-up data released on July 10, five patients have been receiving SPK-9001 experimental gene therapy for the past year, and one of them has been treated for about 18 months after treatment; all of these patients after treatment Conventional coagulation factor IX infusion has been discontinued and shows a continuously increasing level of IX activity. Dr. Federico Mingozzi, a gene therapy scientist at the INSERM research institute in France, once said: "Although it can't be said that a cure has been found, this is the first time it looks good. The real innovation is indeed Showing sustained efficacy. I have never seen it before." Finish line The designer at the beginning of this article, Moritz, was one of the first four patients to receive SPK-9001 gene therapy. Dr. Lindsey George, who is responsible for injecting gene therapy into Moritz, said: "My most exciting moment on the day of the trial was to tell Bill how much his clotting factor is." George said that a huge problem still exists: about 40% of people with hemophilia can't benefit from this gene therapy. That's because the type of virus used in this gene therapy is similar to the virus found in nature. So many people have viral antibodies in their blood that can stop Spark's gene therapy from reaching the liver. This part of the patient was excluded from the study. George said: "Because of this obstacle, it cannot be considered a ready-made treatment." Dr. Catherine's team is working to solve this problem, including releasing the bait virus to absorb antibodies. As Spark's slogan says - "We don't follow the footsteps, we create new ways." Hemophilia is a hereditary disease, so the best way to deal with it is to solve genetic defects. This is also the goal of Spark when it was founded in 2013. The company's current product line consists of eight different gene therapies and is undergoing four clinical trials covering hereditary retinopathy, liver-mediated genetic diseases, and neurogenic diseases such as Huntington's disease. We wish Spark's hemophilia gene therapy will eventually reach the end of success and benefit more patients. But for gene therapy, hemophilia is not the finish line, it's just a starting line. Reference material [1] Gene Therapy Is Curing Hemophilia [2] Blood disease that plagued Europe's royal furniture might be treatable using gene editing [3] A Spark Ignites a Genetic Cure for Hemophilia [4] Why Gene Therapy Caused Leukemia In Some 'Boy In The Bubble Syndrome' Patients [5] Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response [6] Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B [7] Wikipedia Source: WuXi PharmaTech (Wei Signal WuXiAppTecChina) GMP Certificated Immune Globulin Injection Supplier in China Hepatitis B Immunoglobulin,Hep B Immunoglobulin,Hepatitis B Immunoglobulin Vaccine,Hepatitis Immune Globulin FOSHAN PHARMA CO., LTD. , https://www.fospharma.com