Gene therapy of beta-thalassemia
Crispr Therapeutics company plans to conduct the first clinical trials of the treatment of a genetic disease
Crispr Therapeutics plans its first clinical trial for genetic disease
Megan Molteni, WIRED
Translated by Vyacheslav Golovanov, GeekTimes
At the end of 2012, French microbiologist Emmanuelle Charpentier proposed to a group of American scientists to found a company called Crispr. The group included Jennifer Doudna from the University of California at Berkeley, George Church from Harvard University, and his former postdoc Feng Zhang from the Institute. Broadov are the brightest stars of the then narrow field of science studying CRISPR. At that time, hardly a hundred papers were published on a little-known method of directional DNA editing. There was definitely no money in this area. But Charpentier believed that everything should change, and in order to simplify the process of interacting with intellectual property, she suggested that scientists unite.
The dream was noble, but it was not destined to come true. In the following year, science developed rapidly, venture capitalists got wind of it, and all hopes of unification faded and disappeared, washed away by a wave of billion-dollar investments. As a result, the leading luminaries of CRISPR technology organized three companies – Caribou Biosciences, Editas Medicine and Crispr Therapeutics – to use what they did in laboratories to treat diseases. For almost five years, the "big three" have promised to establish precise gene therapy for the treatment of hereditary genetic diseases. And now one of the companies says that it is ready to test its ideas on people.
Recently, Charpentier's company, Crispr Therapeutics, announced that it had sent a request to European regulators for permission to conduct human trials for the treatment of the hereditary disease beta-thalassemia. Trials testing the introduction of a genetic correction in stem cells that produce red blood cells may begin as early as next year. Also, in early 2018, the company plans to send a request for approval of a new drug that helps with sickle cell anemia to the American Food and Drug Administration. The company, whose branches are located in Zug, Switzerland and Cambridge, Massachusetts, says it sends the same data simultaneously to two regulators on two different continents.
Both diseases grow from mutations of a single HBB gene that provides instructions for creating the beta-globin protein, one of the components of hemoglobin that binds oxygen and delivers it to body tissues through red blood cells. One of the mutations leads to insufficient hemoglobin production; the other creates abnormal beta-globin structures, which distorts the shape of red blood cells to the form of a crescent, or sickle. Both diseases can lead to anemia, recurring infections, waves of pain. Crispr Therapeutics has developed a way to kill both diseases with one drug.
It does not work with HBB, but by increasing the expression of another gene responsible for the production of fetal hemoglobin (hemoglobin F). We are all born with fetal, or fetal hemoglobin – this is how cells transfer oxygen between mother and child in the womb. But by the age of six months, your body slams on the brakes, finishes producing hemoglobin F and switches to its adult form. The medicine from Crispr Therapeutics just releases these brakes.
Taking a blood sample, scientists separate hematopoietic stem cells – those that produce red blood cells. Then, in a Petri dish, they beat them with an electric current so that the CRISPR components pass into these cells and turn on the hemoglobin F gene in them. To make room for new, edited stem cells, doctors destroy the patient's existing bone marrow cells with radiation or large doses of chemotherapy. A week after the infusion, new cells find their way home to the bone marrow and begin to produce red blood cells that carry hemoglobin F.
According to the company's data obtained from human and animal cell studies presented at the annual meeting of the American Hematology Society in Atlanta, the treatment shows high editing efficiency. More than 80% of stem cells are carriers of at least one copy of the edited gene that triggers the production of hemoglobin F – this is enough to increase expression by 40%. The recently elected director of Crispr Therapeutics, Sam Kulkarni, says that this is more than enough to reduce the appearance of symptoms and reduce or eliminate the need for transfusions in patients with beta-thalassemia and sickle cell anemia. Previous studies show that even a small change in the percentage of stem cells producing healthy red blood cells can positively affect a person with sickle cell anemia.
"I think this is a significant moment both for us and for the whole region as a whole," says Kulkarni. "Just three years ago, we were talking about CRISPR treatment as science fiction, and here we are."
Around this time last year, Chinese scientists used CRISPR for the first time in humans to treat an aggressive form of lung cancer in clinical trials in Chengdu, Sichuan Province. Since then, immunologists from the University of Pennsylvania began accepting patients with a deadly form of cancer for the first CRISPR trials in the United States – they tried to pump T-lymphocytes so that they attack tumors better. But no one has yet used CRISPR to treat genetic diseases.
Crispr Therapeutics' competitor, Editas, was once a leader in correcting inherited mutations. The company announced that it will start editing genes in patients with a rare retinal disease called Leber's amaurosis this year. But the directors decided in May to push the research to the middle of 2018, after they encountered problems with the production of one of the elements necessary for the delivery of edited genes. Intellia Therapeutics, which Caribou co-founded by awarding it an exclusive CRISPR license to commercialize therapies linked to human genes and cells, is still testing its leading treatment on primates, and does not expect to appear in clinical trials earlier than 2019. And all these races to the clinical finish line are not only for the right to be called the first. Being the first means building a successful business and supply chain.
Clinical applications of CRISPR are maturing much faster than other, older gene editing technologies. Sangamo Therapeutics has been working with a DNA slicing tool called "zinc fingers" since 1995. In November, more than two decades later, doctors finally introduced this tool, along with billions of copies of the edited gene, to 44-year-old Brian Mado, who suffers from a rare genetic disease, Hunter syndrome. He became the first patient to receive treatment in the very first study of gene editing in the body. Despite the emergence of new, more efficient technologies, such as CRISPR, Sangamo continues to focus on zinc fingers, because, as she claims, they are safer and can cause fewer unpleasant genetic consequences.
CRISPR does have some small efficiency problems, although their real magnitude is still a matter of debate. A new study published just Monday in the journal Proceedings of the National Academy of Sciences claims that genetic differences between patients can affect the effectiveness and safety of CRISPR treatment strongly enough to carry out custom treatments. This means that CRISPR companies will have to work much harder to prove to regulators that their treatment is safe enough to use on real people – and to prove to patients that participating in trials is worth the risks. Kulkarni says they checked 6,000 positions in the genome and found no side effects. But only American and European regulators will decide whether such evidence is sufficient to start clinical trials of CRISPR.
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