Crispr Therapeutics plans to conduct the first clinical trials for the treatment of a genetic disease.

At the end of 2012, French microbiologist Emmanuelle Charpentier invited a group of American scientists to establish the company Crispr. The group included Jennifer Dudna [Jennifer Doudna] from the University of California at Berkeley, George Church [George Church] from Harvard University, and his former postdoc Feng Zhang from the Institute. Broadas are the brightest stars of the then narrow field of science that studies CRISPR . At that time, hardly a hundred papers were published on the little-known method of directional DNA editing. There was definitely no money in this area. But Charpentie believed that everything should change, and in order to simplify the process of interaction 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 billions in investments. As a result, three companies — Caribou Biosciences, Editas Medicine and Crispr Therapeutics — organized the leading luminaries of CRISPR technology to use what they did in laboratories to treat diseases. For almost five years, the Big Three promised to establish accurate gene therapy for the treatment of hereditary genetic diseases. And now one of the companies says that it is ready to test their ideas in public.

Last week, Charpentie's company, Crispr Therapeutics, announced it had sent a request to European regulators for permission to conduct human trials to treat a hereditary disease beta-thalassemia . Tests that check for genetic corrections to stem cells that produce red blood cells can 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 US Food and Drug Administration. The company, whose branches are located in Zug, Switzerland and Cambridge, Massachusetts, says it sends the same data to two regulators simultaneously on two different continents.

Both diseases grow from mutations of a single HBB gene, which 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 production of hemoglobin; the other creates abnormal beta-globin structures, which distorts the shape of red blood cells to a crescent or sickle type. Both diseases can lead to anemia, recurring infections, waves of pain. Crispr Therapeutics has developed a way to kill both diseases with one medicine.

It does not work with HBB, but increases 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 carry oxygen between mother and child in the womb. But by the age of six months, your body presses on the brakes, finishes the production of hemoglobin F and switches to its adult form. Crispr Therapeutics cure simply releases these brakes.

Taking a blood sample, scientists separate the hematopoietic stem cells - those that produce red blood cells. Then in the Petri dish, they beat them with a current so that the CRISPR components pass into these cells and include 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 high doses of chemotherapy. A week after the infusion, new cells find their way home to the bone marrow and begin producing red blood cells that carry hemoglobin F.

According to the company's data from human and animal cell research presented at the annual meeting of the American Hematological 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 starts the production of hemoglobin F - this is enough to increase expression by 40%. Newly elected Crispr Therapeutics director Sam Kulkarni [Sam Kulkarni] says this is more than enough to reduce the onset of symptoms and reduce or even eliminate the need for transfusions in patients with beta-thalassemia and sickle cell anemia. Previous studies have shown 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 momentous moment both for us and for the whole region as a whole,” says Kulkarni. “Just three years ago, we talked about CRISPR treatment as science fiction, and here we are.”

At about the same time last year, Chinese scientists first used CRISPR in humans to treat an aggressive form of lung cancer as part of 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 tests in the United States — they tried to pump T-lymphocytes so that they better attack the tumors. But no one has yet used CRISPR for the treatment of genetic diseases.

The competitor Crispr Therapeutics, Editas, was once the leader in the correction of inherited mutations. The company announced that it would edit the genes in patients with a rare retinal disease called amaurosis Leber already this year. But the directors decided in May to postpone the research in the middle of 2018, after having encountered the problems of producing one of the elements necessary for the delivery of the edited genes. Intellia Therapeutics, which Caribou co-founded, by giving it an exclusive CRISPR license to commercialize human genes and cells therapies, is still testing its lead treatment in primates, and does not expect it to appear in clinical trials earlier than 2019. And all these races to the finish line of the clinical line go not only for the right to be called first. To be first is to build a successful business and supply chain.

CRISPR clinical applications mature much faster than other, older gene editing technologies. Sangamo Therapeutics has been working with a DNA cutting 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, suffering 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 concentrate on zinc fingers, because, as she claims, they are safer and can cause less unpleasant genetic consequences.

CRISPR does have some small problems with efficiency, although their real value is still a matter of controversy. The new study, published only on Monday in the journal Proceedings of the National Academy of Sciences, argues that genetic differences between patients can affect the efficacy and safety of CRISPR treatment sufficiently to carry out treatments to order. This means that CRISPR companies will have to work a lot more to prove to regulators that their treatment is safe enough for use on real people - and to prove to patients that participation in trials is worth the risk. Kulkarni says they checked 6,000 positions in the genome and did not find a single side effect. But only American and European regulators will decide if there is enough evidence to begin CRISPR clinical trials.


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