World's first CRISPR gene editing therapy approved for marketing


On November 17, we witnessed a new milestone in the development of biotechnology. A disease therapy based on CRISPR gene editing technology has received conditional marketing approval from the UK's Medicines and Healthcare Products Regulatory Agency (MHRA), becoming the world's first CRISPR gene editing therapy approved by a regulatory agency.

The trade name of this therapy is Casgevy (generic name: exagamglogene autotemcel, abbreviated as exa-cel). It was jointly developed by Vertex Pharmaceuticals, Inc. and CRISPR Therapeutics. It is used to treat two genetic blood diseases—— Transfusion-dependent beta-thalassemia (TDT) and sickle cell disease (SCD).

A news report in the top academic journal "Nature" quoted Professor Kay Davies, a geneticist at the University of Oxford in the UK, as commenting: "This is a landmark approval that opens the door to further applications of CRISPR therapies in the future, with the potential to cure many genetic diseases. "

Sickle cell anemia is a disease caused by a genetic mutation in which a patient's hemoglobin becomes prone to linking together, which transforms the red blood cells from their normal, flexible round shape into a less flexible, crescent-shaped, sickle-like shape. These malformed cells can block blood vessels, causing them to become occluded, damaging their walls, and causing life-threatening blood clots.

Beta-thalassemia is also a type of genetic disease. Normally, hemoglobin is composed of alpha and beta chains. However, patients with beta-thalassemia cannot produce enough beta chains due to genetic mutations, so the ability of red blood cells to bind iron is greatly affected. damage. Patients need to receive regular blood transfusions, but because the patients cannot produce effective red blood cells, the iron obtained from the blood transfusion cannot be consumed. In the long run, the body will accumulate a large amount of iron and damage organ functions. In recent years, with the emergence of drugs that help the body eliminate iron, the quality of life of patients with β-thalassemia has improved to some extent, but there is still a huge drug burden. Both types of patients are in urgent need of a new treatment modality.

Nowadays, Casgevy has become a new strategy that can treat two diseases. It uses gene editing to modify the patient's own hematopoietic stem cells so that the cells can produce high levels of fetal hemoglobin, which is completely healthy and can be carried normally. Hemoglobin form of oxygen. However, fetal hemoglobin is only produced during fetal development, and its expression pathway is shut down after birth.

Some special cases show that when the BCL11A gene is mutated, some adults can also produce fetal hemoglobin. What Casgevy does is to simulate this mutation and use gene editing to cut BCL11A in the patient's hematopoietic stem cells and release the brake on fetal hemoglobin.

According to a paper published in the New England Journal of Medicine, in actual operation, the research team needs to first collect hematopoietic stem cells from the patient and then send them to the laboratory for gene editing. At the same time, the patient must eliminate the original natural hematopoietic stem cells in the bone marrow before re-infusing stem cells. This step is very important, firstly, to reduce the subsequent expression of abnormal hemoglobin, and secondly, to provide new gene-edited hematopoietic stem cells. Leave room for growth.

Because this process of removing natural stem cells requires the use of chemotherapy drugs, patients may experience some degree of side effects and have reduced immunity during this stage. They need to receive special care in the hospital for at least a month in advance to prevent infection.

According to observations from the first batch of patients receiving treatment, patients will experience side effects such as nausea, fatigue, and fever, but there are no serious treatment safety issues. Within 6 months of patient 1 receiving treatment, the proportion of red blood cells expressing fetal hemoglobin would increase from the basic 10.1% to 99.7%, and this could be maintained until 18 months later. The proportion of red blood cells expressing fetal hemoglobin in patient 2 increased to 99.9% at 5 months, and remained close to 100% by the 15th month.

During long-term follow-up, the research team was able to detect high levels of fetal hemoglobin in the patients, and the patients' vaso-occlusive pain disappeared and they no longer needed blood transfusions. It can be said that gene editing therapy gives them a new life.

Following the UK, Exe-cel is also expected to be approved for marketing in some other countries and regions. It is understood that Exe-cel is currently undergoing review by the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA), and the Saudi Food and Drug Administration. Recently, the U.S. FDA held a meeting of the Cell, Tissue, and Gene Therapy Advisory Committee to discuss the Biologics License Application (BLA) for exa-cel for the treatment of patients with sickle cell anemia (SCD), and to consult on potential off-target effects of this therapy. Opinions from outside experts.

Dr. Samarth Kulkarni, CEO of CRISPR Therapeutics, said in the news media: "Genome editing is special and may redefine the medical paradigm for the next 30-40 years. The approval of Exa-cel represents the beginning of it."

Currently, several other CRISPR therapies currently under development are also attracting attention. Including the investigational CRISPR in vivo genome editing therapy NTLA-2001 jointly developed by Intellia Therapeutics and Regeneron. Positive preliminary data from the Phase 1 clinical trial showed that it can improve transthyretin (ATTR) amyloidosis and is about to undergo a global Phase 3 trial. Verve Therapeutics' single base editing therapy VERVE-101, modified based on the CRISPR system, can target specific genes to modify a single letter. The recently announced phase 1b clinical trial results showed the potential to permanently reduce the risk of cardiovascular disease at one time.