Clinical application of gene therapy in tumor and genetic diseases I

Gene therapy refers to the introduction of normal genes into human cells to correct or supplement diseases caused by genetic defects and abnormalities. It is a fundamental therapeutic strategy. The introduced gene may be a homologous gene corresponding to a defective gene, expressing a specific function in vivo, or may be a therapeutic gene unrelated to the defective gene. Here in this article, we mainly talk about the clinical application of gene therapy in cancer and genetic diseases.

1. CAR-T: The most successful application of “ex vivo” gene therapy

CAR-T treatment (Chimeric Antigen Receptor T-Cell Immunotherapy) is currently the most clinically successful application of “ex vivo” gene therapy. At present, CAR-T technology is mainly used for the treatment of hematological tumors. The main representatives are Kymriah (Novartis) and Yescarta (Kite) approved by the FDA in 2017. The treatment of solid tumors is still in the exploration stage, and it still needs to wait for a revolutionary breakthrough. When patients receive CAR-T treatment, scientists first isolate T cells from the patient’s peripheral blood, and then use the vector such as lentivirus to introduce the engineered target gene into T cells, and transform T cells into CAR-T cells. Those CAR-T cells have the ability to specifically recognize and kill tumor cells; after they are expanded to a certain number, they are returned to the patient to achieve tumor treatment.

Taking leukemia as an example, traditional chemotherapy and radiotherapy have been used clinically for decades. It is effective for most leukemias, and its efficacy and side effects are relatively clear. Therefore, it is still the clinically preferred treatment at this stage, but the treatment effect on some patients is not ideal. Therefore, the significance of CAR-T is to provide new treatments for patients who are ineffective in these traditional therapies. Luckily many CAR-T products have achieved very good clinical results. However, leukemia is only the starting point for clinical application of CAR-T, and CAR-T is still a third-line treatment program. In the future, with the continuous improvement and maturity of the technology, CAR-T is expected to be a breakthrough in the treatment of other blood tumors and even solid tumors in addition to leukemia. This will completely change the current pattern of cancer treatment.

2. Thalassemia: gene therapy is expected to subvert existing treatment options

Thalassemia, a globin-producing anemia, usually shows a common anemia state and corresponding complications. The pathogenesis of the disease is that the globin gene defect reduces one or several syntheses of the globin peptide chain in hemoglobin, resulting in a change in the composition of synthetic hemoglobin, which in turn leads to a shortened cell life pf red blood. It manifests as chronic hemolytic anemia. Thalassemia is an autosomal recessive genetic disorder. When both husband and wife are carriers of the causative gene, their offspring have a 25% probability of becoming sick, 50% of the probability is a carrier of the causative gene, and a probability of 25% that the gene is completely normal.

For thalassemia, the current clinical routine treatment is regular blood transfusion, and patients need lifelong treatment, expensive treatment, and easy to produce blood transfusion side effects. The radical treatment is to carry out hematopoietic stem cell transplantation, implanting healthy human hematopoietic stem cells into patients. With this method, the cure for the disease can be achieved, but the biggest obstacle is that the hematopoietic stem cell matching is very difficult. Even if the matching is successful, most patients still need to take immunosuppressive drugs for a long time after receiving the treatment.

The most promising treatment is gene therapy. After collecting hematopoietic stem cells from the patient’s peripheral blood, the normal globin gene is introduced into the virus carrier to restore the normal function of the cells, and the modified hematopoietic stem cells are returned to the patient. Hematopoietic stem cells are derived from the patient itself, so there is no problem with matching and rejection. After the transformed hematopoietic stem cells enter the patient’s body, they will continuously produce new red blood cells with normal functions, thereby achieving the purpose of alleviating or even curing the disease.

Compare those methods, the current clinical treatment of thalassemia has many defects, and gene therapy has largely filled this clinical unmet need. After the technology is further matured, it is expected to be rapidly promoted in the clinic.

3. Sickle cell anemia: genetic editing may erase the “imprint” of natural selection

Sickle cell anemia is an autosomal recessive genetic disease, mainly found in black Africans, as well as in the Middle East, Greece, Turkish Indians, and people who have long-term marriages with these ethnic groups. Normal red blood cells are in the shape of a round cake, while the patient’s red blood cells are sickle-shaped, and their function of carrying oxygen is only half that of normal red blood cells. Symptoms gradually appear after the patient is born for half a year. In addition to the symptoms associated with anemia, clinical patients are often accompanied by growth retardation and abnormal skeletal development.

The pathology of sickle cell anemia is that a single base mutation occurs in the β-globin gene, which changes the amino acid sequence of β-globin, resulting in a decrease in the solubility of hemoglobin, which in turn forms a tubular gel structure, causing the red blood cells to be twisted into a sickle shape. Due to abnormal morphology, sickle-shaped red blood cells tend to accumulate at the branches of fine blood vessels, causing vascular obstruction, and even death.

At present, sickle cell anemia can not be cured, and the clinical treatments can only alleviate symptoms, such as blood transfusion and hematopoietic stem cell transplantation, and gene therapy is expected to cure sickle cell anemia. Unlike the transgenic treatment of thalassemia, sickle cell anemia requires correction of the patient’s own wrong genes. Therefore, after collecting the patient’s hematopoietic stem cells, genetic editing techniques can be used to change the mutated gene back to the normal gene and make the function of the hematopoietic stem cells restored, and then the transformed hematopoietic stem cells are returned to the patient to realize the treatment of the disease.

To be continued in Part II…