Professor shi are: the research development of gene therapy in the Mediterranean anemia | the 2nd China blood subject development conference

2022-06-18 0 By

Thalassemia (thalassemia) is a recessive genetic disease, which is divided into different subtypes according to the different genes involved. The most common are alpha thalassemia and beta thalassemia.According to the severity of the clinical manifestations of the disease, α Thalassemia is divided into static, light, intermediate, severe, β thalassemia is divided into light, intermediate, severe.Mild patients may be asymptomatic, but severe patients may develop organic and functional damage to multiple organs and require lifelong transfusion therapy.At the second China Hematology Development Conference held online from January 14-16, 2022, Prof. Shi Jun, Hospital of Hematology, Chinese Academy of Medical Sciences, introduced the first case of gene therapy in patients with transfusions dependent β thalassemia in China under the title of “Clinical Research on gene therapy in Thalassemia”.Status and Treatment of Thalassemia in China In 2015, the Chinese Thalassemia Blue Book announced that 30 million people in China carry thalassemia genes, 250,000 people are intermediate thalassemia, and 50,000 people are severe thalassemia.About 99% of patients with severe thalassaemia are under 20 years old. The average life expectancy of patients with severe thalassaemia is only 15 years old, the treatment cost is as high as 50,000-100,000 yuan/year, and the blood transfusion volume is as high as 40-50U/ year.The clinical treatment of thalassemia mainly includes regular blood transfusion and iron removal therapy, drug-induced γ globulin expression, fully compatible allogeneic hematopoietic stem cell transplantation and CD34+ hematopoietic stem cell autologous transplantation after gene editing in vitro.Professor Shi Jun said that the incidence of thalassaemia in China is high, and the prognosis of patients with severe blood transfusion dependence is poor and the economic burden is heavy.For the treatment of thalassaemia, blood transfusion and iron removal are symptomatic relief, and there is a lack of drugs that can cure thalassaemia.At present, the preferred radical treatment is fully compatible allogeneic hematopoietic stem cell transplantation, but not all patients can have a fully compatible donor, so autologous transplantation after in vitro genetic engineering editing of CD34+ hematopoietic stem cells is a good treatment.There are two main technology systems for gene therapy of thalassemia. One is the transfection of CD34+ hematopoietic stem cells enriched in the patient’s body with lentivirus as a vector, and the gene editing is completed by introducing β -globulin chain genes, and the other is the technology of CROSPR/Cas9.Induction of γ globin chain gene expression completes gene editing (FIG. 1).Through these two technical systems, erythrocytes can synthesize normal hemoglobin eventually, so as to fundamentally treat thalassemia.FIG. 1 Subsequently, Prof. Jun Shi introduced the first patient with transfusions dependent β thalassemia treated with gene editing CD34+ hematopoietic stem cells using CROSPR/Cas9 technology in the Regenerative Medicine Center of Hematology Hospital, Chinese Academy of Medical Sciences.The baseline clinical characteristics of the first patient were shown in Figure 2. Before treatment, hemoglobin (Hb) and hemoglobin F (HbF) were 67g/L and 3.4g/L, respectively.FIG. 2 The technical process of gene therapy is mainly divided into four steps: ① Monopheresis enrichment of autologous CD34+ hematopoietic stem cells;② Gene engineering editing of CD34+ hematopoietic stem cells;③ Preconditioning before autologous transplantation;④ CD34+ hematopoietic stem cell autologous transplantation after gene editing (Figure 3).FIG. 3 Prof. Shi Jun focused on the safety and efficacy of autologous genetic engineering stem cell transplantation in this patient.In terms of safety, platelets implanted 37 days after autologous genetic engineering stem cell transplantation stabilized at 50-60 ×109/L after 6 months, and reached 100×109/L after 9 months. Platelets were more than 100×109/L after follow-up.Neutrophil implantation basically stabilized at 1.5~2.5×109/L at 24 days and 6 weeks after transplantation.Adverse events in patients included neutropenia, thrombocytopenia, leukopenia and anemia, and grade ≥3 adverse reactions were mainly related to autologous transplantation pretreatment.In addition, 15 days after mobilization of stem cell collection, the patient had an intestinal obstruction, which was considered to be enterocolitis caused by unclean diet and not related to the study drug.Palpitations of drug-related adverse reactions occurred about 10 minutes after stem cell infusion after gene editing, and were alleviated by slowing the infusion rate. This adverse reaction occurred only once.The efficacy was evaluated in four aspects: ① whether anemia was improved;② In vivo hematopoietic implantation ability;③ In vitro colony formation ability;(4) hematopoietic reconstruction of immune function.The Hb and HbF of the patient were 107g/L and 88g/L, respectively, at the 12th month after autologous genetic engineering stem cell transplantation.Moreover, at 12 months after transplantation, the patient’s ability to implant gene-edited hematopoietic stem cells in bone marrow returned to pre-transplantation levels (Figure 4).In vitro colony formation of gene-edited hematopoietic stem cells did not differ from that before transplantation.The proportion and absolute value of CD3+T cells, CD4+/CD8+T cells and CD19+B cells were within the normal range after transplantation.IgG, IgA, IgM, COMPLEMENT C3 and COMPLEMENT C4 were in the normal range.NK cell ratio and absolute value were also in the normal range.Shi concluded that the efficacy of this case was similar to that of an international study of the same type presented at the European Congress of Hematology (EHA) in 2021.In addition, the first case of hematopoietic stem cell editing by genetic engineering and autologous transplantation in the treatment of transfused dependent β thalassaemia was successful. This study was also the first clinical trial related to gene editing approved by the State Food and Drug Administration in China, which had a milestone significance.Professor are blood diseases hospital, Chinese academy of medical sciences (Chinese academy of medical sciences institute of hematology) national blood system diseases, director of the center for regenerative medicine diagnosis and treatment of clinical medical research center, deputy director of the Chinese society of hematology branch of the 11th committee of the Chinese medical association hematology branch of the 11th red blood cells the disease group hematology branch deputy head of the tianjin medical associationVice Chairman: Editorial board member of Chinese Journal of Hematology