Thalassemia, a term echoing throughout the globe, refers to one of the most prevalent and dangerous monogenic hereditary diseases. Patients suffering from severe thalassemia are from the moment of diagnosis shackled to a lifetime of continuous blood transfusions to sustain their lives. Alternatively, they can undergo bone marrow transplantation, but the odds of finding a non-relative donor match are slim - ranging from one in tens of thousands to one in millions.

Since February 2021, the Shenzhen Children's Hospital, in collaboration with Hemogen, a subsidiary company of BGI Group, has been pioneering a gene therapy based on autologous hematopoietic cell transplantation (HCT) for patients with severe thalassemia. To date, all five children who have undergone this treatment have achieved clinical recovery and no longer require blood transfusion therapy. 

Today, we are privileged to talk to the project leader, Dr. Liu Sixi, Director of the Department of Hematology and Oncology at Shenzhen Children's Hospital, about his perspectives on this project and the story behind it. 

Dr. Liu Sixi, Director of the Department of Hematology and Oncology at Shenzhen Children's Hospital.

Q: Can you briefly introduce the thalassemia gene therapy project and its current progress?

Liu: Thalassemia is one of the most common and serious monogenic hereditary diseases worldwide. Clinically, it is divided into four types based on its gene mutation: α, β, γ, and δ thalassemia. The most common types are α-thalassemia and β-thalassemia, with transfusion-dependent patients mainly suffering from severe β-thalassemia.

This made us think: since severe β-thalassemia is mainly caused by gene mutations, could we possibly cure the disease by modifying the genes in vitro? In this project, we extract the patient's autologous hematopoietic stem cells, process them in vitro, and then reinfuse the modified hematopoietic stem cells back into the patient's body to achieve therapeutic purposes. This treatment only changes the genes of the patient's somatic cells, which are the genes of the hematopoietic stem cells, and does not alter the reproductive cells. 

Since this is an entirely new project, the process has also gone through the approval of some institutions of the children's hospital, such as the offices of ethics approval and clinical research project.

To date, our thalassemia gene therapy project has been in operation for over two years. We have provided treatment for five patients, all of whom have been freed from transfusions and have a good quality of life. The first case treated in February 2021 has been off transfusions for over two years now. So overall, the project is running very smoothly.

Q: Could you introduce the current research progress of this technology in the world?

Liu: This technology was first developed in the United States; they have been doing it for over a decade now. To date, no certain or serious adverse events related to lentiviral transfection have been found, which has given us a lot of confidence. In China, BGI is in a leading position in this field.

Q: What role has the technology from Hemogen played in the gene therapy for thalassemia?

Liu: There are mainly two approaches to thalassemia gene therapy. One is to modify hematopoietic stem cells by lentiviral transfection, and the other is through gene editing. 

BGI uses the first approach - lentiviral transfection. After we collect and separate the patient's hematopoietic stem cells clinically, we hand them over to institutions like BGI to perform lentiviral transfection, thereby completing the modification of the hematopoietic stem cells. BGI plays a core role in this step. Afterward, we reinfuse these modified hematopoietic stem cells at the hospital and then observe their therapeutic effect.

Q: Why did you initially choose gene technology to treat thalassemia?

Liu: In the treatment of severe thalassemia, hematopoietic cell transplantation (HCT) is a very mature technology for transfusion-dependent thalassemia. However, some patients still cannot be treated by transplantation due to limitations of donors and the patients' own physical conditions. 

For these patients, thalassemia gene therapy offers a way to rid them of transfusion dependency because the intensity of chemotherapy used in gene therapy is relatively low, causing less harm to the body, and immunosuppressive drugs are not needed after transplantation.

If this technology becomes mature and widely adopted, it may enable this group of patients to be free from transfusion. This is a very important reason why we chose thalassemia gene therapy as a future breakthrough.

Q: During the research process, was there anything that particularly moved you?

Liu: What touched me deeply was the understanding and support of the patients or their parents for this project.

Especially during the preoperative informed consent, on the one hand, you can see their eagerness to escape the state of thalassemia transfusion. On the other hand, because the technology is quite new and may pose some unpredictable risks and challenges, they have shown great tolerance and understanding. I am grateful to them. It is because of such a group of patients and families that our project has been able to move forward smoothly.

So far, the first patient we treated has been in a transfusion-free state for two years, achieving our therapeutic goal. I want to congratulate him.

Q: What does it mean for a patient not to need transfusions within two years after gene therapy? Why two years?

Liu: For benign status, being able to avoid transfusion for two years means the likelihood of relapse becomes very small, and it can be said that the patient has reached a state of being free from thalassemia transfusion. This means that the child can live and study normally.  

The first patient we just mentioned is indeed now studying in school and receiving an education just like the other students. Of course, two years may not be sufficient as an observation period for our entire research study. Nonetheless, we have taken a solid step forward, and I believe the future will be even brighter.

For many years, BGI Group has been dedicated to the screening, treatment, and support for patients with thalassemia, working through means of public welfare, scientific research, and improving people's livelihoods to help achieve the vision of a world free from thalassemia.

In terms of thalassemia prevention and control, as of June 30, 2023, BGI Genomics, a subsidiary of the BGI Group, has provided genetic testing for thalassemia to more than 1.4 million people, aiding in the prevention and control of severe thalassemia. Regarding the rescue of patients with thalassemia, BGI Genomics collaborate with other institution to initiate the "Hua Foundation," which offers permanent free high-resolution HLA typing for children worldwide with severe thalassemia. By June 30, 2023, the "Hua Foundation" had received and completed 19,391 samples for public welfare, benefiting 6,548 families, with 698 children successfully finding fully compatible matches.

Recently, Hemogen independently developed the HGI-001 injection, which has successfully obtained implied permission for clinical trials (investigational new drug, IND) from the National Medical Products Administration (NMPA) of China. This gene therapy product, based on autologous hematopoietic stem cells, is designed to treat transfusion-dependent β-thalassemia and has already been administered to 5 patients in the investigator-initiated clinical trial (IIT). In May this year, with the efforts of Hemogen and other organizations, the world's first patient with α-thalassemia successfully became transfusion-independent following gene therapy.