Base Editing Therapy: A New Direction for China's One-Time Cure of Thalassemia

Thalassemia is an inherited hemolytic anemia caused by globin gene defects. First discovered along the Mediterranean coast, it derives its name from this region. Its core characteristic is impaired hemoglobin (Hb) synthesis due to globin gene mutations, leading to ineffective erythropoiesis and ultimately chronic anemia of varying severity.

Geographically, thalassemia is prevalent in the Mediterranean coast, the Middle East, and Southeast Asia. In China, it exhibits a "high incidence in the south and low in the north" pattern: patients are mostly in southern provinces such as Guangdong, Guangxi, Hainan, Fujian, Yunnan, Guizhou, Sichuan, Hunan, Jiangxi, and Chongqing.

Far More Than Simple Anemia: Over 30 Million Carriers in China

"Thalassemia and iron-deficiency anemia have similar names and symptoms, making them easily confused, but their causes are fundamentally different," Professor Zhai Xiaowen, Vice President of Children's Hospital of Fudan University and academic leader of hematology, explained. "Iron-deficiency anemia is an acquired disease, mainly caused by iron deficiency. In contrast, thalassemia is inherited, resulting from imbalanced synthesis of the globin chains that compose hemoglobin due to gene defects."

Thalassemia is mainly classified into α-thalassemia and β-thalassemia based on the affected globin chain, each further divided into silent, mild, intermediate, and severe subtypes. Severe thalassemia is the most harmful: without timely intervention it may be life-threatening in adolescence. Transfusion-dependent patients require lifelong regular transfusions and iron chelation therapy.

China has over 30 million thalassemia gene carriers, with an estimated tens of thousands of severe cases. Severe patients need transfusions every 2-3 weeks to sustain life. If both spouses carry the same type, their children have a 25% chance of being severe patients, 50% carriers, and 25% normal.

Severe patients must maintain hemoglobin of 95-105 g/L; below this, transfusion is often required. Long-term transfusion leads to iron overload and possible multi-organ damage, so simultaneous iron chelation is essential — imposing a heavy economic and mental burden.

New Technology: Base Editing Therapy

Severe thalassemia mainly relies on allogeneic hematopoietic stem cell transplantation (HSCT), but this is limited by donor matching difficulties, high surgical risks, high costs, and postoperative complications such as infection and rejection.

"Increasingly mature gene editing technology brings hope for a one-time complete cure of β-thalassemia," Zhai Xiaowen said. Based on several cases collaboratively treated by the hospital and Professor Chen Jia's team from ShanghaiTech University using base editing therapy over the past two years, patients maintained stable hemoglobin in the normal range of 110-130 g/L during 12-24 months of follow-up. They no longer need regular transfusions and iron chelation, bone marrow hematopoietic function fully recovered, growth is on track, and no serious adverse reactions occurred.

The core principle of single-base editing for thalassemia gene therapy is to use fetal hemoglobin (HbF) to replace abnormal adult hemoglobin (HbA). After birth, HbF gradually decreases and HbA increases in normal people; thalassemia patients need to activate HbF synthesis through technology. Although HbF's oxygen-carrying capacity is lower, it can maintain basic hematopoietic function and free patients from transfusion dependence.

The ShanghaiTech team achieves direct single-base conversion without cutting the DNA double strand. Compared with traditional gene editing, base editing does not require breaking the double strand, reducing risks of chromosomal abnormalities and large-fragment deletions and achieving higher safety.

From "Shanghai Plan" to "China Plan"

Children's Hospital of Fudan University has completed gene therapy for multiple child subjects (including a 4-year-old Pakistani girl), with effects far exceeding expectations. The process is clear: collect the patient's own stem cells, send them for gene editing, then infuse the edited cells back.

The earliest treated patient has been followed for nearly two years with stable normal hemoglobin, no dependence on subsequent treatment, and can live like a healthy person. In later cases, some patients required no transfusion and hemoglobin rose directly above 130 g/L.

Foreign counterparts have noticed the "Shanghai Plan." Institutions in Europe, America, and Southeast Asia have reached out to learn the details. The "Shanghai Plan" is gradually evolving into a "China Plan" that provides a reference for global thalassemia treatment.

The team also found the technology can treat sickle cell anemia (common in people of African descent) and plans to recruit international patients for free treatment. Zhai believes that with large-scale application, domestic reagent substitution, and gradual insurance coverage, treatment costs will decrease significantly.

Zhai emphasized that although gene editing brings hope of a one-time cure, the core of thalassemia control lies in prevention. China's National Health Commission and southern high-incidence regions are vigorously promoting pre-pregnancy and prenatal screening. Insufficient awareness is the first obstacle, so early screening and testing must be prioritized.