Base Editing Therapy Emerges as a New Direction: China's One-Time Cure Solution for 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, Southeast Asia, and other regions. In China, it exhibits a "high incidence in the south and low in the north" pattern: patients are mostly distributed in southern provinces such as Guangdong, Guangxi, Hainan, Fujian, Yunnan, Guizhou, Sichuan, Hunan, Jiangxi, and Chongqing, while it is relatively rare in northern areas.

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 by non-professionals, but their pathogenic causes are fundamentally different," Professor Zhai Xiaowen, Vice President of Children's Hospital of Fudan University and academic leader of hematology, told China Business News. "Iron-deficiency anemia is an acquired disease, mainly caused by insufficient hemoglobin synthesis due to iron deficiency in the body—such as iron-poor diet, poor iron absorption, or chronic blood loss. In contrast, thalassemia is an inherited disease, resulting from imbalanced synthesis of globin chains that compose hemoglobin due to gene defects."

In the field of hematology, thalassemia is mainly classified into α-thalassemia and β-thalassemia based on the affected globin chain. Each type is further divided into silent, mild, intermediate, and severe subtypes according to severity. Among these, severe thalassemia is the most harmful: without timely intervention, it may be life-threatening in adolescence. Transfusion-dependent thalassemia patients, on the other hand, require lifelong regular blood transfusions and iron chelation therapy.

Statistics show that there are over 30 million thalassemia gene carriers in China, with an estimated tens of thousands of severe cases. "Severe thalassemia poses a great threat to patients' lives. Due to severe impairment of hemoglobin synthesis and significantly shortened red blood cell lifespan, patients need blood transfusions every 2-3 weeks to sustain life. Without timely transfusion, hemoglobin can drop to extremely low levels, causing tissue hypoxia and, in severe cases, cardiac insufficiency and multi-organ damage.

Some children with severe thalassemia may develop severe malformations during fetal development," Zhai Xiaowen explained. Severe thalassemia cases are extremely rare in northern China, and most cases seen in Shanghai are from southern regions or patients with a family history of carriers.

"If both spouses are thalassemia gene carriers, the risk of having a child with severe thalassemia increases significantly, and disease prevention is extremely challenging," Zhai Xiaowen added. If both spouses are carriers of the same type of thalassemia, their children have a 25% chance of being severe thalassemia patients, a 50% chance of being carriers, and a 25% chance of being normal.

Patients with severe thalassemia need to maintain a hemoglobin concentration of 95-105 g/L; below this level, blood transfusion intervention is often required. Long-term blood transfusion can lead to iron overload, which may cause multi-organ damage, so simultaneous iron chelation therapy is essential. However, long-term transfusion and iron chelation therapy not only easily trigger adverse reactions such as fever, allergies, and hemolysis but also impose a heavy economic and mental burden on patients' families.

New Technology: Base Editing Therapy

The treatment of thalassemia requires personalized plans based on disease severity. Severe thalassemia mainly relies on allogeneic hematopoietic stem cell transplantation (HSCT), but this technology is limited by difficulties in donor matching, high surgical risks, high treatment costs, and potential postoperative complications such as infection and rejection.

"Today's increasingly mature gene editing technology brings hope for the one-time complete cure of β-thalassemia," Zhai Xiaowen told China Business News. Based on several cases collaboratively treated by the hospital and Professor Chen Jia's team from ShanghaiTech University using "base editing therapy" in the past two years, patients have maintained stable hemoglobin levels within the normal range of 110-130 g/L during the 12-24 month follow-up period after surgery. They no longer need regular blood transfusions and iron chelation therapy, bone marrow hematopoietic function has fully recovered to normal, growth and development are on track, and no serious adverse reactions have occurred—overall achieving extremely satisfactory results.

Shanghai is not a high-incidence area for thalassemia, so why invest substantial resources in this field? Zhai Xiaowen explained that as a top domestic pediatric specialist hospital, Children's Hospital of Fudan University has accumulated rich experience in rare disease diagnosis and treatment, especially in stem cell transplantation for rare hematological diseases. The hospital's disciplinary advantages provide a solid foundation for thalassemia research. On the other hand, the "scalability" of this gene editing technology is highly attractive: "The main research directions of our department are pediatric hematological tumors and rare disease stem cell transplantation. Many rare diseases can currently only be cured through transplantation. When we first engaged in the thalassemia gene therapy project, we realized that this technology can not only solve thalassemia but also has the potential to be applied to other rare hematological diseases. If gene editing technology can be maturely applied, it may allow patients to break free from dependence on donors and achieve a more convenient 'one-time cure'."

In addition, as all cooperative parties are located in Shanghai, the city's sound scientific research and industrial ecosystem provide support for the smooth progress of the project. The closed-loop of close collaboration in "R&D - transformation - clinical application" reduces communication costs during technology implementation and effectively accelerates the research process.

Zhai Xiaowen further explained that the core principle of single-base editing technology 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. However, thalassemia patients need to activate HbF synthesis through technology. Although its oxygen-carrying capacity is lower than that of HbA, it can maintain basic hematopoietic function and help patients get rid of transfusion dependence."

The research team at ShanghaiTech University achieves direct single-base conversion without cutting the DNA double strand. Compared with traditional gene editing technology, base editing does not require breaking the DNA double strand, thereby reducing the risks of chromosomal abnormalities and large-fragment deletions and achieving higher safety. "This technology only edits key bases, and with an optimized delivery system, it effectively improves targeting efficiency and controls off-target risks," Zhai Xiaowen noted. As an important breakthrough in the field of gene therapy, base editing technology brings new hope for the treatment of monogenic genetic diseases such as β-thalassemia, providing a precise and efficient treatment method. "Strengthening editing site prediction and off-target risk control with the help of artificial intelligence-assisted technology is also an important development direction in the future."

From "Shanghai Plan" to "China Plan"

Currently, Children's Hospital of Fudan University has completed gene therapy for multiple child subjects with thalassemia in clinical research (including a 4-year-old Pakistani girl), with treatment effects far exceeding expectations, making the hope of "one-time cure" clearly visible. Zhai Xiaowen introduced that the hospital's entire treatment process is clear and controllable: collecting the patient's own stem cells, sending them to the laboratory for gene editing, and then infusing the edited stem cells back into the patient's body.

"From the completed cases, the frequency of blood transfusion in patients has significantly decreased after infusion; some patients no longer need transfusions at all, and hemoglobin has gradually risen to the normal range without obvious complications, resulting in a fundamental improvement in quality of life. Among them, the earliest treated patient has been followed up for nearly two years, with stable hemoglobin at a normal level, no dependence on any subsequent treatment, and can live completely like a healthy person. In subsequent cases, some patients did not require any blood transfusion after infusion, and their hemoglobin directly rose to over 130 g/L. In addition, young children treated with this technology have a significantly higher proportion of edited cells in the bone marrow than the average level of previous studies, maintaining long-term dominance. These achievements not only verify the effectiveness of the technology but also confirm the possibility of 'one-time editing and long-term benefits'."

Zhai Xiaowen stated that foreign counterparts have also paid attention to the "Shanghai Plan". Medical institutions in Europe, America, and Southeast Asia have taken the initiative to contact, hoping to learn about the R&D details of single-base editing technology, clinical protocol design, and patient management experience. The hospital team has received many visits from foreign experts, sharing the whole-process experience from technology transformation to clinical implementation, and has also been invited to introduce case results at international academic conferences. The "Shanghai Plan" has gradually evolved into a "China Plan" that provides a reference for global thalassemia treatment.

To further promote the realization of the goal of "one-time cure for thalassemia", Zhai Xiaowen revealed that the team has formulated a multi-dimensional follow-up plan: in terms of long-term monitoring, launching a 15-year follow-up study on treated patients to continuously track the long-term safety and effectiveness of gene editing; in terms of indication expansion, discovering that the technology can be used to treat sickle cell anemia (common in people of African descent, where patients suffer from severe muscle pain in addition to anemia), and planning to recruit international patients for free treatment, so that the hope of "one-time cure" can benefit more rare disease patients.

Gene editing therapy involves multiple complex links, including hematopoietic stem cell collection, in vitro culture, gene editing, cell sorting and expansion, and reinfusion. The R&D costs of core reagents and technology platforms are relatively high. However, Zhai Xiaowen believes that with the large-scale application of the technology, domestic substitution of core reagents, and gradual coverage of medical insurance policies, the treatment cost is expected to decrease significantly in the future, allowing more thalassemia patients to completely break free from long-term transfusion dependence through one-time gene editing therapy. This original Chinese medical technology will also bring the hope of "one-time cure" to patients around the world.

"Although gene editing technology has brought hope for 'one-time cure' to severe patients who have already been born, in addition to treatment, the core of thalassemia prevention and control lies in prevention. China's National Health Commission and governments in high-incidence southern regions are vigorously promoting pre-pregnancy and prenatal thalassemia screening. However, insufficient awareness is the first obstacle: many people lack basic understanding of thalassemia, believing that they will not get the disease if they have no obvious symptoms, and do not recognize the importance of screening. This cognitive misunderstanding makes it difficult to effectively advance the prevention and control window, and many potential patients miss the best opportunity for early detection and intervention. Therefore, great attention must be paid to early screening and testing," Zhai Xiaowen said.