On July 20, 2024, Shanghai, China, CorrectSequence Therapeutics Co., Ltd. (Correctseq) announced a significant milestone in their base editing therapy CS-101 for transfusion-dependent β-thalassemia. Utilizing their pioneering transformer Base Editor (tBE), Correctseq has successfully cured the first overseas patient with transfusion-dependent β-thalassemia in a clinical trial in collaboration with the First Affiliated Hospital of Guangxi Medical University. The patient has achieved a sustained transfusion-free status for over two months, with the hemoglobin level stabilized at above 120 g/L. As a result, the patient has been able to resume a normal life. (The First Affiliated Hospital of Guangxi Medical University: 基因编辑治愈首位外籍患者，老挝18岁地贫女孩获新生 The First Overseas Patient Cured by the Gene Editing Therapy, An 18-Year-Old Girl with β-Thalassemia from Laos is Given A New Life)
This milestone marks China's first documented report of an overseas patient being clinically cured through gene editing therapy. As of the reporting date, the clinical trial for CS-101 has yielded remarkable results. Several patients with transfusion-dependent β-thalassemia who have received CS-101 treatment have all achieved transfusion independence following treatment. Notably, two patients have remained transfusion-free for over six months, with the longest duration exceeding eight months.
CS-101, a pioneering cell and gene therapy based on tBE, holds the promise of a "single treatment, lifetime cure" for patients with β-hemoglobinopathies worldwide. This groundbreaking advancement brings hope for a complete cure to those enduring these health challenges.
The first overseas patient who received CS-101 treatment is from Laos. The patient was diagnosed with transfusion-dependent β-thalassemia and required 2 units of red blood cells (RBC) per month prior to receiving CS-101 treatment. Following the therapy, the patient’s hemoglobin level has reached at above 120 g/L within two months after treatment and maintained at such level as of the report date. As a result, the patient successfully achieved independent of blood transfusions.
In April 2024, CS-101 received IND (Investigational New Drug) approval from the National Medical Products Administration (NMPA) of China. This approval has allowed the Phase I clinical trial to commence, marking a significant milestone in the development of CS-101 as a promising treatment for transfusion-dependent β-thalassemia.
The successful implementation of the CS-101 clinical trial is a testament to the safety of the base editing technology employed and the selection of effective targets. The underlying principle of CS-101 involves the collection of the patient's own hematopoietic stem cells, followed by the utilization of tBE. Pioneered by scientists at ShanghaiTech University (Wang et al., Nat Cell Biol, 2021), this technology enables the precise editing of the DNA sequence within the promoter region of the gene responsible for encoding γ-globin (HBG1/2).
By mimicking a naturally occurring beneficial single-nucleotide variant found in individuals with hereditary persistence of fetal hemoglobin, the tBE reactivates γ-globin expression, resulting in the production of functional HbF (Han et al., Cell Stem Cell, 2023). The edited stem cells are then reintroduced into the patient's body, enabling continuous production of blood cells with functional hemoglobin. This approach eliminates the need for frequent blood transfusions, offering a significant advancement in the treatment of transfusion-dependent β-thalassemia.
Compared to traditional blood transfusion therapy and allogeneic hematopoietic stem cell transplantation, CS-101 offers several compelling advantages. One of the key benefits is its short preparation period. Another is eliminating the need for long waiting time for a matching donor since it utilizes the patient’s own hematopoietic stem cells. CS-101 has the potential to achieve a "single treatment, lifetime cure" within a few weeks.
In comparison to other CRISPR-based β-thalassemia gene editing therapies, CS-101 does not carry safety risks associated with large DNA fragment deletions, chromosomal translocation, or off-target mutations. This enhances the overall safety profile of the treatment and reduces potential complications.
Overall, CS-101 offers a promising approach for the treatment of transfusion-dependent β-thalassemia, providing faster and safer hematopoietic reconstruction, quicker restoration of hemoglobin levels, and a shorter path to achieving transfusion independence compared to other therapies.
CS-101 offers a potential complete cure for β-hemoglobinopathy in a safer, faster, and more efficient manner, instilling new hope for patients worldwide. Hemoglobinopathies encompass the most prevalent group of monogenic diseases globally. Among them, β-thalassemia is particularly prevalent in southern China, as well as in Mediterranean countries, South Asian and Southeast Asian countries. In China alone, there are approximately 30 million individuals carrying the thalassemia mutant gene, with around 300,000 severe and intermediate thalassemia patients. In Southeast Asia, approximately 300 million people carry the thalassemia mutant gene, accounting for 44.60% of the total population in the region.
Another common genetic hemoglobinopathy is sickle cell disease (SCD), which is prevalent in various countries worldwide. Approximately 3.5% of the global population carries the mutant gene for SCD, and around 300,000 newborns worldwide are affected by SCD each year.
The Phase I clinical trial for the treatment of β-thalassemia with CS-101 is proceeding steadily. In tandem, a clinical trial targeting SCD with CS-101 are in active preparation, which is an important step towards addressing the needs of SCD patients. A global recruitment program for SCD patients is recently launched, underscoring Correctseq’s commitment in providing care and resolution for patients worldwide.
Correctseq is dedicated to expediting the clinical translation of pioneering gene editing technologies. By developing best-in-class gene editing therapy and first-in-class base editing therapy, Correctseq aims to provide safe, reliable, and cost-effective treatment options for patients worldwide.