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CS-101 from CorrectSequence Therapeutics successfully cures patient with transfusion-dependent β-thalassemia

SHANGHAI, January 10, 2024 /PRNewswire/ -- On January 8, 2024, in Shanghai, China, CorrectSequence Therapeutics Co., Ltd. (Correctseq), using innovative transformer Base Editing (tBE) technology to help people with serious illnesses, announced positive results from its base editing therapy for transfusion-dependent β-thalassemia, CS-101. In collaboration with the First Affiliated Hospital of Guangxi Medical University, the investigator-initiated trial (IIT) of CS-101 has successfully cured the first patient treated with transfusion-dependent β-thalassemia, resulting in an absence sustained transfusions for more than two months. Eight weeks after CS-101 treatment, the patient's fetal hemoglobin (HbF) level increased to ~95 g/L, representing ~81% of total hemoglobin. The percentage of cells expressing HbF (F cells) has increased to ~80%. As of the date of the report, the patient's hemoglobin level has remained at 130 g/L or higher and the patient has resumed his normal life. Notably, to the best of our knowledge, this is the first global report on successful clinical cure of hemoglobinopathy with base editing therapy.

Hemoglobinopathies, encompassing β-thalassemia and sickle cell diseases (SCD), are the most common group of monogenic diseases in the world, with approximately 7% of the world's population carrying the mutant gene. Around 400,000 newborns suffer from hemoglobinopathies each year worldwide. β-Thalassemia is a genetic disease caused by mutations in the β-globin gene, resulting in defective hemoglobin production. Correctseq's CS-101 is a personalized treatment that begins with the collection of autologous hematopoietic stem cells from patients with β-thalassemia. Transformer Base Editor (tBE) technology (Wang et al., Nat Cell Biol, 2021), developed by scientists at ShanghaiTech University, is used to precisely edit the DNA sequence of the promoter region of the gene that encodes γ- globin (HBG1/2) to mimic the single nucleotide variant that occurs naturally in the population with hereditary persistence of fetal hemoglobin, thereby reactivating γ-globin expression to produce functional HbF. Finally, the edited stem cells are infused back into the patient, allowing them to continually produce blood cells with intact hemoglobin and eliminating the need for frequent blood transfusions. While several gene editing strategies have been explored to restore normal hemoglobin levels in patients with β-thalassemia, base editing of the BCL11A binding site in the HBG1/2 promoter by tBE, as in CS-101 treatment exhibited the highest level of γ-globin reactivation both in vitro and in vivo (Han et al., Cell Stem Cell, 2023).

In Correctseq's CS-101 IIT study, the first patient with transfusion-dependent β-thalassemia (β0/β type) received tBE-based gene editing therapy in October 2023. This patient began receiving blood transfusions at at the age of two years and had been receiving 4 units of red blood cells (RBC) every two weeks before starting treatment with CS-101. After receiving CS-101 treatment, the patient successfully achieved hematopoietic reconstruction, with neutrophil engraftment within 16 days, and stopped receiving blood transfusions on day 14 after transplant. Four weeks after treatment, the patient's HbF concentration was ~16 g/L, representing ~21% of total hemoglobin, and the proportion of F cells was ~23%. Eight weeks after treatment, the patient's HbF concentration increased to ~95 g/L, representing ~81% of total hemoglobin, and the proportion of F cells was ~80%. As of the date of the report, the patient's hemoglobin level has remained at 130 g/L or higher and no adverse effects related to CS-101 have been observed.

Compared with other CRISPR-based β-thalassemia gene editing therapies, CS-101 using tBE technology shows effective hematopoietic reconstruction, earlier recovery to normal range of hemoglobin level, and shorter time to achieve independence of the transfusion. Importantly, CS-101 carries no safety risks, such as large DNA fragment deletions, chromosomal rearrangements, or off-target mutations, thanks to innovative tBE technology. As a result, Correctseq's CS-101 has the potential to become a best-in-class gene editing therapy and the first-in-class base editing therapy for β-hemoglobinopathies.

The success of Correctseq's CS-101 IIT study offers great hope for a cure for patients with β-hemoglobinopathies. In addition to this first adolescent patient who was successfully cured, one adult patient has been transfusion-free for more than a month after receiving CS-101 treatment. The ongoing IIT study is expected to yield more promising results. CS-101 is now entering the IND stage, which will allow for the treatment of additional patients and further evaluation of safety and efficacy. A research study using CS-101 to treat patients with SCD is also actively being prepared. Correctseq is determined to efficiently advance the clinical translation of innovative gene editing technologies, providing hope of a “one treatment, cure for life” to patients with serious diseases around the world.

Acknowledgments: First Affiliated Hospital of Guangxi Medical University, ShanghaiTech University, Shanghai Clinical Research and Trial Center.

Acerca de CorrectSequence Therapeutics

CorrectSequence TherapeuticsTM (CorrectseqTM), incubated by ShanghaiTech University, aims to use our innovative gene editing technology to help people with serious diseases. We have developed multiple state-of-the-art base editing systems, which offer significant advantages in controlling off-target effects and improving in vivo editing efficiency. Our goal is to discover, develop, manufacture and commercialize curative genetic medicines for various diseases. Multiple projects are underway for genetic diseases, cancer immunotherapy, metabolic diseases and infectious diseases.

For more information about transformer Base Editor technology and its therapeutic applications, visit: www.correctsequence.com or contact: BD@correctsequence.com.

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