Development of Best-in-Class Gene Editing Therapy for β-Hemoglobinopathies Using Innovative Transformer Base Editor (tBE)

β-thalassemia and sickle cell disease (SCD) are among the most prevalent monogenic disorders worldwide and both these β-hemoglobinopathies are caused by mutations in the β-globin gene HBB. Reactivating the expression of the γ-globin genes ( HBG1/2) mimicking the naturally occurring hereditary persistence of HbF (HPFH) is expected to be a universal strategy to treat β-thalassemia and SCD by the induction of fetal hemoglobin (HbF). To achieve this goal, CorrectSequence Therapeutics' first pipeline, CS-101, uses transformer Base Editor (tBE) to precisely edit human hematopoietic stem cells (HSC) ex vivo to induce the expression of γ-globin for treatment of β-thalassemia and sickle cell disease. Compared with the commonly used gene editing methods such as CRISPR/Cas nucleases or other base editors, tBE is a base editing system that avoids to cause DNA double strand breaks or off-target mutations. With the safety advantages of tBE, CS-101 targets one of the most potent targets to activate γ-globin expression without causing unexpected off-target mutations. A commercial scale manufacturing process to ex vivo edit HSC has been developed and validated with more than 10 batches of commercial scale production, all of which exhibited consistent process performance and product quality. Pre-clinical in vivo studies showed that while tBE-mediated editing of HSC induces robust γ-globin expression, tBE did not cause adverse effect on the engraftment or differentiation of the HSC in mice after transplantation. Clinical study for CS-101 is underway and it holds great promise to become the best-in-class gene editing treatment for β-hemoglobinopathies.