tBE Base Editing Therapy Achieves Durable Remission in Sickle Cell Disease and β-Thalassemia Across Diverse Genetic Backgrounds

CorrectSequence Therapeutics (搜索)搜索该词条 (Correctseq), in collaboration with multiple institutions, has published clinical research in Cell Stem Cell demonstrating that its base-editing therapy CS-101查看药品详情/CS-206 (搜索)搜索该药品—developed with the transformer Base Editor (tBE)—achieved consistent efficacy and safety in β-hemoglobinopathy patients of diverse genetic origins. The paper, titled "Clinical base editing for β-hemoglobinopathies across different genetic backgrounds," was published online on September 7, 2026, and follows the team's prior clinical report on five Chinese transfusion-dependent β-thalassemia (搜索)搜索该疾病 (TDT) patients treated with CS-101, all of whom achieved transfusion independence (Lai et al., Nature, 2026).

The new study extends treatment to four additional patients from Nigeria, Laos, Malaysia, and Pakistan—one with sickle cell disease (搜索)搜索该疾病 (SCD) and three with TDT. All achieved rapid hematopoietic reconstitution, sustained high-level pan-cellular HbF expression, complete transfusion independence or freedom from vaso-occlusive crises (VOCs), with no detectable off-target edits or product-related adverse events.

Broad Applicability Across Ethnicities and Mutations

β-hemoglobinopathies are among the most common monogenic disorders, with SCD affecting over 300,000 and TDT over 40,000 newborns annually worldwide. Pathogenic mutations vary significantly across populations. The team previously developed the ultra-high-precision tBE (Wang et al., Nat Cell Biol, 2021) to precisely edit the HBG1/2 (搜索)搜索该靶点 promoter region in autologous hematopoietic stem and progenitor cells (HSPCs) collected from patients, reactivating γ-globin expression.

The four patients' genotypes in the current study encompassed βS/βS SCD and three TDT genotypes—β⁰/βᴵ, β⁰/β⁰ with a large deletion, and β⁰/β⁰ with single-nucleotide insertion—validating the strategy's universal applicability across diverse mutational backgrounds.

Clinical Data: Rapid Engraftment and Durable Response

The SCD patient, a 21-year-old female from Nigeria who experienced more than four VOCs during the year prior to enrollment, achieved neutrophil and platelet engraftment on days 13 and 21 post-infusion, respectively. Total hemoglobin level increased from 7.7 g/dL at baseline to 12.9 g/dL at month 3, remaining above 11 g/dL. HbF level increased from 3.5% to 62.2%, while HbS level decreased from 76.1% to 31.6%, stabilizing at a ~6:4 ratio. At 15.5 months follow-up, no VOCs occurred.

The three TDT patients, ages 3–29 from Laos, Malaysia, and Pakistan, achieved median neutrophil engraftment at 13 days and platelet engraftment at 27 days. Mean total hemoglobin concentration reached 11.6 ± 1.2 g/dL and mean HbF concentration increased to 9.8 g/dL at month 3. At a median follow-up of 17.5 months, all achieved sustained transfusion independence. No off-target edits or product-related adverse events were detected.

Comparison with Nuclease-Based Gene Editing

In SCD clinical trials, tBE achieved superior neutrophil engraftment (13 days) compared to Cas9 (27 days) and Cas12a (23 days), and superior platelet engraftment (21 days) versus Cas9 (35 days) and Cas12a (25 days). tBE sustained HbF at greater than 60% of total hemoglobin, markedly outperforming Cas9 and Cas12a regimens, which remained below 50%.

Unlike nucleases that rely on DNA double-strand breaks (DSBs), tBE enables precise base conversion without cutting DNA, avoiding p53 activation, apoptosis, large deletions, and chromosomal rearrangements. Its dual gRNA and "lock-and-key" design further minimizes off-target risks. Through a cleavable "lock," tBE becomes active only at on-target sites to induce highly efficient editing; when binding at off-target sites, tBE is "locked" to avoid triggering off-target mutations.

Global Progress and Regulatory Pathway

To date, CS-101查看药品详情 and CS-206 (搜索)搜索该药品 have treated more than 30 patients across China, Africa, Southeast Asia, and South Asia, with 100% of patients achieving transfusion independence or freedom from VOCs, accompanied by sustained, high-level hemoglobin expression. CS-101, described as the world's first ongoing base-editing therapy candidate to enter clinical development, dosed its first patient in October 2023, has completed Phase I, and is now being evaluated in pivotal trials. All patients treated in Phase I have maintained transfusion independence for more than one year, with the longest duration approaching almost three years.

Professor Chen Jia, founder of Correctseq and Director of the Gene Editing Center at ShanghaiTech University, stated: "This Cell Stem Cell paper validates tBE's broad applicability across diverse genetic backgrounds, completing the translational journey from bench to global clinical application. Our team is also exploring RNA editing, prime editing, and mitochondrial DNA editing for other therapeutic areas."

Dr. Mou Xiaodun, CEO of Correctseq, added: "The data demonstrate tBE as a global Best-in-Class platform. We are also expanding into metabolic and cardiovascular diseases including hypertriglyceridemia/familial chylomicronemia syndrome (FCS), ASCVD/hyperlipoproteinemia, homozygous familial hypercholesterolemia (HoFH), and metabolic dysfunction-associated steatohepatitis (MASH). We are accelerating multiple pipelines toward global IND submission to bring China-originated gene editing to more patients worldwide."