ASH Clinical News | Base Editing Contributes to Meaningful HbF Production in Beta Thalassemia

July 2026

Lara C. Pullen  

Original article: https://ashpublications.org/ashclinicalnews/news/9329/Base-Editing-Contributes-to-Meaningful-HbF 

Both transformer Base Editing (tBE) and CRISPR-Cas9 nuclease-mediated editing can induce precise, targeted base substitutions in human hematopoietic stem cells. tBE has an advantage over CRISPR-Cas9 in that it does not generate DNA double-strand breaks (DSBs), thereby avoiding the consequent p53-mediated stress and apoptosis. This difference has been demonstrated in preclinical studies, which have shown that tBE-modified hematopoietic stem and progenitor cells (HSPCs) exhibit reduced cell-cycle arrest and apoptosis, along with enhanced proliferative capacity compared with Cas9-edited cells.

Now, a team of researchers in China has extended their preclinical findings into the clinic, and the investigators report that an infusion of autologous CD34+ cells modified using a tBE at clinical scale (CS-101) can lead to rapid and sustained increases in both total hemoglobin and fetal hemoglobin (HbF) levels in patients with beta thalassemia, as well as early and enduring transfusion independence. Yongrong Lai, MD, PhD, professor of hematology at the First Affiliated Hospital of Guangxi Medical University in China, and colleagues published these findings in Nature.

The investigators sought to determine if cytosine base editing mediated by tBE at BCL11A binding motifs within the HBG1/2 promoter regions can reactivate HbF. Their paper describes how all five patients infused with CS-101, including three with the β0/β0 of β0/β0-like genotype, discontinued transfusions within one month. The patients’ mean HbF levels reached 11.5 ± 0.9 g/dL at three months post-treatment and 12.9 ± 1.6 g/dL at 15 months.

Senior investigator Jia Chen, PhD, director of the Gene Editing Center at ShanghaiTech University in China, explained, "Our tBE-based approach largely avoids DSBs, which may contribute to improved safety and more efficient hematopoietic recovery." The median time to neutrophil engraftment was 16 days, and the median time to platelet engraftment was 25 days.

The CS-101 infusion had adverse effects that were largely consistent with those typically associated with busulfan myeloablative conditioning. "The 'lock-and-key' design of tBE restricts editing activity to the intended target sites while minimizing off-target activity," Dr. Chen explained. "Consistent with this, no detectable off-target editing was observed in our cohort, supporting a favorable long-term safety profile."

The researchers found that the base-editing efficiencies of the BCL11A binding motif in the HBG1/2 promoters remained stable in both peripheral blood mononuclear cells (PBMCs) and bone marrow cells over the follow-up period and that even a single cytosine edit was sufficient to disrupt BCL11A binding at these sites.

"We found that a cytosine editing frequency of greater than about 30% at the HBG1/2 promoter was sufficient to drive robust HbF production," Dr. Chen said. "For example, Patient 3 exhibited editing frequencies of approximately 30% in both peripheral blood and bone marrow cells, while Patient 5 showed about 50% editing. Despite this difference, Patient 3 maintained HbF levels of about 12.8 g/dL at one-year post-treatment, compared with about 11 g/dL in Patient 5."

When the investigators further analyzed editing across the four BCL11A binding motifs present in the diploid genome (two HBG1 and two HBG2 alleles) at the single-cell level, they found that approximately one-third of CD34+ HSPCs remained unedited in treated patients. Moreover, the base-editing spectra from the study participants were similar across all five patients and remained stable throughout the follow-up period. Dr. Chen concluded from this that erythroid cells with one or more edited motifs (ranging from one to three) can contribute meaningfully to HbF production.

The authors cited limitations to the study, including a small patient cohort, a single-center design, and a relatively short follow-up period (median 23.0 months after CS-101 transfusion).

Any conflicts of interest declared by the authors can be found in the original article.

Reference

Lai Y, Liu R, Wang L, et al. Clinical application of base editing for treating β-thalassemia. Nature. Published online April 8, 2026. doi: 10.1038/s41586-026-10342-9.