Clinical application of base editing for treating β-thalassaemia | Nature

## Summary
Article ADS CAS PubMed PubMed Central Google Scholar Thompson, A. Article CAS PubMed PubMed Central Google Scholar Wienert, B., Martyn, G. Article CAS PubMed PubMed Central Google Scholar Kosicki, M., Tomberg, K. & Bradley, A. Article ADS CAS PubMed PubMed Central Google Scholar Wognum, B., Yuan, N., Lai, B. & Miller, C.

## Article Content
Subjects
Genetic engineering
Stem-cell research
Translational research
Abstract
β-Thalassaemia is caused by reduced or absent production of β-haemoglobin
1
,
2
,
3
,
4
. Previously, we performed laboratory-scale electroporation of CD34
+
haematopoietic stem and progenitor cells from patients with β-thalassaemia using a transformer base editor
5
,
6
. The aim was to target the binding motif of the transcription repressor BCL11A in the
HBG1
and
HBG2
promoters
7
to reactivate fetal haemoglobin (HbF) production. Here we present results of a phase 1 clinical trial (ClinicalTrials.gov identifier: NCT06024876) of five patients who received autologous CD34
+
cells modified using a transformer base editor at clinical scale (CS-101). With a median follow-up of 23.0 months after CS-101 infusion, the median times to neutrophil and platelet engraftment were 16 days and 25 days, respectively. Moreover, all patients had stopped red blood cell transfusions, with a median time to the last transfusion of 18 days after CS-101 infusion. The mean total haemoglobin and HbF concentrations were 12.4 ± 1.0 and 11.5 ± 0.9 g dl
–1
, respectively, at month 3 after infusion. These levels remained at similar or higher levels throughout the follow-up period, which indicated rapid haematopoietic reconstitution. The adverse events of CS-101 were generally consistent with those of busulfan myeloablative conditioning and autologous haematopoietic stem and progenitor cell transplantation. No deaths or cancer occurrences were reported. In summary, CS-101 can lead to rapid and sustained increases in both total haemoglobin and HbF levels, which resulted in early and enduring transfusion independence.
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Fig. 1: Preclinical study of tBE-mediated editing in HSPCs from healthy donors.
Fig. 2: Preclinical study of tBE-mediated editing in patient HSPCs.
Fig. 3: Clinical outcomes.
Fig. 4: Base editing and off-target mutation in patients.
Data availability
The original DNA sequencing data from this study are currently being deposited in the Sequence Read Archive (SRA) database (accession number:
PRJNA1222469
). Raw gel images are included as Supplementary Fig.
1
.
Source data
are provided with this paper.
Code availability
The custom Perl and Shell scripts for calculating frequencies of base substitution are available at GitHub (
https://github.com/YangLab/CFBI
).
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## Expert Analysis

### Merits
N/A

### Areas for Consideration
N/A

### Implications
- In summary, CS-101 can lead to rapid and sustained increases in both total haemoglobin and HbF levels, which resulted in early and enduring transfusion independence.
- Go to natureasia.com Buy this article Purchase on SpringerLink Instant access to the full article PDF. 39,95 € Prices may be subject to local taxes which are calculated during checkout Fig. 1: Preclinical study of tBE-mediated editing in HSPCs from healthy donors.
- Gene therapy for β-thalassemia: current and future options.
- Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage.

### Expert Commentary
This article covers pubmed, article, google topics. Readability: Flesch-Kincaid grade 0.0. Word count: 2304.