CRISPR/Cas9 Cell Therapy Increases Hemoglobin in Transfusion-Dependent β-Thalassemia Across HBB Genotypes


Data from 3 early phase clinical trials assessing BRL-101 in 10 patients were presented at the ASH 2023 meeting.

BRL-101 (BRL Medicine) CRISPR/Cas9-edited cell therapy increased total hemoglobin (Hb) and fetal hemoglobin (HbF) in patients with transfusion-dependent β-thalassemia (TDT) regardless of β0/β0 or non-β0/β0 genotype.

These data were presented in a poster at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition, held December 9-12, in San Diego, California by Biao Zheng, PhD, chief executive officer, BRL Medicine.

“β-Thalassemia is an inherited hemolytic disease that is prevalent worldwide. Over 200 mutations in the HBB gene, which encodes adult hemoglobin, result in β-thalassemia. Hereditary persistence of HbFcan alleviate the symptoms of anemia. CRISPR-Cas9-mediated disruption of the BCL11A erythroid enhancer results in the reduction of BCL11A expression and the induction of fetal γ-globin, which is a practicable therapeutic strategy for treating TDT,” Zheng and coauthors wrote.

The data are from 4 patients from a sponsor-initiated phase 1/2 clinical trial (NCT05577312) and 6 patients from 2 investigator-initiated clinical trials (NCT04211480, NCT04205435) enrolled between October 2019 and November 2022. Investigators mobilized and obtained autologous CD34+ cells from these patients and then edited them with CRISPR-Cas9 RNP at the +58 erythroid specific enhancer region of the BCL11A gene before reinfusing into the patients after myeloablative busulfan conditioning.

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The trials assessed adverse events (AEs), neutrophil and platelet engraftment, and efficacy measures including proportion of participants that became transfusion-independent (TI), Hb and HbF levels, and proportion of red blood cells expressing HbF in peripheral blood. Patients were evaluated for TI starting 42 days after the last transfusion and if Hb was above 90 g/L.

The 10 total patients assessed had a median age of 12.4 years (range, 6-26) and a median follow-up of 24.6 months (range, 4.3-39.2) as of July 20, 2023. Five were β0/β0, 4 were β0/β+, and 1 was β+/β+. All patients achieved TI and the median duration of TI was 22.1 months (range, 1.3-37.2). HbF levels ranged 2.3 to 140.7 g/L and Hb levels ranged from 105.7 to 149 g/L. The proportion of HbF-expressing red blood cells in peripheral blood reached 96.5% at 6 months after infusion and then continued to rise and remained around 98-99%.

In terms of safety, the treatment-related AEs observed aligned with the typical safety profile of myeloablation and autologous stem cell transplantation and consisted mainly of hematological malignancies. Three patients experienced serious, over grade 3 AEs related to BRL-101; these were not specified. Four patients experienced other serious AEs including decreased platelet count (possibly related to BRL-101), shock, febrile infection, soft tissue infection, and veno-occlusive liver disease (others related to busulfan treatment). All serious AEs resolved and there were no deaths during treatment or withdrawals related to BRL-101.

“Whether genotype was β0/β0 or non-β0/β0, BRL-101 demonstrated clinically meaningful increases in total Hb and HbF which occurred early and have been maintained over time, the safety profile of BRL-101 is generally consistent with that of myeloablative conditioning and autologous hematopoietic stem cell transplant. The updated data with 10 patients reported here are consistent with previous reports and support continued investigation of BRL-101 as a potential functional cure for patients with TDT,” Zheng and coauthors concluded.

Click here to read more coverage of the ASH 2023 meeting.

Zheng B, Liu R, Zhang X, et al. Efficacy and safety of Brl-101, CRISPR-Cas9-mediated gene editing of the BCL11A enhancer in transfusion-dependent β-thalassemia. Presented at: 2023 ASH Annual Meeting & Exposition, December 9-12; San Diego, California. Abstract 4995
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