On August 4, 2022, BRL Medicine Inc. (hereinafter referred to as " BRL Medicine ") announced that he world's first CRISPR gene editing treatment of children with β0/β0 severe thalassaemia in cooperation between BRL Medicine and Xiangya Hospital of Central South University, has been free from blood transfusion dependence for more than 2 years and has started its normal life and study. Meanwhile, the results of the clinical trial were published today in Nature Medicine, a top international medical academic journal (Impact Factor: 87.241).

As the first clinical study based on CRISPR gene editing in the treatment of β0/β0 severe thalassemia published in a top academic journal, the article published detailed clinical data and more comprehensively interpreted the efficacy and safety characteristics of patients treated with BRL-101.

Gene therapy, one treatment can achieve a lifelong cure

Inducing the expression of γ-globin (fetal hemoglobin HbF) by gene editing is a highly promising strategy for the treatment of β-thalassemia caused by mutations in the HBB gene. The team of BRL Medicine published the clinical data of the therapy in detail today in an article in Nature Medicine , and evaluated the safety and efficacy of gene therapy in children with transfusion-dependent β-thalassemia (TDT).

The trial transplanted gene-edited autologous hematopoietic stem progenitor cells ( HSPCs) into two pediatric patients, one of whom had a genotype of β0/β0, was classified as the most severe type of TDT; Another treated child also had TDT. As of the time of submission of the article, the fetal hemoglobin of the two children increased from 2.55g/L and 1.75g/L at the baseline to 149g/L and 139g/L at the latest visit ,respectively, and the total hemoglobin content also reached 152g /L and 140g/L, and have achieved freedom from blood transfusion dependence for more than 16 months after treatment (freedom from transfusion dependence is defined as a total hemoglobin of 90 g/L or more without transfusion). The toxicity associated with myeloablative pretreatment was mild throughout the course of treatment , no serious infection occurred, and they were discharged at 52 and 40 days after transplantation, respectively . As shown in the figure below, the number of red blood cells and overall hemoglobin level in both patients began to increase steadily around day 45 and reached healthy levels around day 75. As of now, the two subjects had been free from blood transfusion dependence for more than 24 months.

Change trend of red blood cells and overall hemoglobin after transplantation

Exploratory analysis of indel patterns of post-edited reconstructed PBMCs revealed that no abnormal clonal amplification was observed during the nearly two-year follow-up period. At the same time, the researchers performed single-cell RNA sequencing on PBMCs reconstituted after gene editing, and comprehensively analyzed the transcriptome of blood lineages recombined from unedited or edited HSPCs, indicating that BCL11A erythroid-specific enhancer editing did not lead to significant transcriptional changes in non-erythrocytes, did not affect the development and expression of functionally related genes in B cells and DC cells. These results showed that the therapy had no obvious side effects.

In summary, the study provides proof of principle for transplantation and long-term engraftment of autologous HSPC that can achieve CRISPR/Cas9 editing, and demonstrates that sustained elevation of fetal hemoglobin levels is sufficient to ameliorate transfusion-dependent β-thalassemia, even for β0/β0 genotype in which β-globin chain production is completely inhibited.

At present, BRL Medicine has achieved good results in the clinical trials for the treatment of β0/β0 patients with severe thalassaemia by using the self-developed hematopoietic stem cell platform (ModiHSC^®) based on gene editing technology, and has successfully helped many patients with β thalassaemia to be free from blood transfusion dependence nationwide. In the future, the age of the research subjects for this project will be further expanded to 35 years old, which is expected to benefit the   older patients and patients with no hope of being matched in the field of thalassemia transplantation.