Gene correction of beta thalassemia mutations via CRISPR/Cas9 technology

Research Hosting Organization: Vinmec Research Institute Stem Cell and Gene Technology

Principle Investigator: Dr. Le Thi Thanh Huong

Time: 2016 - 2019

Introduction: Beta thalassemia is a blood disorder that reduces the production of hemoglobin. Beta thalassemia is caused by mutations in the HBB gene which instruct for making beta-globin protein, a component of hemoglobin. There are more than 200 different mutations has been found in HBB gene. Up to date, stem cell therapy which involved in the transplantation of hematopoietic stem cells from matched donor is the common treatment for beta thalassemia patient. However, the lack of donor, the risk of graft versus host disease and graft rejection after stem cell therapy are the limitations of this approach.

Recently, scientists are paying more attention on using gene therapy for the treatment of various genetic diseases. Follow that, the mutations caused diseases will be corrected in autologous stem cells and then return back to patients. Many gene editing tools for gene correction has been developed. Among these, CRISPR/Cas9 has been found to be the most efficient, simple and flexible approach up to date. In principle, CRISPR/Cas9 creates a double strand break at the target gene and a repair template is incorporated into genome, therefore a mutated gene will be replaced by a normal gene therefore can rescure gene function.

In Vietnam, it is estimated that there are ten millions of carriers and 20.000 patients suffered from beta thalassemia. In these patients, the mutation at codon 17 (A>T) is among the most popular mutations. The substitution A to T at the codon seventeenth of the beta-globin gene creates a premature stop codon, resulting in the malfunction beta-globin chain in the red blood cells.

In our project, we are trying to correct HBB gene mutation at codon 17 using CRISPR/Cas9 in CD34+ hematopoietic stem cells. We reason that transplant edited cells back to patient could potentially cure beta thalassemia. The results of the project have great impact on our understanding of clinical application of newly developed technology CRISPR/Cas9 for the treatment of monogenic disease and bring the hope for many patients.