Sickle cell gene therapy

Abstract

The autosomal recessive hemoglobinopathy sickle cell disease (SCD) has been the subject of much pioneering genetic research developed to determine the molecular basis of disease. However, turning the results of this research into a new therapeutic approach for SCD has been a long time coming.A recent study by Pawliuk et al. [1xCorrection of sickle cell disease in transgenic mouse models by gene therapy. Pawliuk, R. et al. Science. 2001; 294: 2368–2371Crossref | PubMed | Scopus (362)See all References][1] represents a major breakthrough. In this study, an optimized lentiviral vector based on HIV-1 was used to transduce murine bone marrow cells with a modified human β-globin gene, βA-T87Q, that inhibits the effect of abnormal sickle cell hemoglobin (HbS). To ensure cell- specific expression of the βA-T87Q gene, elements from the human βglobin locus control region were used to promote transcription. In normal mice, βA-T87Q-positive cells were detected in 99% of red blood cells ten months after transplantation of transduced bone marrow. Analysis of secondary transplants from these mice showed evidence for transduction of hematopoietic stem cells suggesting that long-term correction of SCD could be possible.To assess the possible clinical benefit of expressing the βA-T87Q variant, bone marrow from two different transgenic models of SCD were transduced and transplanted into normal or SCD transgenic recipients. Marked changes were seen in several clinically relevant markers in those animals that received βA-T87Q-transduced bone marrow when compared with animals that received mock-transduced bone marrow. Improvements observed included a decreased percentage of sickle cells induced under increased oxygen pressure, a change in the kinetics of HbS polymerization towards values seen in HbS heterozygous individuals and a prevention of the splenomegaly associated with one of the transgenic models of SCD.Although these findings are exciting, several issues must first be addressed before clinical studies can begin. In particular, there needs to be an extensive assessment of the safety of the lentiviral vector system and a means of ensuring efficient transduction and engraftment of transduced cells so that the highest percentage of modified red blood cells possible is obtained.