Inhibition of Sickle Cell Disease-Derived Red Blood Cell Sickling by CAL-H Lentiviral Vector with Modified Human Y-Globin and shRNA734

The study focuses on the impact of hereditary persistence of fetal hemoglobin (HbF) on Sickle Cell Disease (SCD). It examines the role of CSL200, a gene therapy product using autologous CD34+ hematopoietic stem/progenitor cells (HSPCs) transduced with the CAL-H lentiviral vector, which expresses a modified γ-globin gene and a short-hairpin RNA. This gene therapy is being tested in clinical trials for severe SCD patients. The modified γ-globin gene has an enhanced affinity for α-globin, leading to increased HbF production. The short-hairpin RNA targets a specific mRNA to facilitate chemoselection post-transplantation.

The research's objective was to assess the ability of the modified HbF to prevent RBC sickling from SCD-donor HSPCs transduced with the CAL-H vector. The methods involved evaluating HbF production, oxidative stability, and anti-sickling activity in RBCs differentiated from the transduced cells. Results showed that the transduced progenitors effectively matured into RBCs with reduced sickling percentages as the vector's multiplicity of infection increased. There was a significant inverse correlation between RBC sickling and vector copy number. The modified HbF also demonstrated improved resistance to oxidative stress-induced changes compared to the wild-type γ-globin.

The conclusion highlights that the CAL-H-transduced cells from SCD donors can differentiate into mature RBCs with sufficient HbF to prevent sickling under deoxygenated conditions, suggesting the potential efficacy and safety of this gene therapy approach for SCD patients. The study supports the further development of CSL200 as a durable treatment option. The abstract is presented as an oral presentation in a session dedicated to sickle cell disease.