Exagamglogene autotemcel is a cell therapy consisting of autologous CD34+ HSPCs ex vivo edited by CRISPR/Cas9-technology. The highly specific guide RNA enables CRISPR/Cas9 to make a precise DNA double-strand break at the critical transcription factor binding site (GATA1) in the erythroid specific enhancer region of the BCL11A gene. As a result of the editing, GATA1 binding is irreversibly disrupted and BCL11A expression reduced. Reduced BCL11A expression results in an increase in γ-globin expression and foetal haemoglobin (HbF) protein production in erythroid cells, addressing the absent globin in transfusion-dependent β-thalassemia (TDT) and the aberrant globin in sickle cell disease (SCD), which are the underlying causes of disease. In patients with TDT, γ-globin production is expected to correct the α-globin to non-α-globin imbalance, thereby reducing ineffective erythropoiesis and haemolysis and increasing total haemoglobin levels. In patients with severe SCD, HbF expression is expected to reduce intracellular HbS concentration, preventing the red blood cells from sickling.
Exagamglogene autotemcel is an autologous cellular therapy medicinal product consisting of CD34+ cells that have been edited ex vivo by CRISPR/Cas9. The nature of exagamglogene autotemcel is such that conventional studies on pharmacokinetics, absorption, distribution, metabolism, and elimination are not applicable.
Exagamglogene autotemcel is a CD34+ cell product edited with CRISPR/Cas9 technology; therefore, conventional mutagenicity, carcinogenicity and fertility, reproductive and developmental toxicity studies have not been conducted.
Toxicological characteristics were assessed in sub-lethally irradiated, immunodeficient NSG mice treated with a dose of 3.33 × 107 edited CD34+ cells/kg of body weight. There was no evidence of target organ toxicity or tumorigenicity in the 20-week study.
In vitro studies with exagamglogene autotemcel manufactured from healthy donors and patients showed no evidence of off target editing.
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