Sustained expression of hemopexin in an animal model of sickle cell anemia Open Access

HPX gene transfer using a viral vector can increase HPX expression in an animal model of SCD, without causing toxicity.

Sickle cell disease is a condition characterized by vasocclusive episodes and sustained hemolysis, leading to a chronic inflammatory state. Several studies have shown that the release of heme to the extracellular space due to hemolysis contributes to the inflammatory cascade observed in these patients. Hemopexin (HPX), the molecule responsible for removing excess heme from the circulation, is depleted in these patients. We have previously demonstrated that the intravenous infusion of an AAV-based gene transfer vector was capable to induce the transgenic expression HPX in a dose-dependent manner in C57Bl6 mice. Here we explored the effect of this vector in a mice model of sickle cell anemia. Townes mice were transduced with 2x10¹³ vg/kg and followed up for up to 48 weeks. HPX expression was confirmed in liver samples by both western blot and qPCR (HPX), but gene transfer was not able to restore circulating levels of HPX in Townes mice, as shown in models without hemolysis. Indirect surrogate markers of a beneficial effect of delivering HPX were observed including increased expression of heme-oxygenase 1 upon heme overload, greater weight gain on the long term follow-up and a significant decrease in TNF-α levels. No signs of liver or hematological toxicity were observed. Our results demonstrate the potential and challenges of therapeutic strategies based on the long-term delivery of HPX in an animal model of sickle cell anemia.