| Full text | |
| Author(s): |
de Lima, Franciele
;
Hounkpe, Bidossessi Wilfried
;
Peachazepi de Moraes, Carla Roberta
;
Borba, Ivanio Teixeira
;
Costa, Fernando Ferreira
;
De Paula, Erich, V
Total Authors: 6
|
| Document type: | Journal article |
| Source: | Experimental Biology and Medicine; v. N/A, p. 9-pg., 2023-07-15. |
| Abstract | |
Heme is a fundamental molecule for several biological processes, but when released in the extracellular space such as in hemolytic diseases, it can be toxic to cells and tissues. Hemopexin (HPX) is a circulating protein responsible for removing free heme from the circulation, whose levels can be severely depleted in conditions such as sickle cell diseases. Accordingly, increasing HPX levels represents an attractive strategy to mitigate the deleterious effects of heme in these conditions. Gene transfer of liver-produced proteins with adeno-associated virus (AAV) has been shown to be an effective and safety strategy in animal and human studies mainly in hemophilia. Here, we report the feasibility of increasing HPX levels using an AAV8 vector expressing human HPX (hHPX). C57Bl mice were injected with escalating doses of our vector, and expression was assessed by enzyme immunoassay (ELISA), Western blot, and quantitative polymerase chain reaction (qPCR). In addition, the biological activity of transgenic hHPX was confirmed using two different models of heme challenge consisting of serial heme injections or phenylhydrazine-induced hemolysis. Sustained expression of hHPX was confirmed for up to 26 weeks in plasma. Expression was dose-dependent and not associated with clinical signs of toxicity. hHPX levels were significantly reduced by heme infusions and phenylhydrazine-induced hemolysis. No clinical toxicity or laboratory signs of liver damage were observed in preliminary short-term heme challenge studies. Our results confirm that long-term expression of hHPX is feasible and safe in mice, even in the presence of heme overload. Additional studies are needed to explore the effect of transgenic HPX protein in animal models of chronic hemolysis. (AU) | |
| FAPESP's process: | 20/05985-9 - Evaluation of the mechanisms of hemostatic activation in COVID-19 and their modulation by bradykinin inhibitors |
| Grantee: | Erich Vinicius de Paula |
| Support Opportunities: | Regular Research Grants |