Advanced search
Start date
Betweenand

Evaluation of the efficacy and safety of a strategy based on gene therapy with a viral vector for expression of hemopexin in animal models of sickle cell disease

Grant number: 18/23484-7
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): April 01, 2019
Effective date (End): February 28, 2022
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Erich Vinicius de Paula
Grantee:Franciele de Lima
Home Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated research grant:14/00984-3 - Red blood cell disorders: pathophysiology and new therapeutic approaches, AP.TEM

Abstract

Sickle cell disease (SCD) is the most frequent hereditary hemoglobinopathy in the world, which despite the advances in pathophysiological knowledge and in the treatment of support, continues to have a great negative impact on the quality of life and survival of patients. It has been known for at least 50 years that patients with SCD have elevated levels of free heme in circulation, associated with the consumption of the heme purifying protein - hemopexin (HPX). More recently the role of elevated heme levels in the activation and perpetuation of inflammation underlying the pathophysiology of SCD has been demonstrated, in particular by studies showing its ability to promote vasoconstriction and severe acute lung injury in SCD animal models. Interestingly, these deleterious effects of heme were completely abolished by the use of the HPX protein in these models. In the last two years, our laboratory has developed a gene therapy vector based on the AAV virus serotype 8 capable of promoting the stable expression of this protein at therapeutic levels for at least 6 weeks. The vector uses a liver-specific promoter and has a vector-like structure used in recently successful gene therapy strategies for diseases whose treatment involves the supplementation of systemically secreted liver-secreted proteins such as HPX. This project aims to evaluate the efficacy and safety of using this vector (rAAV8-HPX) in an SCD animal model. We will evaluate the effect of this expression on clinical and laboratory parameters that illustrate the natural history of SCD in mice and represent important pathophysiological elements of this condition. The data that will be generated have the potential to serve as preclinical evidence on the usefulness of this vector in the treatment of SCD, besides contributing to the understanding of the role of heme in the pathophysiology of SCD.