Pre-clinical evaluation of a therapeutic strategy of murine experimental sepsis based on gene therapy with non-viral vectors expressing sFlt-1

• Grant number: 12/10752-7
• Support Opportunities: Scholarships in Brazil - Master
• Start date: September 01, 2012
• End date: August 31, 2014
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Erich Vinicius de Paula
• Grantee: Vanessa Boury Faiotto
• Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

epsis is a major challenge of medical practice, with mortality of up to 70% in severe cases. In recent decades, great efforts have been made in target-specific therapies, focusing on pro-inflammatory cytokines and coagulation activation as the main therapeutic targets. Unfortunately the positive results in animal models have not translated into significant changes in the treatment of sepsis. In contrast, little attention has been given to a critical event in the pathophysiology of sepsis, which is the breakdown of endothelial barrier (EB). Proteins involved in angiogenesis such as VEGF and its receptors are essential to control the integrity of BE, since the formation of the circulatory system (incorporation of endothelial cells to primitive vascular tubes) depends on the dynamic control of their integrity in embryonic life. Recent studies have shown that this embryonic program of EB breakdown, mediated by VEGF and its natural antagonist sFlt-1, is also activaded in sepsis. However, these mechanisms are not yet being explored as a therapeutic target.We intend to evaluate in preclinical models of sepsis a new treatment strategy for sepsis, based on gene therapy with nonviral vectors, and expression of a natural inhibitor of VEGF. We intend to use the cDNA of a soluble form of the receptor VEGFR1 (sFlt-1), a natural antagonist of VEGF, which in recent studies using protein formulation has been shown to minimize the undesirable effects of VEGF in sepsis (proof of concept studies). The evaluation of efficacy will consist in the confirmation of transgene expression, evaluation of the impact of gene therapy on BE integrity (Evans blue method), and the assessment of mortality and tissue damage.

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

FAIOTTO, Vanessa Boury. Evaluation of the feasibility of gene transfer with non-viral vectors in a murine model of sepsis. 2014. Master's Dissertation - Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas Campinas, SP.