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Title: Insulin growth-factor 1Ea gene transfer therapy after myocardial infarction
Author: Gallego Colon, Enrique
ISNI:       0000 0004 6495 6052
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Cardiovascular diseases (CVD) are the major cause of death globally with myocardial infarction (MI) being one of the main causes of mortality. The limited regenerative capacity of adult human tissues is particularly pertinent to the heart, which cannot repair itself fully after injury; instead, the damaged myocardium is replaced by fibrotic scar tissue and the heart progressively decrement in function. To date, efforts to develop interventions for alleviation of this inevitable destructive progression have proven largely ineffective. Although over the past decades, treatment for myocardial ischemia has made significant progress, myocardial infarction remains an unsolved therapeutic target. In attempting to address this problem, insulin growth factor splicing variant 4 (IGF-1Ea) has been extensively tested for its therapeutic properties in the resolution of tissue injury. In the heart, constitutive overexpression of IGF-1Ea (αMHC.IGF-1Ea) restored heart functionality post-infarct, reducing scar formation and increased anti-apoptotic signalling. This thesis provides deeper understanding on the role of IGF-1Ea in early modulation of the inflammatory process after myocardial infarction in αMHC.IGF-1Ea transgenic mice. In fact, the enhanced repair in αMHC.IGF-1Ea after myocardial infarction is due to IGF-1Ea modulating several aspects of the cellular repair process after MI, including immune cell recruitment, cytokine expression, and reduction of the extracellular matrix turnover. However, the heart-specific transgene is constitutively expressed from birth and does not simulate delivery to humans in the clinic. With a better understanding of IGF-1Ea in cardiac repair, this thesis also focused on the design of both cell- and gene-based approaches to deliver the IGF-1Ea therapeutic payload into the heart by (i) adoptive immunotherapy approach using bone-marrow derived-macrophages mediated cell delivery of IGF-1Ea and (ii) IGF-1Ea gene transfer to the heart using a cardiotropic adeno-associated viral vector (AAV9) after ischemia/reperfusion. Of the two approaches, only the gene-based approach was able to deliver IGF-1Ea into the heart achieving therapeutically relevant levels. AAV9-mediated IGF1Ea gene transfer proved to be a potential therapeutic clinical approach to prevent the adverse ventricular remodeling after myocardial infarct. The knowledge acquired in this thesis will be relevant to inform and design future therapeutic approaches for the treatment of patients suffering from myocardial infarction.
Supervisor: Rosenthal, Nadia Sponsor: European Union
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral