Regeneration of the heart with gene and cell therapy
Author(s)
Green, Amanda Claire
Type
Thesis
Abstract
Cardiovascular disease is the largest cause of morbidity and mortality in the industrialised world. Many patients with a longstanding history of coronary artery disease, multiple coronary interventions and a number of prior coronary events are no longer suitable for conventional revascularisation strategies and are often referred to as "no-option" patients. Despite intensive medical treatment, many present with clinical signs of heart failure and/or angina in the presence of underperfused, viable myocardium. I investigated two new strategies proposed to treat this patient population; angiogenesis induced by gene therapy in a pre-clinical model of myocardial ischaemia and regenerative therapy with autologous bone marrow derived putative stem cells in a Phase IIA pilot clinical trial.
After establishing the ameroid porcine model of myocardial ischaemia, the efficacy of epicardially delivered Hypoxia Inducible Factor-1 alpha (HIF-1) was assessed with adenovirus (AdHIF-1α) and two plasmid constructs. AdHIF-1α was found to significantly increase myocardial blood flow and left ventricular function in this model. In a further study electromechanical mapping of ischaemic territory and endocardial delivery with AdHIF-1α demonstrated similar trends.
I present the first clinical trial to demonstrate the feasibility of retrograde coronary venous delivery of putative stem cells to the heart. The inclusion of 111-In oxide labelled cells demonstrated a sustained myocardial signal up to 21 days. Retention of cells within the myocardium is likely to be critical in allowing a biologically important paracrine function or stem cell differentiation. In the six-month follow-up, there were no major safety concerns, although only hypothesis generating efficacy endpoints were included, significant improvements were seen in Quality of life, New York Heart Association (NYHA) class and myocardial oxygen consumption (MVO2). A positive correlation was seen with the number of CD34+ cells delivered and change in MVO2. Further randomised placebo controlled trials are required to elucidate further any perceived improvements in efficacy.
After establishing the ameroid porcine model of myocardial ischaemia, the efficacy of epicardially delivered Hypoxia Inducible Factor-1 alpha (HIF-1) was assessed with adenovirus (AdHIF-1α) and two plasmid constructs. AdHIF-1α was found to significantly increase myocardial blood flow and left ventricular function in this model. In a further study electromechanical mapping of ischaemic territory and endocardial delivery with AdHIF-1α demonstrated similar trends.
I present the first clinical trial to demonstrate the feasibility of retrograde coronary venous delivery of putative stem cells to the heart. The inclusion of 111-In oxide labelled cells demonstrated a sustained myocardial signal up to 21 days. Retention of cells within the myocardium is likely to be critical in allowing a biologically important paracrine function or stem cell differentiation. In the six-month follow-up, there were no major safety concerns, although only hypothesis generating efficacy endpoints were included, significant improvements were seen in Quality of life, New York Heart Association (NYHA) class and myocardial oxygen consumption (MVO2). A positive correlation was seen with the number of CD34+ cells delivered and change in MVO2. Further randomised placebo controlled trials are required to elucidate further any perceived improvements in efficacy.
Date Issued
2012
Date Awarded
2012-03
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Alton, Eric
Clague, Jonathan
Sponsor
Medicor Foundation
Publisher Department
National Heart and Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)