Key result
Direct epicardial or endocardial AAV9 injection achieves strong cardiac expression in dogs unlike intracoronary infusion.
Why the study?
Does the route of administration affect the efficiency of cardiac AAV9 gene delivery in adult canines?
Does the route of administration affect the efficiency of cardiac AAV9 gene delivery in adult canines?
Direct myocardial injection of AAV9 vectors, particularly using a novel catheter, provides robust and long-term cardiac gene expression in large animals that can be tracked noninvasively.
Direct injection may enable efficient cardiac AAV9 delivery in adult large animals; leaves open optimal routes and human translation.
Heart failure is a leading cause of morbidity and mortality, and cardiac gene delivery has the potential to provide novel therapeutic approaches. Adeno-associated virus serotype 9 (AAV9) transduces the rodent heart efficiently, but cardiotropism, immune tolerance, and optimal delivery strategies in large animals are unclear. In this study, an AAV9 vector encoding canine sodium iodide symporter (NIS) was administered to adult immunocompetent dogs via epicardial injection, coronary infusion without and with cardiac recirculation, or endocardial injection via a novel catheter with curved needle and both end- and side-holes. As NIS mediates cellular uptake of clinical radioisotopes, expression was tracked by single-photon emission computerized tomography (SPECT) imaging in addition to Western blot and immunohistochemistry. Direct epicardial or endocardial injection resulted in strong cardiac expression, whereas expression after intracoronary infusion or cardiac recirculation was undetectable. A threshold myocardial injection dose that provides robust nonimmunogenic expression was identified. The extent of transmural myocardial expression was greater with the novel catheter versus straight end-hole needle delivery. Furthermore, the authors demonstrate that cardiac NIS reporter gene expression and duration can be quantified using serial noninvasive SPECT imaging up to 1 year after vector administration. These data are relevant to efforts to develop cardiac gene delivery as heart failure therapy.
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Moulay et al. (2015) studied Heart failure. AAV9 vector encoding canine sodium iodide symporter (NIS) vs. Intracoronary infusion or cardiac recirculation was evaluated on Cardiac NIS reporter gene expression. Direct epicardial or endocardial injection of an AAV9 vector resulted in strong cardiac expression in adult dogs, whereas expression after intracoronary infusion was undetectable.
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