Cardiac AAV9 gene delivery strategies in adult canines: Assessment by long-term serial SPECT imaging of sodium iodide symporter expression

Gilles Moulay, Tomohito Ohtani, Ozgur Ogut, Adam Guenzel, Atta Behfar, Rosita Zakeri, Philip Haines, Jimmy Storlie, Lorna Bowen, Linh Pham, David Kaye, Gurpreet Sandhu, Michael O'Connor, Stephen Russell, Margaret Redfield

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1211-1221
Number of pages11
JournalMolecular Therapy
Volume23
Issue number7
DOIs
StatePublished - Jul 1 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Fingerprint Dive into the research topics of 'Cardiac AAV9 gene delivery strategies in adult canines: Assessment by long-term serial SPECT imaging of sodium iodide symporter expression'. Together they form a unique fingerprint.

Cite this