Cardiac AAV9 Gene Delivery Strategies in Adult Canines: Assessment by Long-term Serial SPECT Imaging of Sodium Iodide Symporter Expression.
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.
Mayo Clinic, Rochester, Minnesota, USA.
Gilles
G
Moulay
Osaka University, Osaka, Japan.
Tomohito
T
Ohtani
Mayo Clinic, Rochester, Minnesota, USA.
Ozgur
O
Ogut
Mayo Clinic, Rochester, Minnesota, USA.
Adam
A
Guenzel
Mayo Clinic, Rochester, Minnesota, USA.
Atta
A
Behfar
Mayo Clinic, Rochester, Minnesota, USA.
Rosita
R
Zakeri
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Philip
P
Haines
Mayo Clinic, Rochester, Minnesota, USA.
Jimmy
J
Storlie
Mayo Clinic, Rochester, Minnesota, USA.
Lorna
L
Bowen
Mayo Clinic, Rochester, Minnesota, USA.
Linh
L
Pham
Baker Heart Research Institute, Melbourne, Australia.
David
D
Kaye
Mayo Clinic, Rochester, Minnesota, USA.
Gurpreet
G
Sandhu
Mayo Clinic, Rochester, Minnesota, USA.
Michael
M
O'Connor
Mayo Clinic, Rochester, Minnesota, USA.
Stephen
S
Russell
Mayo Clinic, Rochester, Minnesota, USA. Electronic address: redfield.margaret@mayo.edu.
Margaret
M
Redfield
D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004285:Dogs; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006333:Heart Failure / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D009206:Myocardium / Q000378:metabolism; D010496:Pericardium / Q000473:pathology; D027981:Symporters / Q000008:administration & dosage / Q000235:genetics*; D015899:Tomography, Emission-Computed, Single-Photon; D000099209:Sodium-Iodide Symporters
D027981:Symporters; D000099209:Sodium-Iodide Symporters