Safety and efficacy of high-dose adeno-associated virus 9 encoding sarcoplasmic reticulum Ca2+ adenosine triphosphatase delivered by molecular cardiac.

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Safety and efficacy of high-dose adeno-associated virus 9 encoding sarcoplasmic reticulum Ca2+ adenosine triphosphatase delivered by molecular cardiac surgery with recirculating delivery in ovine ischemic cardiomyopathy Michael G. Katz, MD, PhD, Anthony S. Fargnoli, MS, Richard D. Williams, BS, Nury M. Steuerwald, PhD, Alice Isidro, PA-C, Anna V. Ivanina, PhD, Inna M. Sokolova, PhD, Charles R. Bridges, MD, ScD The Journal of Thoracic and Cardiovascular Surgery Volume 148, Issue 3, Pages 1065-1073.e2 (September 2014) DOI: 10.1016/j.jtcvs.2014.05.070 Copyright © 2014 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 A, Quantitative polymerase chain reaction of sarcoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA2a) biodistribution in heart and liver tissue (genome copies/100 ng DNA). B, Relative expression by reverse transcriptase-quantitative polymerase chain reaction of SERCA2a/glyceraldehyde 3-phosphate dehydrogenase in heart and liver tissue. Gray columns, molecular cardiac surgery with recirculating delivery adeno-associated virus 9/SERCA2a group; black columns, control group. *P = .05 for differences between groups; ‡P < .05 for differences within groups. AAV, Adeno-associated virus; LV, left ventricular; mRNA, messenger RNA. The Journal of Thoracic and Cardiovascular Surgery 2014 148, 1065-1073.e2DOI: (10.1016/j.jtcvs.2014.05.070) Copyright © 2014 The American Association for Thoracic Surgery Terms and Conditions

Figure 2 Baseline and 3- and 12-weeks postinfarction values for (A) left ventricular (LV) ejection fraction (%), (B) stroke volume index (mL/m2), (C) end-systolic diameter (mm), (D) end-diastolic diameter (mm), (E) left ventricular wall thickness (mm), and (F) left ventricular fractional wall thickening (%). Gray columns, molecular cardiac surgery with recirculating delivery of adeno-associated virus 9/sarcoplasmic reticulum Ca2+ adenosine triphosphatase group; black columns, control group. *P < .05 for differences between groups. The Journal of Thoracic and Cardiovascular Surgery 2014 148, 1065-1073.e2DOI: (10.1016/j.jtcvs.2014.05.070) Copyright © 2014 The American Association for Thoracic Surgery Terms and Conditions

Figure 3 Morphometric analysis of myocytes and mitochondria. Hematoxylin and eosin-stained infarct border zone tissue cross-section (scale bar = 40 μm) from (A) the control group and (B) molecular cardiac surgery with recirculating delivery of adeno-associated virus 9/sarcoplasmic reticulum Ca2+ adenosine triphosphatase group (MCARD-AAV9/SERCA2a). C, Average cross-sectional cardiac myocyte area in infarct border zone (μm2). Transmission electron microscopy of infarct border zone tissue (scale bar = 1 μm) from (D) control group (arrows indicate mitochondrial swelling) and (E) MCARD-AAV9/SERCA2a group (arrows indicate normal-appearing mitochondria). Average stereologic estimates of (F) mitochondrial fractional volume (%) and (G) mitochondrial density (per μm2). Gray columns, MCARD-AAV9/SERCA2a group; black columns, control group. *P < .05 for differences between groups. The Journal of Thoracic and Cardiovascular Surgery 2014 148, 1065-1073.e2DOI: (10.1016/j.jtcvs.2014.05.070) Copyright © 2014 The American Association for Thoracic Surgery Terms and Conditions

Figure 4 Oxidative markers in infarct and remote tissue zones. A, Malondialdehyde (MDA) concentration (pmol/mg protein). B, 4-Hydroxynonenal–protein conjugates in hydroxynonenal–bovine serum albumin equivalents (μg/μg protein). Gray columns, molecular cardiac surgery with recirculating delivery of adeno-associated virus 9/sarcoplasmic reticulum Ca2+ adenosine triphosphatase group; black columns, control group. *P < .05 for differences within groups. BSAeq, Body surface area equivalents; HNE, 4-hydrooxynonenal conjugate. The Journal of Thoracic and Cardiovascular Surgery 2014 148, 1065-1073.e2DOI: (10.1016/j.jtcvs.2014.05.070) Copyright © 2014 The American Association for Thoracic Surgery Terms and Conditions

Figure 5 Time course of transgene-specific T-cell responses to pools of adeno-associated virus 9 (AAV9) capsid peptides and pools of sarcoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA2a) transgene in peripheral blood mononuclear cells (PBMCs) after administration of AAV9/SERCA2a. SFU, Number of interferon-γ spot-forming units in Enzyme-Linked ImmunoSpot assay of left ventricular tissue samples; No stim, negative control; PMA+ION, positive control. Red line indicates positive result threshold; A, B, C, and D each refer to a specific sheep in the molecular cardiac surgery with recirculating delivery-AAV9/SERCA2a group. The Journal of Thoracic and Cardiovascular Surgery 2014 148, 1065-1073.e2DOI: (10.1016/j.jtcvs.2014.05.070) Copyright © 2014 The American Association for Thoracic Surgery Terms and Conditions