SUMO-1 Gene Transfer Improves Cardiac Function in a Large-Animal Model of Heart Failure

2013 ◽  
Vol 5 (211) ◽  
pp. 211ra159-211ra159 ◽  
Author(s):  
L. Tilemann ◽  
A. Lee ◽  
K. Ishikawa ◽  
J. Aguero ◽  
K. Rapti ◽  
...  
Keyword(s):  
Heart Failure ◽  
Animal Model ◽  
Gene Transfer ◽  
Cardiac Function ◽  
Large Animal Model ◽  
Large Animal

Abstract 113: SUMO1 Gene Transfer Rescues Cardiac Function in a Large Animal Model of Heart Failure

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Lisa M Tilemann ◽  
Kiyotake Ishikawa ◽  
Changwon Kho ◽  
Ahyoung Lee ◽  
Jaime Aguero ◽  
...  
Keyword(s):  
Heart Failure ◽  
Gene Transfer ◽  
Cardiac Function ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Balloon Occlusion ◽  
Large Animal Model ◽  
Swine Model ◽  
Large Animal ◽  
Cardiac Sarcoplasmic Reticulum

Recently, small ubiquitin-related modifier 1 (SUMO1) was found to enhance the activity and stability of the cardiac sarcoplasmic reticulum Ca2+ ATPase, SERCA2a. In both, human and rodent models of heart failure (HF), the total amount of myocardial SUMO1 is decreased and its knock down results in severe HF. Adeno-associated vector (AAV) mediated SUMO1 gene transfer significantly improves cardiac function in murine models of HF. As a critical step towards clinical translation, we evaluated the effects of SUMO1 gene transfer in a swine model of ischemic heart failure. One month after balloon occlusion of the proximal LAD, 21 animals were randomized to receive either AAV1.SUMO1 at two doses, AAV1.SERCA2a, AAV1.SUMO1+AAV1.SERCA2a, or saline via antegrade coronary infusion. In addition, three pigs served as controls and underwent sham procedures. The ejection fraction and the maximum dP/dt significantly increased after gene transfer of SUMO1 at both doses, SERCA2a and the combination of SUMO1 and SERCA2a (p=0.034, p=0.028) compared to saline infusion. The increase in maximum dP/dt was most pronounced in the group that received both SUMO1 and SERCA2a. Furthermore, the increase in end-systolic and end-diastolic volumes was normalized in the treatment groups, while they further deteriorated in the saline group (p=0.001, p=0.022). SUMO1 and SERCA2a gene transfer significantly improved cardiac function and concomitant gene delivery of SUMO1 and SERCA2a had a synergistic effect on improving these parameters in the HF animals. These results strongly support the critical role of SUMO1 for SERCA2a function and underline the therapeutic potential in heart failure patients.

Comparative analysis of parvalbumin and SERCA2a cardiac myocyte gene transfer in a large animal model of diastolic dysfunction

2004 ◽  
Vol 286 (6) ◽  
pp. H2314-H2321 ◽  
Author(s):  
Jennifer C. Hirsch ◽  
Andrea R. Borton ◽  
Faris P. Albayya ◽  
Mark W. Russell ◽  
Richard G. Ohye ◽  
...  
Keyword(s):  
Heart Failure ◽  
Animal Model ◽  
Gene Transfer ◽  
Diastolic Dysfunction ◽  
Human Heart ◽  
Cardiac Myocyte ◽  
Left Ventricular ◽  
Large Animal Model ◽  
Large Animal ◽  
Human Heart Failure

Diastolic dysfunction results from impaired ventricular relaxation and is an important component of human heart failure. Genetic modification of intracellular calcium-handling proteins may hold promise to redress diastolic dysfunction; however, it is unclear whether other important aspects of myocyte function would be compromised by this approach. Accordingly, a large animal model of humanlike diastolic dysfunction was established through 1 yr of left ventricular (LV) pressure overload by descending thoracic aortic coarctation in canines. Serial echocardiography documented a progressive increase in LV mass. Diastolic dysfunction with preserved systolic function was evident at the whole organ and myocyte levels in this model, as determined by hemispheric sonomicrometric piezoelectric crystals, pressure transducer catheterization, and isolated myocyte studies. Gene transfer of the sarco(endo)plasmic reticulum calcium-ATPase (SERCA2a) and parvalbumin (Parv), a fast-twitch skeletal muscle Ca2+ buffer, restored cardiac myocyte relaxation in a dose-dependent manner under baseline conditions. At high Parv concentrations, sarcomere shortening was depressed. In contrast, during β-adrenergic stimulation, the expected enhancement of myocyte contraction (inotropy) was abrogated by SERCA2a but not by Parv. The mechanism of this effect is unknown, but it could relate to the uncoupling of SERCA2a/phospholamban in SERCA2a myocytes. Considering that inotropy is vital to overall cardiac performance, the divergent effects of SERCA2a and Parv reported here could impact potential therapeutic strategies for human heart failure.

Abstract 2883: Retroinfusion-facilitated Inotropic AAV9-S100A1 Gene Therapy Restores Global Cardiac Function In A Clinically Relevant Pig Heart Failure Model

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Sven T Pleger ◽  
Changguang Shan ◽  
Jan Kziencek ◽  
Oliver Mueller ◽  
Raffi Bekeredjian ◽  
...  
Keyword(s):  
Heart Failure ◽  
Gene Therapy ◽  
Gene Transfer ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Large Animal ◽  
Circumflex Artery ◽  
Cell Counts ◽  
Clinical Conditions

Background: Cardiac expression of the Ca-dependent inotropic protein S100A1 is decreased in human end-stage heart failure (HF) and cardiomyocyte-targeted viral-based S100A1 gene transfer rescued failing myocardium in small animal models in vivo and in vitro via improved systolic and diastolic sarcoplasmic reticulum Ca-handling. We therefore hypothesized that cardioselective AAV9-S100A1 gene therapy will improve cardiac performance in a large animal experimental HF model under clinical conditions. Methods and Results: Left ventricular (LV) posterolateral myocardial infarction (MI) was induced in pigs by occlusion of the left coronary circumflex artery and resulted in LV failure (HF) 2 weeks post-MI reflected by a 40% and 27% reduction in LV +dp/dt max. and EF, respectively, as assessed by LV catheterization and echocardiography. Post-MI HF pigs were then randomized for retroinfusion of AAV9-luciferase (luc; n=6, 1.5×10 13 total viral particles, tvp) and AAV9-S100A1 (S100A1; n=6, 1.5×10 13 tvp) driven by a cardioselective promoter via the anterior cardiac vein while the left anterior descending artery was temporarily occluded. 14 weeks after cardiac gene transfer, the S100A1-treated HF group showed significantly enhanced S100A1 protein expression (+46.7±17.9%, P<0.05 vs. control groups) in targeted remote LV myocardium and improved indices of cardiac function and remodeling (luc vs. S100A1: +dp/dtmax: 983±81 vs. 1526±83 mmHg/s, EF: 39±2.1 vs. 61±3.7 %, P<0.05 S100A1 vs. luc, LV endsystolic diameter: luc 4.45±0.1 vs. S100A1 3.43 ±0.1 cm, P<0.05 S100A1 vs. luc, HR: 72±4 vs. 69±2, beats/min, P=n.s. S100A1 vs. luc). Importantly, analyses of renal, hepatic and hematopoetic function showed no alteration as assessed by unchanged transaminases, retention values and white blood cell counts compared to sham pigs. Conclusions: Our translational study provides proof of concept that AAV9-S100A1 based HF gene therapy is feasible and restores cardiac function in a large animal HF model under clinical conditions. Next, certified toxicological analysis and different AAV9-S100A1 dosage protocols will be assessed to eventually advance to first phase I/II clinical studies determining therapeutic efficiency of cardiac S100A1 gene therapy in HF patients.

Abstract 297: Paroxysmal And Sustained Atrial Fibrillation In A New Large Animal Model Of Nonischemic Heart Failure

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Saad Sikanderkhel ◽  
Olawale Onibile ◽  
Gregory P Walcott ◽  
Steven M Pogwizd
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Animal Model ◽  
Holter Monitoring ◽  
Aortic Insufficiency ◽  
Large Animal Model ◽  
Large Animal ◽  
Aortic Constriction ◽  
Holter Monitor ◽  
Human Scale

Introduction: Atrial fibrillation is common in heart failure (HF). Understanding of the mechanisms of atrial fibrillation (AF) is limited by the paucity of large animal AF models, especially in the failing heart. We developed a large animal model of nonischemic heart failure (HF) in dogs by combined aortic insufficiency and aortic constriction and observed that a number of HF dogs developed paroxysmal AF on holter monitor. Here we characterize the spontaneously-occurring pAF in these HF dogs and perform electrophysiologic (EP) assessment of atrial refractoriness and AF inducibility along with echocardiographic imaging of left ventricle (LV) and left atrium (LA). Methods: HF was induced in dogs by aortic insufficiency and aortic constriction, and serial echocardiography (for LV fractional shortening (FS) and LA size) and Holter monitoring was performed. In control and HF dogs, EP study of atrial refractory period (AERP) and AF inducibility (duration and atrial cycle length (CL)) was performed. Results: By Holter monitoring, paroxysmal AF was noted in 5 dogs with episodes ranging from 15 to 94 beats long (mean of 49±27 beats, n=12). In EP studies, control dogs (N=3) exhibited AERP of 176±8 ms. Burst pacing resulted in AF of very brief duration (mean 32±24 sec) and a mean AF CL of 138±6 ms. LV FS averaged 37% and LA size averaged 4.3 cm2. HF dogs (N=5) exhibited RAERP of 150±8 (p=0.05 vs control). Two of these dogs had sustained AF with ventricular response up to 230 bpm on Holter monitor. In the other 3 HF dogs, burst pacing induced AF with a mean duration of 232±185 sec (at times with conversion to atrial flutter) and with a mean AF CL = 110±4 ms (p=0.002 vs control). Echo data showed LVFS averaged 30% and LA area of 14.9 cm2 (p=0.05 vs control). Conclusion: Thus we have developed a novel large animal model of HF that exhibits paroxysmal and sustained AF. This model will provide an opportunity for the study of underlying AF mechanisms, the progression of remodeling in HF hearts leading to AF, and the assessment of human-scale interventions to better treat and prevent this arrhythmia.

Abstract 8: Effectiveness of Combination Allogeneic Stem Cells in a Novel Large Animal Model of Chronic Kidney Disease-induced Heart Failure With Preserved Ejection Fraction (HFpEF)

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Angela Castellanos Rieger ◽  
Bryon A Tompkins ◽  
Makoto Natsumeda ◽  
Victoria Florea ◽  
Kevin Collon ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Kidney Disease ◽  
Animal Model ◽  
Cell Therapy ◽  
Renal Artery ◽  
Cardiorenal Syndrome ◽  
Large Animal Model ◽  
Large Animal ◽  
Preserved Ejection Fraction ◽  
Lv Mass

Background: Chronic Kidney Disease (CKD) is an independent risk factor for cardiovascular morbidity and mortality. Left ventricular (LV) hypertrophy and heart failure with preserved ejection fraction (HFpEF) are the primary manifestations of the cardiorenal syndrome in 60 to 80% of CKD patients. Therapies that improve morbidity and mortality in HFpEF are lacking. Stem cell therapy reduces fibrosis, increases neovascularization, and promotes cardiac repair in ischemic and non-ischemic cardiomyopathies. We hypothesized that stem cell treatment ameliorates HFpEF in a CKD model. Methods: Yorkshires pigs (n=27) underwent 5/6 nephrectomy via renal artery embolization and 4-weeks later received either: allogeneic (allo-) MSC (10х10 6 ), allo-kidney c-kit + cells (c-kit; 10х10 6 ), combination (MSC+c-kit; 1:1 ratio [5х10 6 each]), or placebo (each n=5). Cell therapy was delivered via the patent renal artery. Kidney function, renal and cardiac MRI, and PV loops were measured at baseline, and at 4- and 12-weeks (euthanasia) post-embolization. Results: The CKD model was confirmed by increased creatinine and BUN and decreased GFR. Mean arterial pressure (MAP) was not different between groups from baseline to 4 weeks (p=0.7). HFpEF was demonstrated at 4 weeks by increased LV mass (20.3%; p= 0.0001), wall thickening (p<0.008), EDP (p=0.01), EDPVR (p=0.005), and arterial elastance (p=0.03), with no change in EF. Diffuse intramyocardial fibrosis was evident in histological analysis and delayed enhancement MRI imaging. After 12 weeks, there was a significant difference in MAP between groups (p=0.04), with an increase in the placebo group (19.97± 8.65 mmHg, p=0.08). GFR significantly improved in the combination group (p=0.033). EDV increased in the placebo (p=0.009) and c-kit (p=0.004) groups. ESV increased most in the placebo group (7.14±1.62ml; p=0.022). EF, wall thickness, and LV mass did not differ between groups at 12 weeks. Conclusion: A CKD large animal model manifests the characteristics of HFpEF. Intra-renal artery allogeneic cell therapy was safe. A beneficial effect of cell therapy was observed in the combination and MSC groups. These findings have important implications on the use of cell therapy for HFpEF and cardiorenal syndrome.

scholarly journals Cardiac AAV9-S100A1 Gene Therapy Rescues Post-Ischemic Heart Failure in a Preclinical Large Animal Model

2011 ◽  
Vol 3 (92) ◽  
pp. 92ra64-92ra64 ◽  
Author(s):  
S. T. Pleger ◽  
C. Shan ◽  
J. Ksienzyk ◽  
R. Bekeredjian ◽  
P. Boekstegers ◽  
...  
Keyword(s):  
Heart Failure ◽  
Gene Therapy ◽  
Animal Model ◽  
Ischemic Heart ◽  
Large Animal Model ◽  
Large Animal ◽  
Ischemic Heart Failure

Novel Large Animal Model of Acute Experimental Hypertensive Heart Failure

2010 ◽  
Vol 16 (8) ◽  
pp. S14-S15
Author(s):  
Paul M. McKie ◽  
S. Jeson Sangaralingham ◽  
Tomoko Ichiki ◽  
Alessandro Cataliotti ◽  
Guido Boerrigter ◽  
...  
Keyword(s):  
Heart Failure ◽  
Animal Model ◽  
Large Animal Model ◽  
Large Animal

Gene Transfer of Canine FVIIa Results in Partial Correction of Canine Hemophilia: A Model for FVIII/FIX Gene-Based Bypassing Agents.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 195-195 ◽  
Author(s):  
Paris Margaritis ◽  
Elise Roy ◽  
Harre D. Downey ◽  
Shangzen Zhou ◽  
Elizabeth Merricks ◽  
...  
Keyword(s):  
Gene Expression ◽  
Animal Model ◽  
Gene Transfer ◽  
Hemophilia A ◽  
Active Form ◽  
Factor Ix ◽  
Factor Vii ◽  
Large Animal Model ◽  
Large Animal ◽  
Partial Correction

Abstract Despite its extensive use particularly in the management of hemophilic inhibitor patients, recombinant Factor VIIa (rhFVIIa) infusion has important limitations stemming from the nature of FVIIa itself, since its short half-life necessitates repeated injections and also carries high treatment costs. To overcome these, we have designed a gene transfer approach using a modified FVII transgene that is cleaved intracellularly and secreted in the active form, FVIIa. Using the human and murine analogue of this engineered transgene we have shown phenotypic correction of hemophilia B mice, following adeno-associated virus (AAV) - mediated, liver-directed gene delivery (Margaritis et al., 2004). In order to demonstrate efficacy in a large animal model of hemophilia, we cloned the canine Factor VII cDNA and generated the canine homologue of our modified transgene (cFVIIa). Recombinant cFVII zymogen and cFVIIa were purified and characterized in vitro in a clotting-based assay using canine reagents only (activated partial thromboplastin time [aPTT]). We found that cFVIIa had activity indistinguishable from rhFVIIa, while cFVII zymogen had negligible activity (5% rhFVIIa). In order to demonstrate in vivo efficacy, we produced 4 lots of an AAV8-based vector directing liver-specific expression of cFVIIa with similar vector titers (2–5 E13 vector genomes [vg]/ml). In hemophilia A (HA) or B (HB) mice, tail-vein delivery of 0.3 – 1.2 E12 vg/mouse (1.2 – 4.8 E13 vg/kg) resulted in long-term normalization of the hemophilic phenotype, demonstrating that cFVIIa can correct the defect in murine hemophilia. We proceeded to infuse 4 hemophilia dogs, with increasing vector doses: HB male (2.06 E13 vg/kg); HA male (6.25 E13 vg/kg); HA female (1.25 E14 vg/kg); HA male (1.25 E14 vg/kg). None of the dogs showed any adverse effects following vector delivery at any dose (the initial HB dog has been followed for almost 2 years [ongoing]). We followed the level of gene expression by clotting assays (prothrombin time [PT]/aPTT) and whole blood clotting time (WBCT). The initial dose of 2.06 E13 vg/kg resulted in a transient reduction in the PT/aPTT/WBCT. A considerable and sustained reduction in PT (18 sec, normal is ∼25 sec), aPTT (19 sec, normal is ∼30 sec, hemophilic is &gt;40sec) and WBCT (25min, normal is ∼15min, hemophilic is &gt;40min) was observed following administration of 6.25 E13 vg/kg in an HA male dog. Two more HA dogs were infused with 1.25 E14 vg/kg (male and female). The female HA dog exhibited only a modest decrease in aPTT (22sec), despite the vector dose increase, and a reduction in WBCT (30min), an observation that could be due to previously described gender-specific effects on gene expression. From preliminary and ongoing observations, the male HA dog infused also exhibited a decrease in WBCT. As an efficacy endpoint, the dogs exhibited a total of 3 bleeding episodes (none likely to be spontaneous, occurred in the lowest dose HB dog) in a cumulative time period of 38.5 months, compared to the expected 16 episodes (Brunetti-Pierri et al., 2005). In summary, our results demonstrate for the first time that gene transfer using a Factor VIII/Factor IX bypassing agent (canine FVIIa) can result in partial correction of the hemophilic phenotype in a large animal model of hemophilia.

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