Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial

@article{Greenberg2016CalciumUB,
  title={Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial},
  author={Barry H. Greenberg and Javed Butler and G. Michael Felker and Piotr Ponikowski and Adriaan A. Voors and Akshay S. Desai and Denise D Barnard and Alain Bouchard and Brian E. Jaski and Alexander Richard Lyon and Janice M. Pogoda and Jeffrey J. Rudy and Krisztina Maria Zsebo},
  journal={The Lancet},
  year={2016},
  volume={387},
  pages={1178-1186}
}
BACKGROUND Sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA2a) activity is deficient in the failing heart. Correction of this abnormality by gene transfer might improve cardiac function. We aimed to investigate the clinical benefits and safety of gene therapy through infusion of adeno-associated virus 1 (AAV1)/SERCA2a in patients with heart failure and reduced ejection fraction. METHODS We did this randomised, multinational, double-blind, placebo-controlled, phase 2b trial at 67… Expand
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Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): A Phase 2 Trial of Intracoronary Gene Therapy of Sarcoplasmic Reticulum Ca2+-ATPase in Patients With Advanced Heart Failure
TLDR
The Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease study demonstrated safety and suggested benefit of adeno-associated virus type 1/sarcoplasmic reticulum Ca2+-ATPase in advanced heart failure, supporting larger confirmatory trials. Expand
Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial.
TLDR
Quantitative evidence of biological activity across a number of parameters important for assessing HF status could be detected in several patients without preexisting neutralizing antibodies in this open-label study, although the number of patients in each cohort is too small to conduct statistical analyses. Expand
Design of a phase 2b trial of intracoronary administration of AAV1/SERCA2a in patients with advanced heart failure: the CUPID 2 trial (calcium up-regulation by percutaneous administration of gene therapy in cardiac disease phase 2b).
TLDR
Available data indicate that calcium up-regulation by AAV1/SERCA2a gene therapy is safe and of potential benefit in advanced heart failure patients. Expand
Long-Term Effects of AAV1/SERCA2a Gene Transfer in Patients With Severe Heart Failure: Analysis of Recurrent Cardiovascular Events and Mortality
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After a single intracoronary infusion of AAV1/SERCA2a in patients with advanced heart failure, positive signals of cardiovascular events persist for years, and no safety concerns were noted during the 3-year follow-up. Expand
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Results of recent clinical trials using recombinant adeno-associated virus (AAV) gene delivery offer the promise, for the first time, that heart failure can be reversed, and a “quiet revolution” may end up being one of the most significant and remarkable breakthroughs in modern medical practice. Expand
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TLDR
It is reported that long-term overexpression of SERCA2a by in vivo rAAV1-mediated intracoronary gene transfer preserved systolic function, potentially prevented diastolic dysfunction, and improved ventricular remodeling in a swine heart failure model. Expand
Improvement in Survival and Cardiac Metabolism After Gene Transfer of Sarcoplasmic Reticulum Ca2+-ATPase in a Rat Model of Heart Failure
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It is shown that unlike inotropic agents that improve contractile function at the expense of increased mortality and worsening metabolism, gene transfer of SERCA2a improves survival and the energy potential in failing hearts. Expand
Recirculating cardiac delivery of AAV2/1SERCA2a improves myocardial function in an experimental model of heart failure in large animals
TLDR
Cardiac recirculation delivery of AAV2/1SERCA2a elicited a dose-dependent improvement in cardiac performance determined by left ventricular pressure analysis, and brain natriuretic peptide expression was reduced consistent with reversal of the HF molecular phenotype. Expand
Concomitant intravenous nitroglycerin with intracoronary delivery of AAV1.SERCA2a enhances gene transfer in porcine hearts.
TLDR
It is demonstrated that IV infusion of NTG significantly improves cardiac gene transfer efficiency in porcine hearts and resulted in increased viral transduction efficiency, both in terms of messenger RNA (mRNA) as well as protein levels in the whole left ventricle (LV) compared to control animals. Expand
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