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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New insights into SERCA2a gene therapy in heart failure: pay attention to the negative effects of B-type natriuretic peptides
TLDR
The current knowledge of SERCA2a gene therapy for heart failure is summarised, potential interaction between BNP levels and therapeutic effects ofSERCA 2a gene transfer is analysed and directions for future research to solve the identified problems are provided. Expand
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The results from the 5 patients at 3 years follow up confirmed that viral DNA was delivered to the failing human heart in 2 patients receiving gene therapy with vector detectable at follow up endomyocardial biopsy or cardiac transplantation. Expand
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The FLOURISH study is a double‐blind, placebo‐controlled, multicenter Phase 3 clinical trial that will randomize 536 patients to a one‐time IC administration of RT‐100 (1012 vp) or placebo in a 1:1 ratio to investigate the prospect of reduction of heart failure hospitalization and other clinical adverse events and improvement in EF. Expand
Intracoronary Sarcoplasmic Reticulum Calcium-ATPase Gene Therapy in Advanced Heart Failure Patients with reduced Ejection Fraction: A Prospective Cohort Study
TLDR
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The function and significance of SERA2a in congestive heart failure: an analysis of gene therapy trials.
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The function and significance of SERCA2a in CHF is illustrated, and possible causes of the controversial clinical trials results are analyzed, with the aim of stimulating future research on the relationship between SERca2a and CHF. Expand
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The basic principles of gene transfer for cardiac disease are touched upon, including discussion of different vectors and delivery methods, and gene-based therapeutic interventions that have been tested clinically in patients are reviewed, primarily focusing on randomized, placebo-controlled clinical trials. Expand
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References

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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
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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
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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
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TLDR
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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TLDR
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
TLDR
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
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TLDR
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