Clinical TrialCalcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID Trial), a First-in-Human Phase 1/2 Clinical Trial
Section snippets
Study Overview
The CUPID trial is a multicenter, Phase 1/2 trial. The Phase 1 portion is an open-label, sequential dose escalation study. The Phase 2 portion is a randomized, double-blind, placebo-controlled, parallel-group, dose ranging, feasibility trial that compares the use of intracoronary administered AAV1/SERCA2a at 2 or 3 dose levels with placebo. Detailed information about the study design rationale and protocol has been published elsewhere.4 Patient data available through mid-September 2008 were
Results
The results include data from the Phase 1 portion of this ongoing study for Cohorts 1 and 2 (12-month follow-up), and Cohort 3 (6-month follow-up).
Discussion
Despite pharmacological and device therapies, morbidity and mortality in HF is significant, and hence investigation of new therapeutic platforms such as cell and gene therapies is warranted. In this first in man study of gene transfer in HF, AAV1/SERCA2a appears to have an acceptable safety profile, given the high expected morbidity and mortality in the HF study population.34, 36, 37 These data are consistent with the safety profile established for other recombinant AAV vectors, which has been
Conclusions
Early results of the Phase 1 open label portion of this first-in-human study of AAV1/SERCA2a in advanced HF showed no unexpected safety concerns. Biological activity was assessed across independent parameters important in evaluation of HF status. Although the number of patients in each cohort was small, quantitative evidence of biological activity could be detected in individual patients without preexisting NAbs. Further clinical evaluation is therefore warranted.
Acknowledgments
The authors would like to thank Anthony N. DeMaria, MD, and Ajit B. Raisinghani, MD, for their evaluation of echocardiograms at the UCSD Medical Center Echocardiography Core Laboratory; Craig A. Thompson, MD, MMSc, for his contribution to the infusion protocol method; Jeffery J. Rudy for managing the study; Kim Wagner, MA, for manuscript preparation; and Alex Yaroshinsky, PhD, for data summaries and assessment of clinically meaningful changes in efficacy end points.
References (48)
- et al.
Successes and failures of current treatment of heart failure
Lancet
(1998) - et al.
Design of a phase 1/2 trial of intracoronary administration of AAV1/SERCA2a in patients with heart failure
J Card Fail
(2008) - et al.
SERCA2a gene therapy for heart failure: ready for primetime?
Mol Ther
(2008) - et al.
Gene transfer in cardiac myocytes
Surg Clin North Am
(2004) - et al.
Diastolic dysfunction in human cardiac allografts is associated with reduced SERCA2a gene expression
Am J Transplant
(2006) - et al.
Reversal of cardiac dysfunction after long-term expression of SERCA2a by gene transfer in a pre-clinical model of heart failure
J Am Coll Cardiol
(2008) - et al.
Restoration of mechanical and energetic function in failing aortic-banded rat hearts by gene transfer of calcium cycling proteins
J Mol Cell Cardiol
(2007) - et al.
Human immunoglobulin inhibits liver transduction by AAV vectors at low AAV2 neutralizing titers in SCID mice
Blood
(2006) - et al.
Impact of cardiac resynchronization therapy on exercise performance, functional capacity, and quality of life in systolic heart failure with QRS prolongation: COMPANION trial sub-study
J Card Fail
(2008) - et al.
Further evidence supporting an SEM-based criterion for identifying meaningful intra-individual changes in health-related quality of life
J Clin Epidemiol
(1999)
Prognostic value of low-dose dobutamine echocardiography in patients with idiopathic dilated cardiomyopathy
Chest
Echocardiographic predictors of morbidity and mortality in patients with advanced heart failure
J Am Coll Cardiol
Long-term suppression of experimental arthritis following intramuscular administration of a pseudotyped AAV2/1-TNFR:Fc vector
Mol Ther
Evidence of multiyear factor IX expression by AAV-mediated gene transfer to skeletal muscle in an individual with severe hemophilia B.
Mol Ther
Targeted high-efficiency, homogeneous myocardial gene transfer
J Mol Cell Cardiol
Heart Disease and stroke statistics—2009 update. A Report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee
Circulation Epub
Implantable left ventricular assist devices
N Engl J Med
Overwhelming evidence of the beneficial effects of SERCA gene transfer in heart failure
Circ Res
Modulation of ventricular function through gene transfer in vivo
Proc Natl Acad Sci
Gene therapy in the treatment of heart failure
Physiology
Heart failure: a silver bullet to treat heart failure
Gene Ther
Relation between myocardial function and expression of sarcoplasmic reticulum Ca2+–ATPase in failing and nonfailing human myocardium
Circ Res
Unchanged protein levels of SERCA II and phospholamban but reduced calcium2+ uptake and calcium2+–ATPase activity of cardiac sarcoplasmic reticulum from dilated cardiomyopathy patients compared with patients with nonfailing hearts
Circulation
Alterations in sarcoplasmic reticulum gene expression in human heart failure. A possible mechanism for alterations in systolic and diastolic properties of the failing myocardium
Circ Res
Cited by (373)
Gene therapy for heart failure: A novel treatment for the age old disease
2024, Disease-a-MonthAnalysis of Adeno-Associated Virus Serotype 8 (AAV8)-antibody complexes using epitope mapping by molecular imprinting leads to the identification of Fab peptides that potentially evade AAV8 neutralisation
2023, Nanomedicine: Nanotechnology, Biology, and MedicineLncRNA JPX targets SERCA2a to mitigate myocardial ischemia/reperfusion injury by binding to EZH2
2023, Experimental Cell ResearchNovel targets in drug discovery
2023, Pharmacognosy: Fundamentals, Applications, and Strategies, Second EditionViral vectors engineered for gene therapy
2023, International Review of Cell and Molecular Biology
Funding for this study was provided by Celladon Corporation, La Jolla, CA. RJH is supported in part by grants from the National Institutes of Health: R01 HL078691, HL080498, HL 78731, HL083156, and a Leducq Transatlantic Network.
R.J. Hajjar: Celladon Corporation, ownership interest (includes stock and stock options, and rights in patents); D.M. Mancini, Celladon Corporation, consultant/advisory board; B. Greenberg, Celladon Corporation, consultant/advisory board; H. Dittrich, Celladon Corporation, ownership interest (includes stock options), consultant/advisory board; K. Borow, Celladon Corporation, significant, consultant/advisory board; K.M. Zsebo, Celladon Corporation, employment.