Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID Trial), a First-in-Human Phase 1/2 Clinical Trial

Jaski, Brian E.; Jessup, Mariell; Mancini, Donna; Cappola, Thomas P.; Pauly, Daniel F.; Greenberg, Barry; Borow, Kenneth; Dittrich, Howard C.; Zsebo, Krisztina M.; Hajjar, Roger J.

doi:10.1016/j.cardfail.2009.01.013

Cited by 400 publications

(325 citation statements)

References 44 publications

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“…11,70 In these studies, SERCA2a gene therapy is performed with an AAV1 vector without enhanced tropism for CM, allowing an unbiased transgene expression. Additionally, only patients with cardioverter defibrillator were included in the study to lower the risk of fatal tachyarrhythmias, as inhomogeneous transgene expression might result in non-uniform SR Ca 2+ load, triggering the risk of ventricular tachyarrhythmias.…”

Section: Clinical Implementationmentioning

confidence: 99%

Targeting S100A1 in heart failure

Ritterhoff

Most

2012

Gene Ther

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Heart failure (HF) is the common endpoint of many cardiovascular diseases with a 1-year survival rate of about 50% in advanced stages. Despite increasing survival rates in the past years, current standard therapeutic strategies are far away from being optimal. For this reason, the concept of cardiac gene therapy for the treatment of HF holds great potential to improve disease progression, as it specifically targets key pathologies of diseased cardiomyocytes (CM). The small calcium (Ca 2+ )-binding protein S100A1 presents a promising target for cardiac gene therapy, as it has been identified as a central regulator of cardiac performance and the Ca 2+ -driven network within CM. S100A1 was shown to regulate sarcoplasmic reticulum, sarcomere and mitochondrial function by modulating target protein activity. Furthermore, deranged S100A1 expression has been linked to HF in human ischemic and dilated cardiomyopathies as well as in various HF animal models. Proof-of-concept studies in small and large animal models as wells as in human failing CM could demonstrate feasibility and efficacy of S100A1 genetically targeted therapy. This review summarizes the developmental steps of S100A1 gene therapy for the implementation into first human clinical trials.

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Section: Clinical Implementationmentioning

confidence: 99%

Targeting S100A1 in heart failure

Ritterhoff

Most

2012

Gene Ther

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“…5 More recently, a first clinical trail for treatment of patients with advanced heart failure has been initiated. 6 As cardiac gene transfer efficiency of plasmid DNA is low even after local injection 7 viral vector systems have gained increasing interest. Among them the adeno-associated virus (AAV) vectors are currently the most potent and promising vectors used for delivery of transgenes to the heart.…”

Section: Introductionmentioning

confidence: 99%

microRNA122-regulated transgene expression increases specificity of cardiac gene transfer upon intravenous delivery of AAV9 vectors

et al. 2010

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Adeno-associated virus (AAV) vectors with capsids of AAV serotype 9 enable an efficient transduction of the heart upon intravenous injection of adult mice but also transduce the liver. The aim of this study was to improve specificity of AAV9 vector-mediated cardiac gene transfer by microRNA (miR)-dependent control of transgene expression. We constructed plasmids and AAV vectors containing target sites (TSs) of liver-specific miR122, miR192 and miR148a in the 3¢ untranslated region (3¢UTR) of a luciferase expression cassette. Luciferase expression was efficiently suppressed in liver cell lines expressing high levels of the corresponding miRs, whereas luciferase expression was unaffected in cardiac myocytes. Intravenous injections of AAV9 vectors bearing three repeats of miR122 TS in the 3¢UTR of an enhanced green fluorescent expression (EGFP) expression cassette resulted in the absence of EGFP expression in the liver of adult mice, whereas the control vectors without miR TS displayed significant hepatic EGFP expression. EGFP expression levels in the heart, however, were comparable between miR122-regulated and control vectors. The liver-specific de-targeting in vivo using miR122 was even more efficient than transcriptional targeting with a cardiac cytomegalovirus (CMV)-enhanced myosin light chain (MLC) promoter. These data indicate that miR-regulated targeting is a powerful new tool to further improve cardiospecificity of AAV9 vectors.

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“…16,50 CUPID (Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease) is a multicenter trial designed to evaluate the safety profile and the biological effects of gene transfer of the SERCA2a complimentary DNA by delivering a rAAV1 (AAV1.SERCA2a) in patients with advanced HF. Participants in this trial were administered a single intracoronary infusion of AAV1.SERCA2a in an open-label approach.…”

Section: Serca2a Gene Therapymentioning

confidence: 99%

“…Participants in this trial were administered a single intracoronary infusion of AAV1.SERCA2a in an open-label approach. 16,50 Cohorts 1-4 of three patients each received sequentially a single escalating dose of AAV1.SERCA2a. A 12-month follow-up of these patients showed an acceptable safety profile.…”

Section: Serca2a Gene Therapymentioning

confidence: 99%

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Sarcoplasmic reticulum and calcium cycling targeting by gene therapy

Hulot

Senyei

2012

Gene Ther

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Although progress in conventional treatments is making steady and incremental gains to reduce mortality associated with heart failure (HF), there remains a need to explore potentially new therapeutic approaches. HF induced by different etiologies such as coronary artery disease, hypertension, diabetes, infection or inflammation results generally in calcium cycling dysregulation at the myocyte level. Recent advances in understanding of the molecular basis of these calcium cycling abnormalities, together with the evolution of increasingly efficient gene transfer technology, has placed HF within the reach of gene-based therapy. Furthermore, the recent successful completion of a phase 2 trial targeting the sarcoplasmic reticulum calcium pump ushers in a new era for gene therapy for the treatment of HF.

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Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID Trial), a First-in-Human Phase 1/2 Clinical Trial

Abstract: Background-SERCA2a deficiency is commonly seen in advanced heart failure (HF). This study is designed to investigate safety and biological effects of enzyme replacement using gene transfer in patients with advanced HF.

Cited by 400 publications

References 44 publications

Targeting S100A1 in heart failure

Targeting S100A1 in heart failure

microRNA122-regulated transgene expression increases specificity of cardiac gene transfer upon intravenous delivery of AAV9 vectors

Sarcoplasmic reticulum and calcium cycling targeting by gene therapy

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