SERCA2a gene transfer prevents intimal proliferation in an organ culture of human internal mammary artery

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Abstract

Coronary restenosis, a major complication of percutaneous balloon angioplasty, results from neointimal proliferation of vascular smooth muscle cells (VSMCs). The sarco/endoplasmic reticulum calcium ATPase isoform 2a (SERCA2a), specific to contractile VSMCs, has been reported previously to be involved in the control of the Ca ²⁺-signaling pathways governing proliferation and migration. Moreover, SERCA2a gene transfer was reported to inhibit in vitro VSMC proliferation and to prevent neointimal thickening in a rat carotid injury model.

The aim of this study was to evaluate the potential therapeutic interest of SERCA2a gene transfer for prevention of in-stent restenosis using a human ex vivo model of left internal mammary artery (hIMA) intimal thickening.

Left hIMAs, obtained at the time of aorto-coronary bypass surgeries, were subjected to balloon dilatation followed by infection for 30 min with adenoviruses encoding either human SERCA2 and GFP or control gene (beta-galactosidase) and GFP. Proliferation of subendothelial VSMCs and neointimal thickening were observed in balloon-injured hIMA maintained 14 days in organ culture under constant pressure and perfusion. SERCA2a gene transfer prevented vascular remodeling and significantly (p<0.01, n=5) reduced neointimal thickening in injured arteries (intima/media ratio was 0.07 ± 0.01 vs 0.40 ± 0.03 in βGal-infected arteries).

These findings could have potential implications for treatment of pathological in stent-restenosis.

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Most cited references 50

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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.

BRIAN E. JASKI, MARIELL L. JESSUP, DONNA MANCINI … (2011)

Adeno-associated virus type 1/sarcoplasmic reticulum Ca(2+)-ATPase was assessed in a randomized, double-blind, placebo-controlled, phase 2 study in patients with advanced heart failure. Thirty-nine patients received intracoronary adeno-associated virus type 1/sarcoplasmic reticulum Ca(2+)-ATPase or placebo. Seven efficacy parameters were assessed in 4 domains: symptoms (New York Heart Association class, Minnesota Living With Heart Failure Questionnaire), functional status (6-minute walk test, peak maximum oxygen consumption), biomarker (N-terminal prohormone brain natriuretic peptide), and left ventricular function/remodeling (left ventricular ejection fraction, left ventricular end-systolic volume), plus clinical outcomes. The primary end point success criteria were prospectively defined as achieving efficacy at 6 months in the group-level (concordant improvement in 7 efficacy parameters and no clinically significant worsening in any parameter), individual-level (total score for predefined clinically meaningful changes in 7 efficacy parameters), or outcome end points (cardiovascular hospitalizations and time to terminal events). Efficacy in 1 analysis had to be associated with at least a positive trend in the other 2 analyses. This combination of requirements resulted in a probability of success by chance alone of 2.7%. The high-dose group versus placebo met the prespecified criteria for success at the group-level, individual-level, and outcome analyses (cardiovascular hospitalizations) at 6 months (confirmed at 12 months) and demonstrated improvement or stabilization in New York Heart Association class, Minnesota Living With Heart Failure Questionnaire, 6-minute walk test, peak maximum oxygen consumption, N-terminal prohormone brain natriuretic peptide levels, and left ventricular end-systolic volume. Significant increases in time to clinical events and decreased frequency of cardiovascular events were observed at 12 months (hazard ratio=0.12; P=0.003), and mean duration of cardiovascular hospitalizations over 12 months was substantially decreased (0.4 versus 4.5 days; P=0.05) on high-dose treatment versus placebo. There were no untoward safety findings. The Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) study demonstrated safety and suggested benefit of adeno-associated virus type 1/sarcoplasmic reticulum Ca(2+)-ATPase in advanced heart failure, supporting larger confirmatory trials. http://www.clinicaltrials.gov. Unique identifier: NCT00454818.

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Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications.

Gaku Nakazawa, Michael Joner, Renu Virmani … (2007)

Although rare, stent thrombosis remains a severe complication after stent implantation owing to its high morbidity and mortality. Since the introduction of drug-eluting stents (DES), most interventional centers have noted stent thrombosis up to 3 years after implantation, a complication rarely seen with bare-metal stents. Some data from large registries and meta-analyses of randomized trials indicate a higher risk for DES thrombosis, whereas others suggest an absence of such a risk. Several factors are associated with an increased risk of stent thrombosis, including the procedure itself (stent malapposition and/or underexpansion, number of implanted stents, stent length, persistent slow coronary blood flow, and dissections), patient and lesion characteristics, stent design, and premature cessation of antiplatelet drugs. Drugs released from DES exert distinct biological effects, such as activation of signal transduction pathways and inhibition of cell proliferation. As a result, although primarily aimed at preventing vascular smooth muscle cell proliferation and migration (ie, key factors in the development of restenosis), they also impair reendothelialization, which leads to delayed arterial healing, and induce tissue factor expression, which results in a prothrombogenic environment. In the same way, polymers used to load these drugs have been associated with DES thrombosis. Finally, DES impair endothelial function of the coronary artery distal to the stent, which potentially promotes the risk of ischemia and coronary occlusion. Although several reports raise the possibility of a substantially higher risk of stent thrombosis in DES, evidence remains inconclusive; as a consequence, both large-scale and long-term clinical trials, as well as further mechanistic studies, are needed. The present review focuses on the pathophysiological mechanisms and pathological findings of stent thrombosis in DES.

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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.

Brian Jaski, Mariell Jessup, Donna M Mancini … (2009)

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. A total of 9 patients with advanced HF (New York Heart Association [NYHA] Class III/IV, ejection fraction [EF] < or = 30%, maximal oxygen uptake [VO2 max] <16 mL.kg.min, with maximal pharmacological and device therapy) received a single intracoronary infusion of AAV1/SERCA2a in the open-label portion of this ongoing study. Doses administered ranged from 1.4 x 10(11) to 3 x 10(12) DNase resistant particles per patient. We present 6- to 12-month follow-up data for these patients. AAV1/SERCA2a demonstrated an acceptable safety profile in this advanced HF population. Of the 9 patients treated, several demonstrated improvements from baseline to month 6 across a number of parameters important in HF, including symptomatic (NYHA and Minnesota Living with Heart Failure Questionnaire, 5 patients), functional (6-minute walk test and VO2 max, 4 patients), biomarker (NT-ProBNP, 2 patients), and LV function/remodeling (EF and end-systolic volume, 5 patients). Of note, 2 patients who failed to improve had preexisting anti-AAV1 neutralizing antibodies. 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. These findings support the initiation of the Phase 2 double-blind, placebo-controlled portion of this study.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9421525

Journal ID (pubmed-jr-id): 8603

Journal ID (nlm-ta): Gene Ther

Journal ID (iso-abbrev): Gene Ther.

Title: Gene therapy

ISSN (Print): 0969-7128

ISSN (Electronic): 1476-5462

Publication date Nihms-submitted: 12 June 2012

Publication date (Electronic): 05 July 2012

Publication date (Print): April 2013

Publication date PMC-release: 01 October 2013

Volume: 20

Issue: 4

Pages: 396-406

Affiliations

[1 ]Mount Sinai School of Medicine, Cardiovascular Research Centre, New York, NY 10029, USA; Transatlantic Cardiovascular Research Center: Inserm/UPMC/Mount Sinai school of Medicine – Paris/New York

[2 ]INSERM UMRS 956, UPMC-Paris 6, Paris, F75013 France; Transatlantic Cardiovascular Research Center: Inserm/UPMC/Mount Sinai school of Medicine – Paris/New York

[3 ]Institut de Cardiologie, Hôpital Pitié-Salpêtrière, Paris, F75013 France

[4 ]Paris Cardiovascular Research Center, Inserm U970, HEGP, Paris, France

[5 ]Univ Paris 6, UR4, Paris, France; Transatlantic Cardiovascular Research Center: Inserm/UPMC/Mount Sinai school of Medicine – Paris/New York

[6 ]Lady Davis Institute for Medical Research, McGill University, Montreal, Canada

Author notes

Correspondence to L. Lipskaia: Mount Sinai School of Medicine, Atran Laboratory Building, One Gustave L. Levy Place, Box 1030, New York, NY 10029-6574. Tel: 212-241-5737; Fax: 212-241-4080; larissa.lipskaia@ 123456mssm.edu

[*]

Authors share senior authorship

Article

Manuscript ID: NIHMS382285

DOI: 10.1038/gt.2012.50

PMC ID: 3465616

PubMed ID: 22763406

SO-VID: 4b0f75a4-be9a-4321-a4f0-b1b2466e28e2

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