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.
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.
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DOI：
10.1161/circulationaha.111.022889
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发表时间：
2011-07-19
期刊：
影响因子：
37.8
通讯作者：
Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) Investigators
中科院分区：
文献类型：
--
作者：
Jessup M;Greenberg B;Mancini D;Cappola T;Pauly DF;Jaski B;Yaroshinsky A;Zsebo KM;Dittrich H;Hajjar RJ;Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) Investigators
SERCA 2a缺乏通常见于晚期心力衰竭（HF）。本研究旨在研究晚期HF患者使用基因转移进行酶替代的安全性和生物学效应。在这项正在进行的研究的开放标签部分，共有9例晚期HF患者（纽约心脏协会[NYHA] III/IV级，射血分数[EF] ≤ 30%，最大摄氧量[VO 2 max] <16 mL·kg·min，接受最大药物和器械治疗）接受了AAV 1/SERCA 2a的单次冠状动脉内输注。给药剂量范围为每例患者1.4 × 1011至3 × 1012个DNA酶耐药颗粒。我们提供了这些患者6至12个月的随访数据。AAV 1/SERCA 2a在该晚期HF人群中表现出可接受的安全性特征。在接受治疗的9例患者中，有几例患者在HF的许多重要参数方面表现出从基线至第6个月的改善，包括症状性（NYHA和明尼苏达心力衰竭生活问卷，5例患者）、功能性（6分钟步行试验和VO 2 max，4例患者）、生物标志物（NT-ProBNP，2例患者）和LV功能/重塑（EF和收缩末期容积，5例患者）。值得注意的是，2名未能改善的患者具有预先存在的抗AAV 1中和抗体。在这项开放标签研究中，在几例既无中和抗体的患者中，可以检测到对评估HF状态很重要的许多参数的生物活性的定量证据，尽管每个队列中的患者数量太少，无法进行统计分析。这些结果支持启动本研究的II期双盲、安慰剂对照部分。
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] ≤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 × 1011 to 3 × 1012 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.