Design of a phase 1/2 trial of intracoronary administration of AAV1/SERCA2a in patients with heart failure

被引:154
作者
Hajjar, Roger J. [1 ]
Zsebo, Krisztina [2 ]
Deckelbaum, Lawrence [3 ]
Thompson, Craig [4 ]
Rudy, Jeff [2 ]
Yaroshinsky, Alex [2 ]
Ly, Hung
Kawase, Yoshiaki
Wagner, Kim [2 ]
Borow, Kenneth [5 ]
Jaski, Brian [6 ]
London, Barry [7 ]
Greenberg, Barry [8 ]
Pauly, Daniel F. [9 ]
Patten, Richard [10 ]
Starling, Randall [11 ]
Mancini, Donna [12 ]
Jessup, Mariell [13 ]
机构
[1] Mt Sinai Sch Med, Cardiovasc Res Ctr, New York, NY 10029 USA
[2] Celladon Corp, San Diego, CA USA
[3] Johnson & Johnson Pharmaceut Res & Dev LLC, Radnor, PA USA
[4] Dartmouth Coll, Div Cardiol, Hanover, NH 03755 USA
[5] Encorium Grp Inc, Wayne, PA USA
[6] Sharp Hosp, San Diego Cardiac Ctr, San Diego, CA USA
[7] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA
[8] Univ Calif San Diego, Med Ctr, San Diego, CA 92103 USA
[9] Univ Florida, Shands Hosp, Gainesville, FL USA
[10] Tufts Univ, New England Med Ctr, Boston, MA 02111 USA
[11] Cleveland Clin, Cleveland, OH 44106 USA
[12] Columbia Univ Hosp, New York, NY USA
[13] Hosp Univ Penn, Philadelphia, PA 19104 USA
关键词
gene therapy; heart failure; sarcoplasmic reticulum calcium ATPase; adeno-associated vector;
D O I
10.1016/j.cardfail.2008.02.005
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: Heart failure (HF) remains a major cause of morbidity and mortality in North America. With an aging population and an unmet clinical need by current pharmacologic and device-related therapeutic strategies, novel treatment options for HF are being explored. One such promising strategy is gene therapy to target underlying molecular anomalies in the dysfunctional cardiomyocyte. Prior animal and human studies have documented decreased expression of SERCA2a, a major cardiac calcium cycling protein, as a major defect found in HF. Methods and Results: We hypothesize that increasing the activity of SERCA2a in patients with moderate to severe HF will improve their cardiac function, disease status, and quality of life. Gene transfer of SERCA2a will be performed via an adeno-associated viral (AAV) vector, derived from a nonpathogenic virus with long-term transgene expression as well as a clinically established favorable safety profile. Conclusions: We describe the design of a phase 1 clinical trial of antegrade epicardial coronary artery infusion (AECAI) administration of AAVI/SERCA2a (MYDICAR) to subjects with HF divided into 2 stages: in Stage 1, subjects will be assigned open-label MYDICAR in one of up to 4 sequential dose escalation cohorts; in Stage 2, subjects will be randomized in parallel to 2 or 3 doses of MYDICAR or placebo in a double-blinded manner.
引用
收藏
页码:355 / 367
页数:13
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