An Open-Label Dose Escalation Study to Evaluate the Safety of Administration of Nonviral Stromal Cell-Derived Factor-1 Plasmid to Treat Symptomatic Ischemic Heart Failure

作者：Penn Marc S^*; Mendelsohn Farrell O; Schaer Gary L; Sherman Warren; Farr MaryJane; Pastore Joseph; Rouy Didier; Clemens Ruth; Aras Rahul; Losordo Douglas W

来源：Circulation Research, 2013, 112(5): 816-825.

DOI：10.1161/CIRCRESAHA.111.300440

• chemokine
• chronic heart failure
• clinical trial
• gene transfer
• stem cell

Rationale: Preclinical studies indicate that adult stem cells induce tissue repair by activating endogenous stem cells through the stromal cell-derived factor-1: chemokine receptor type 4 axis. JVS-100 is a DNA plasmid encoding human stromal cell-derived factor-1. %26lt;br%26gt;Objective: We tested in a phase 1, open-label, dose-escalation study with 12 months of follow-up in subjects with ischemic cardiomyopathy to see if JVS-100 improves clinical parameters. %26lt;br%26gt;Methods and Results: Seventeen subjects with ischemic cardiomyopathy, New York Heart Association class III heart failure, with an ejection fraction %26lt;= 40% on stable medical therapy, were enrolled to receive 5, 15, or 30 mg of JVS-100 via endomyocardial injection. The primary end points for safety and efficacy were at 1 and 4 months, respectively. The primary safety end point was a major adverse cardiac event. Efficacy end points were change in quality of life, New York Heart Association class, 6-minute walk distance, single photon emission computed tomography, N-terminal pro-brain natruretic peptide, and echocardiography at 4 and 12 months. The primary safety end point was met. At 4 months, all of the cohorts demonstrated improvements in 6-minute walk distance, quality of life, and New York Heart Association class. Subjects in the 15- and 30-mg dose groups exhibited improvements in 6-minute walk distance (15 mg: median [range]: 41 minutes [3-61 minutes]; 30 mg: 31 minutes [22-74 minutes]) and quality of life (15 mg: -16 points [+1 to -32 points]; 30 mg: -24 points [+17 to -38 points]) over baseline. At 12 months, improvements in symptoms were maintained. %26lt;br%26gt;Conclusions: These data highlight the importance of defining the molecular mechanisms of stem cell-based tissue repair and suggest that overexpression of stromal cell-derived factor-1 via gene therapy is a strategy for improving heart failure symptoms in patients with ischemic cardiomyopathy. (Circ Res. 2013;112:816-825.)

• 出版日期2013-3-1
• 单位西北大学