title: 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.
abstract: BACKGROUND
  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.
  
  
  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.
  
  
  RESULTS
  Seventeen subjects with ischemic cardiomyopathy, New York Heart Association class III heart failure, with an ejection fraction ≤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.
  
  
  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.
authors: Summa Cardiovascular Institute, Summa Health System, Skirball Laboratory for Cardiovascular Cellular Therapeutics, Department of Integrative Medical Sciences, Northeast Ohio Medical University, Akron, OH 44304, USA. mpenn2@neomed.edu
authors: Marc S
authors: MS
authors: Penn
authors: Farrell O
authors: FO
authors: Mendelsohn
authors: Gary L
authors: GL
authors: Schaer
authors: Warren
authors: W
authors: Sherman
authors: Maryjane
authors: M
authors: Farr
authors: Joseph
authors: J
authors: Pastore
authors: Didier
authors: D
authors: Rouy
authors: Ruth
authors: R
authors: Clemens
authors: Rahul
authors: R
authors: Aras
authors: Douglas W
authors: DW
authors: Losordo
mesh_terms: D000368:Aged; D054377:Chemokine CXCL12 / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D017079:Exercise Tolerance; D005260:Female; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods*; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D010957:Plasmids; D049268:Positron-Emission Tomography; D011788:Quality of Life; D016896:Treatment Outcome
chemical_list: D054377:Chemokine CXCL12; D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain