title: Phase I study of multi-gene cell therapy in patients with peripheral artery disease.
abstract: Alternative treatment strategies for claudication are needed and cell-based therapies designed to induce angiogenesis are promising. The purpose of this report was to conduct a Phase I safety, dose-escalating, non-randomized, open-label study of autologous, fully differentiated venous endothelial and smooth muscle cells called MultiGeneAngio (MGA) for claudication due to peripheral artery disease. Twelve subjects, at two centers, received a single intra-arterial infusion of a suspension of equal amounts of transduced autologous venous smooth muscle cells expressing vascular endothelial growth factor (VEGF165) and endothelial cells expressing angiopoietin-1 (Ang-1) (Cohort 1: 1 × 10(7), Cohort 2: 2 × 10(7), Cohort 3: 5 × 10(7), Cohort 4: 7 × 10(7)). The treatment was given unblinded and in the more symptomatic lower extremity. Transduced cells were tested for in vitro doubling time, telomerase activity, and gene expression. The main outcomes were clinical safety and tolerability. Other safety measures included ankle-brachial index (ABI) and walking time on a treadmill. All subjects were male (mean age 60 ± 5 years) including 25% with diabetes mellitus. At 1-year follow-up, there was one serious adverse event possibly related to MGA. Safety endpoints including VEGF and Ang-1 plasma protein levels were within normal ranges in all subjects. The mean maximal walking time increased from baseline to 1 year and the index limb ABI was unchanged, indicating no safety concerns. MGA, an autologous, transduced, cell-based therapy was well tolerated and safe in this Phase I study. Further evaluation is warranted in randomized human studies.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifier: NCT00390767.
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA pagross@umich.edu.
authors.forename: P Michael
authors.initials: PM
authors.lastname: Grossman
authors.affiliation: Department of Medicine, Cardiovascular Division, Vascular Medicine Section, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Emile R
authors.initials: ER
authors.lastname: Mohler
authors.affiliation: Michigan Institute for Clinical and Health Research, University of Michigan Medical Center, Ann Arbor, MI, USA.
authors.forename: Blake J
authors.initials: BJ
authors.lastname: Roessler
authors.affiliation: Department of Medicine, Cardiovascular Division, Vascular Medicine Section, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Wilensky
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.affiliation: Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Edward Y
authors.initials: EY
authors.lastname: Woo
authors.affiliation: Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, USA.
authors.forename: Gilbert R
authors.initials: GR
authors.lastname: Upchurch
authors.affiliation: Department of Vascular Surgery, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Jacob
authors.initials: J
authors.lastname: Schneiderman
authors.affiliation: Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, Bruce Rappaport Faculty of Medicine, Technion IIT, Haifa, Israel MultiGene Vascular Systems Ltd, Haifa, Israel.
authors.forename: Belly
authors.initials: B
authors.lastname: Koren
authors.affiliation: Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, Bruce Rappaport Faculty of Medicine, Technion IIT, Haifa, Israel MultiGene Vascular Systems Ltd, Haifa, Israel.
authors.forename: Marina
authors.initials: M
authors.lastname: Hutoran
authors.affiliation: Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, Bruce Rappaport Faculty of Medicine, Technion IIT, Haifa, Israel MultiGene Vascular Systems Ltd, Haifa, Israel.
authors.forename: Diana
authors.initials: D
authors.lastname: Gershstein
authors.affiliation: Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, Bruce Rappaport Faculty of Medicine, Technion IIT, Haifa, Israel MultiGene Vascular Systems Ltd, Haifa, Israel.
authors.forename: Moshe Y
authors.initials: MY
authors.lastname: Flugelman
mesh_terms: D000368:Aged; D042501:Angiogenic Proteins / Q000096:biosynthesis* / Q000235:genetics; D042683:Angiopoietin-1 / Q000096:biosynthesis / Q000235:genetics; D055109:Ankle Brachial Index; D049109:Cell Proliferation; D017690:Cell Transplantation / Q000379:methods*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000637:transplantation*; D005080:Exercise Test; D017079:Exercise Tolerance; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007383:Intermittent Claudication / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery*; D008297:Male; D008824:Michigan; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000637:transplantation*; D018919:Neovascularization, Physiologic; D010414:Pennsylvania; D058729:Peripheral Arterial Disease / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery*; D020127:Recovery of Function; D019098:Telomerase / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
chemical_list: C467630:ANGPT1 protein, human; D042501:Angiogenic Proteins; D042683:Angiopoietin-1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019098:Telomerase
keywords: cell therapy; claudication; peripheral artery disease; vascular