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Safety and efficacy of plasmid DNA expressing two isoforms of hepatocyte growth factor in patients with critical limb ischemia

Gene Therapy volume 23, pages 306–312 (2016)Cite this article

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A Corrigendum to this article was published on 07 April 2016

Abstract

VM202, a plasmid DNA that expresses two isoforms of hepatocyte growth factor, may elicit angiogenic effects that could benefit patients with critical limb ischemia (CLI). In a phase 2, double-blind trial in 52 CLI patients, we examined the safety and potential efficacy of intramuscular injections of low-dose (n=21) or high-dose (n=20) VM202 or placebo (n=11) in the affected limb (days 0, 14, 28 and 42). Adverse events and serious adverse events were similar among the groups; no malignancy or proliferative retinopathy was seen. In exploratory efficacy analyses, we found no differences in ankle or toe-brachial index, VAS, VascuQuol or amputation rate among the groups. Complete ulcer healing was significantly better in high-dose (8/13 ulcers; P<0.01) versus placebo (1/9) patients. Clinically meaningful reductions (>50%) in ulcer area occurred in high-dose (9/13 ulcers) and low-dose (19/27) groups versus placebo (1/9; P<0.05 and P<0.005, respectively). At 12 months, significant differences were seen in TcPO2 between the high-dose and placebo groups (47.5±17.8 versus 36.6±24.0 mm Hg, respectively; P<0.05) and in the change from baseline among the groups (P<0.05). These data suggest that VM202 is safe and may provide therapeutic bioactivity in CLI patients.

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References

  1. Belch JJ, Topol EJ, Agnelli G, Bertrand M, Califf RM, Clement DL et al. Critical issues in peripheral arterial disease detection and management: a call to action. Arch Intern Med 2003; 163: 884–892.

    Article  Google Scholar 

  2. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG et al. Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg 2007; 45: S5–67.

    Article  Google Scholar 

  3. Hirsch AT, Hartman L, Town RJ, Virnig BA . National health care costs of peripheral arterial disease in the Medicare population. Vasc Med 2008; 13: 209–215.

    Article  Google Scholar 

  4. Jayasankar V, Woo YJ, Pirolli TJ, Bish LT, Berry MF, Burdick J et al. Induction of angiogenesis and inhibition of apoptosis by hepatocyte growth factor effectively treats postischemic heart failure. J Card Surg 2005; 20: 93–101.

    Article  Google Scholar 

  5. Matsumoto K, Nakamura T . Emerging multipotent aspects of hepatocyte growth factor. J Biochem 1996; 119: 591–600.

    Article  CAS  Google Scholar 

  6. Pyun WB, Hahn W, Kim DS, Yoo WS, Lee SD, Won JH et al. Naked DNA expressing two isoforms of hepatocyte growth factor induces collateral artery augmentation in a rabbit model of limb ischemia. Gene Ther 2010; 17: 1442–1452.

    Article  CAS  Google Scholar 

  7. Hahn W, Pyun WB, Kim DS, Yoo WS, Lee SD, Won JH et al. Enhanced cardioprotective effects by coexpression of two isoforms of hepatocyte growth factor from naked plasmid DNA in a rat ischemic heart disease model. J Gene Med 2011; 13: 549–555.

    Article  CAS  Google Scholar 

  8. Ajroud-Driss S, Christiansen M, Allen JA, Kessler JA . Phase 1/2 open-label dose-escalation study of plasmid DNA expressing two isoforms of hepatocyte growth factor in patients with painful diabetic peripheral neuropathy. Mol Ther 2013; 21: 1279–1286.

    Article  CAS  Google Scholar 

  9. Henry TD, Hirsch AT, Goldman J, Wang YL, Lips DL, McMillan WD et al. Safety of a non-viral plasmid-encoding dual isoforms of hepatocyte growth factor in critical limb ischemia patients: a phase I study. Gene Ther 2011; 18: 788–794.

    Article  CAS  Google Scholar 

  10. Kim JS, Hwang HY, Cho KR, Park EA, Lee W, Paeng JC et al. Intramyocardial transfer of hepatocyte growth factor as an adjunct to CABG: phase I clinical study. Gene Ther 2013; 20: 717–722.

    Article  CAS  Google Scholar 

  11. Kawaida K, Matsumoto K, Shimazu H, Nakamura T . Hepatocyte growth factor prevents acute renal failure and accelerates renal regeneration in mice. Proc Natl Acad Sci USA 1994; 91: 4357–4361.

    Article  CAS  Google Scholar 

  12. Raval Z, Losordo DW . Cell therapy of peripheral arterial disease: from experimental findings to clinical trials. Circ Res 2013; 112: 1288–1302.

    Article  CAS  Google Scholar 

  13. Powell RJ, Simons M, Mendelsohn FO, Daniel G, Henry TD, Koga M et al. Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia. Circulation 2008; 118: 58–65.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge the dedicated collaboration with Emile R. Mohler, MD, Director of Vascular Medicine, University of Pennsylvania Health System; Tracie C. Collins, MD, MPH, Chair & Professor, Kansas Public Health Department; and J. Michael White, PhD at JM White Associates, who are DSMB members. Funded by ViroMed Co., Ltd, Seoul, Korea and supported by the Industrial Strategic Technology Development Program (grant no. 10031644, 'Clinical development of cardiovascular therapeutics (VM202) using novel hepatocyte growth factor gene in the US') funded by the Ministry of Trade, Industry & Energy (MI, Korea).

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Authors and Affiliations

  1. Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    M R Kibbe & D W Losordo

  2. University of Minnesota Medical School, Minneapolis, MN, USA

    A T Hirsch

  3. Cardiology P.C. Research, Birmingham, AL, USA

    F O Mendelsohn

  4. The Methodist Hospital, Houston, TX, USA

    M G Davies

  5. Boston University School of Medicine, Boston, MA, USA

    H Pham & V Driver

  6. University of Oklahoma HSC, Oklahoma City, OK, USA

    J Saucedo

  7. University of North Carolina School of Medicine, Chapel Hill, NC, USA

    W Marston

  8. Ewha Womans University Medical Center, Seoul, Korea

    W-B Pyun

  9. Seoul National University Hospital, Seoul, Korea

    S-K Min

  10. Saint Louis University Hospital, Louis, MO, USA

    B G Peterson

  11. Jobst Vascular, Toledo, OH, USA

    A Comerota

  12. Yonsei University Severance Cardiovascular Hospital, Seoul, Korea

    D Choi

  13. Vascular & Interventional Specialists of Orange County, Inc., Orange, CA, USA

    J Ballard

  14. Stem Cell Center, Texas Heart Institute, Houston, TX, USA

    R A Bartow & E C Perin

  15. Columbia University Medical Center, New York, NY, USA

    W Sherman

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  1. M R Kibbe
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  2. A T Hirsch
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  9. S-K Min
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  11. A Comerota
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  14. R A Bartow
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  15. D W Losordo
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  16. W Sherman
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  17. V Driver
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  18. E C Perin
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Corresponding author

Correspondence to E C Perin.

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Competing interests

Warren Sherman receives consulting fees from ViroMed. The remaining authors declare no conflicts of interest. We retain sole responsibility for the data, statistical analysis and manuscript content.

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Supplementary Information accompanies this paper on Gene Therapy website .

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Kibbe, M., Hirsch, A., Mendelsohn, F. et al. Safety and efficacy of plasmid DNA expressing two isoforms of hepatocyte growth factor in patients with critical limb ischemia. Gene Ther 23, 306–312 (2016). https://doi.org/10.1038/gt.2015.110

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  • DOI: https://doi.org/10.1038/gt.2015.110

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